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Lu, Victor M., and Kerrie L. McDonald. "Lanthanum nanoparticles to target the brain: proof of biodistribution and biocompatibility with adjuvant therapies." Nanomedicine 15, no. 22 (September 2020): 2107–17. http://dx.doi.org/10.2217/nnm-2020-0165.
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Aim: To determine the biodistribution of lanthanum (III) oxide (La2O3) nanoparticle (NP) therapy to the brain and its biocompatibility with radiation therapy (RT) and chemotherapy (CT). Materials & methods: Healthy balb/c nude mice were administered 4 weekly doses of La2O3 NP therapy via tail vein injection. Organ weights and lanthanum concentrations were evaluated. Results: La2O3 NP penetrated the brain. Concentrations were found to peak in the brain at 24 h after injection and persisted at 8 weeks after injection. Neither RT nor CT affected biodistribution. No adverse events or safety concerns in other organs were noted. Conclusion: La2O3 NP can reach the brain to target neurological disease and is biocompatible with RT and CT in a biological system.
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Zhu, Xiangyu, Si-ping Ma, Dongxiang Yang, Yanlong Liu, Yong-peng Wang, Tao Lin, Yan-xi Li, Shi-hua Yang, Wan-chuan Zhang, and Xin-ling Wang. "miR-142-3p Suppresses Cell Growth by Targeting CDK4 in Colorectal Cancer." Cellular Physiology and Biochemistry 51, no. 4 (2018): 1969–81. http://dx.doi.org/10.1159/000495721.
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Background/Aims: Deregulation of microRNAs (miRNAs) has been associated with a variety of cancers, including colorectal cancer (CRC). Here, we investigated anomalous miR-142-3p expression and its possible functional consequences in primary CRC samples. Methods: The expression of miR-142-3p was measured by quantitative RT-PCR in 116 primary CRC tissues and adjacent non-tumor tissues. The effect of miR-142-3p up- or down-regulation in CRC-derived cells was evaluated in vitro by cell viability and colony formation assays and in vivo by growth assays in xenografted nude mice. Results: Using quantitative RT-PCR, we found that miR-142-3p was down-regulated in 78.4 % (91/116) of the primary CRC tissues tested when compared to the adjacent non-tumor tissues. We also found that the miR-142-3p mimic reduced in vitro cell viability and colony formation by inducing cell cycle arrest in CRC-derived cells, and inhibited in vivo tumor cell growth in xenografted nude mice. Inversely, we found that the miR-142-3p inhibitor increased the viability and colony forming capacity of CRC-derived cells and tumor cell growth in xenografted nude mice. In addition, we identified CDK4 as a potential target of miR-142-3p by predictions and dual-luciferase reporter assays. Concordantly, we found that miR-142-3p mimics and inhibitors could decrease and increase CDK4 protein levels in CRC-derived cells, respectively. Conclusion: From our results we conclude that miR-142-3p may act as a tumor suppressor in CRC and may serve as a tool for miRNA-based CRC therapy.
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Wang, R. F., W. L. Campbell, W. W. Cao, R. M. Colvert, M. A. Holland, and C. E. Cerniglia. "Diagnosis of mouse hepatitis virus contamination in mouse population by using nude mice and RT-PCR." Molecular and Cellular Probes 13, no. 1 (February 1999): 29–33. http://dx.doi.org/10.1006/mcpr.1998.0211.
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Zhao, Lijuan, Fei Wang, and Wei Fan. "Cisplatin Nano-Liposomes Promoting Apoptosis of Retinoblastoma Cells Both In Vivo and In Vitro." Nanoscience and Nanotechnology Letters 12, no. 4 (April 1, 2020): 536–42. http://dx.doi.org/10.1166/nnl.2020.3127.
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This study was established to investigate the effects of cisplatin nano-liposomes on the apoptosis of the human retinoblastoma (RB) cell line Y79 in vitro and in vivo. Y79 cells were cultured and then exposed to Annexin V/PI to test their apoptosis, tested with the Caspase-3 activity detection kit to examine the change in activity of Caspase-3, and subjected to western blotting to test Bcl-2 and Bax protein expression. Y79-cell-transplanted tumor model in nude mice was also established and divided into three groups, with five nude mice in each. Cisplatin nano-liposomes were applied to the experimental group, cisplatin was injected into the control group, while saline was administered to the blank group, after which the nude mice were killed and the tumor was removed. Tumor volumes and weights in the three groups were compared. Nucleic acid extraction from magnetic beads was adopted to extract DNA, RT-PCR was employed to test Bcl-2 and Bax mRNA levels in tumor tissues, and in situ cell death assay kit was applied to test apoptotic cells. In comparison to the cisplatin solution and DMSO groups, the cisplatin liposome group showed higher Y79 apoptotic rate, Caspase-3 activity, and Bax protein expression, and lower Bcl-2 protein expression (all P < 0 05). In comparison with the control and blank groups, the experimental group showed lower tumor volume, weight, and Bcl-2 mRNA level of nude mice. In addition, in comparison with the control group, the experimental group showed higher cellular apoptotic rate and Bax mRNA level. In terms of the clinical effects of cisplatin nano-liposomes on a tumor transplant in nude mice with cervical cancer, they were shown to promote tumor apoptosis.
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Zhao, Qian, Xin Zhu, Jin-ming Ke, Xiao-yu Su, Jing Yi, De-long Wu, Jiang Lin, and Zhao-qun Deng. "Circular RNA BMI1 Serves as a Potential Target for Diagnosis and Treatment in Esophageal Cancer." Technology in Cancer Research & Treatment 20 (January 1, 2021): 153303382110330. http://dx.doi.org/10.1177/15330338211033075.
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Aims: Previous studies have confirmed that BMI1 is elevated in esophageal cancer, which is a potential therapeutic target for esophageal cancer. However, the clinical significance of circular RNA BMI1 (circ-BMI1) in esophageal cancer is not yet clear. Herein, we revealed the clinical implication of circ-BMI1 in esophageal cancer, and provided a theoretical basis for molecular diagnosis and potential targeted therapy of esophageal cancer. Methods: Firstly, 10 fresh paired esophageal cancer tissues and paracancer tissues, 49 esophageal cancer serum samples and 28 healthy control serum samples were involved in our study. Differential expression and clinical significance of circ-BMI1 in esophageal cancer patients and healthy controls were evaluated by quantitative Real-time RT-PCR (RT-qPCR). Secondly, effects of circ-BMI1 differential expression on biological function of esophageal cancer cell line Eca109 were analyzed. Effects of circ-BMI1 on cell proliferation, migration and colony forming ability were evaluated by CCK-8, wound healing, and colony-forming assay. Cell apoptosis, drug sensitivity tests were also be conducted. Finally, influence of Eca109 cells differentially expressed by circ-BMI1 on tumorigenicity in nude mice was studied. Results: Expression of circ-BMI1 in serum and tissues of esophageal cancer patients was significantly decreased compared to controls ( P < 0.001 and P = 0.003, respectively). Area under the receiver operating characteristic curve (ROC) was 0.726. Cell proliferation, migration and colony forming ability of circBMI1-Eca109 cells were obviously decreased than that of NC-Eca109 cells ( P < 0.05). circBMI1-Eca109 cells were more sensitive to 5-fluorouracil and cisplatin, and tumor volume of nude mice in circBMI1-Eca109 group was smaller ( P < 0.05). Conclusions: The study indicated that expression of circ-BMI1 was significantly down-regulated in esophageal cancer. Overexpression of circ-BMI1 inhibited proliferation, migration, colony formation of Eca109 cells, and tumor growth of Eca109 cells in nude mice. circ-BMI1 may be a potential target for diagnosis and treatment in esophageal cancer.
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Wang, Jishi, Yuan Yang, Wei Zhang, and Pengxiang Guo. "Targeted Anti-Tumor Research of Mesenchymal Stem Cells Delivered Enzyme-Prodrug Gene CYP450." Blood 114, no. 22 (November 20, 2009): 3582. http://dx.doi.org/10.1182/blood.v114.22.3582.3582.
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Abstract Abstract 3582 Poster Board III-519 Objective Cytochrome P450(CYP450-CYP1A2 /CYP2B6/CYP2C9) was transfected into human bone marrow-derived mesenchymal stem cells (hBMSCs), and the targed anti-tumor effect of BMSC-CYP450 cooperated with enzyme-prodrug(Dacarbazine (DTIC)/Cyclophosphamide (CPA)) was measured to provide laboratory data base for gene directed enzyme prodrug targeted anti-tumor therapy (GDEPT) which used BMSC as vehicles. Methods We respectively cloned CYP1A2/CYP2B6/CYP2C9 cDNA from human liver and constructed recombinant adenovirus vectors(pAd5CMV-NpA-CYP1A2/ pAd5CMV-NpA-CYP2B6/pAd5CMV-NpA-CYP2C9) which titer was 1×1012 pfu/mL. These hBMSCs were separated, cultured, purified, and detected by morphology, flow cytometry, osteogenic, adipogenic and chondrogenic induction, and RT-PCR(A surface marker for the identification of MSCs-the neural ganglioside GD2 gene). The tropism of BMSCs for cancer cells was detected by Transwell inserts technique. These recombinant vectors were transferred into BMSCs and A375/K562 cells, and the expression of EGFP and CYP1A2/CYP2B6/CYP2C9 was detected by fluorescence microscope, RT-PCR and Western blot respectively. Inverted microscope, MTT and Annexin V-FITC/PI detected the anti-tumor effect of CYP450 recombinant adenovirus vectors combined with chemotherapeutic prodrug DTIC/CPA in vitro. A human melanoma(A375) BALB/c nude mice model and a human myelocytic leukemia(K562) BALB/c nude mice model was constructed and detected by immuno-histochemistry analysis. The CYP1A2 gene tranfected BMSCs were injected into the A375 BALB/c nude mice model in combination with DTIC through caudal vein, while CYP2B6/CYP2C9 gene tranfected BMSCs were injected into K562 BALB/c nude mice model in combination with CPA in the same way. The measurement of tumors size, fluorescence microscope and TUNEL were used to detect anti-tumor effect of BMSCs-CYP1A2 cooperating with DTIC and BMSCs-CYP2B6/CYP2C9 with CPA in vivo. Results We constructed the recombinant adenovirus vectors pAd5CMV-NpA-CYP1A2/pAd5CMV-NpA-CYP2B6/pAd5CMV-NpA-CYP2C9 and pAd5CMV-NpA-EGFP successfully. BMSCs was separated successfully, and it respectively showed that BMSCs can migrate through the polycarbonate filter toward K562 and A375 cells in the lower chamber in vitro. Fluorescence microscope detected the expression of EGFP, while both RT-PCR and Western blot detected high expression of CYP1A2/CYP2B6/CYP2C9 in gene-transfected group cells. Inverted microscope, MTT and Annexin V-FITC/PI confirmed that BMSCs transferred with CYP1A2/CYP2B6/CYP2C9 recombinant adenovirus vectors could activate DTIC/CPA and increase its anti-tumor effect(In the DTIC/CPA concentration(0.05 mmol/L/2.5 mmol/L) which BMSCs was relatively safe, the cell apoptosis was (38.38±2.27)% (P<0.01), (42.69±2.03)% (P<0.01) and (39. 51±1.94)% (P<0.01) in BMSCs-CYP1A2+A375 group, BMSCs-CYP2B6+K562 group and BMSCs-CYP2C9+K562 group respectively. ). A375 and K562 BALB/c nude mice model was constructed successfully. The sizes of the tumor in the nude mice treated with transfected BMSCs and DTIC/CPA were significantly smaller than control case and changed along with concentration(P< 0.01, P< 0.05).BMSCs was congregated to tumor site in fluorescence microscope. Apoptosis of tumor cells was conspicuously more in BMSCs-CYP1A2+A375/BMSCs-CYP2B6+K562/BMSCs-CYP2C9+K562 treatment group than in control group by TUNEL. Conclusion BMSCs had the tropism for cancer cells in vitro and vivo. DTIC can be catalyzed by CYP2E1/CYP1A2, while CPA by CYP2B6/CYP2C9 in vitro and vivo. BMSC-based enzyme prodrug system of CYP2E1/CYP1A2 and DTIC can induce A375 cells apoptosis, while BMSC-based enzyme prodrug system of CYP2B6/CYP2C9 and CPA can induce K562 cells apoptosis in vitro and targetedly in vivo. Disclosures: No relevant conflicts of interest to declare.
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Wason, Melissa, Heng Lu, Lin Yu, Satadru Lahiri, Debarati Mukherjee, Chao Shen, Soumen Das, Sudipta Seal, and Jihe Zhao. "Cerium Oxide Nanoparticles Sensitize Pancreatic Cancer to Radiation Therapy through Oxidative Activation of the JNK Apoptotic Pathway." Cancers 10, no. 9 (September 1, 2018): 303. http://dx.doi.org/10.3390/cancers10090303.
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Side effects of radiation therapy (RT) remain the most challenging issue for pancreatic cancer treatment. Cerium oxide nanoparticles (CONPs) are currently being tested in pre-clinical trials as an adjuvant to sensitize pancreatic cancer cells to RT and protect normal tissues from the harmful side effects. CONPs were not able to significantly affect RT-induced DNA damage in cancer cells, thereby ruling out sensitization through increased mitotic catastrophe. However, activation of c-Jun terminal kinase (JNK), a key driver of RT-induced apoptosis, was significantly enhanced by co-treatment with CONPs and RT in pancreatic cancer cells in vitro and human pancreatic tumors in nude mice in vivo compared to CONPs or RT treatment alone. Further, CONP-driven increase in RT-induced JNK activity was associated with a marked increase in Caspase 3/7 activation, indicative of apoptosis. We have previously shown that CONPs increase reactive oxygen species (ROS) production in cancer cells. ROS has been shown to drive the oxidation of thioredoxin 1 (TRX1) which results in the activation of apoptosis signaling kinase 1 (ASK1). The increase in ASK1 activation following the co-treatment with CONPs followed by RT suggests that the increased JNK activation is the result of increased TRX1 oxidation. The ability of CONPs to sensitize pancreatic cancer cells to RT was mitigated when the TRX1 oxidation was prevented by mutagenesis of a cysteine residue or when the JNK activation was blocked by an inhibitor. Taken together, these data demonstrate an important mechanism for CONPs in specifically killing cancer cells and provide novel insights into the utilization of CONPs as a radiosensitizer and therapeutic agent for pancreatic cancer.
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Tang, Renyan, Jianmin Zhu, Ying Liu, Ning Wu, and Jinbin Han. "Formulation Comprising Arsenic Trioxide and Dimercaprol Enhances Radiosensitivity of Pancreatic Cancer Xenografts." Technology in Cancer Research & Treatment 20 (January 1, 2021): 153303382110363. http://dx.doi.org/10.1177/15330338211036324.
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Objective: To investigate the efficacy of a formula comprising arsenic trioxide and dimercaprol (BAL-ATO) as a radiosensitizing agent in model mice with pancreatic cancer xenografts. Methods: Female BALB/c nude mice bearing SW1990 human pancreatic cancer xenografts were divided into four treatment arms, including control, radiotherapy (RT), BAL-ATO, and RT + BAL-ATO groups. Survival and tumor volume were analyzed. We also assessed apoptosis in tumor samples by live imaging and detected hypoxia by confocal laser microscope observation. We further investigated the mechanisms of BAL-ATO action in RT by detecting affected proteins by western blot and immunohistochemistry assays. Results: Median survival was significantly longer in the RT + BAL-ATO group (64.5 days) compared with the control (49.5 days), RT (39 days), and BAL-ATO (48 days) groups ( P < 0.001). RT + BAL-ATO inhibited the growth of tumors in mice by 73% compared with the control group, which was significantly higher than the rate of inhibition following RT alone (59%) ( P < 0.01). Further analysis showed an improved microenvironment in terms of hypoxia in tumors treated with BAL-ATO alone or RT + BAL-ATO. Expression of signaling molecules associated with pancreatic cancer stem cells, including CD24, CD44, ALDH1A1, Gli-1, and Nestin, was detected in tumors treated with BAL-ATO alone or in combination with RT. Conclusion: These data suggest that BAL-ATO function as a radiosensitizer in mice with pancreatic cancer xenografts, via mechanisms involving hypoxia reduction and inhibition of signaling pathways associated with pancreatic cancer stem cells. BAL-ATO may thus be a promising radiosensitizing agent in patients with pancreatic cancer.
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Li, Xian, Long Xia, Xiaohui Ouyang, Qimuge Suyila, Liya Su, and Xiulan Su. "Bioactive Peptides Sensitize Cells to Anticancer Effects of Oxaliplatin in Human Colorectal Cancer Xenografts in Nude Mice." Protein & Peptide Letters 26, no. 7 (July 22, 2019): 512–22. http://dx.doi.org/10.2174/0929866526666190405124955.
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<P>Background: Despite new agent development and short-term benefits in patients with Colorectal Cancer (CRC), metastatic CRC cure rates have not improved due to high rates of oxaliplatin resistance and toxicity. There is an urgent need for effective tools to prevent and treat CRC and reduce morbidity and mortality of CRC patients. Exploring the effects of bioactive peptides on the antitumor to CRC was of vital importance to the clinical application. </P><P> Objective: This study aimed to investigate the therapeutic impact of Anticancer Bioactive Peptides (ACBP) on anticancer effect of oxaliplatin (LOHP) in human colorectal cancer xenografts models in nude mice. </P><P> Methods: HCT-116 cells were cultured in vitro via CCK-8 assays and the absorbance was measured at 450 nm. Apoptosis and cell cycle were assessed by Flow Cytometry (FCM) in vitro. HCT-116 human colorectal cancer cells inoculated subcutaneously in nude mice of treatment with PBS (GG), ACBP, LOHP, ACBP+LOHP (A+L) in vivo. The quality of life was assessed by dietary amount of nude mice, the weight of nude mice, inhibition rates, tumor weight and tumor volume. Immunohistochemistry and RT-qPCR method was conducted to determine the levels of apoptosisregulating proteins/genes in transplanted tumors. </P><P> Results: ACBP induced substantial reductions in viable cell numbers and apoptosis of HCT116 cells in combined with LOHP in vitro. Compared with the control GG group, ACBP combined low dose oxaliplatin (U) group demonstrated significantly different tumor volume, the rate of apoptosis, the expression levels of Cyt-C, caspase-3,8,9 proteins and corresponding RNAs (P<0.05). The expression of pro-apoptotic proteins in the cytoplasm around the nucleus was significantly enhanced by ACBP. Short term intermittent use of ACBP alone indicted a certain inhibitory effect on tumor growth, and improve the quality of life of tumor bearing nude mice. </P><P> Conclusion: ACBP significantly increased the anti-cancer responses of low dose oxaliplatin (L-LOHP), thus, significantly improving the quality of life of tumor-bearing nude mice.</P>
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Liu, Yang. "Detection of blood AFPmRNA in nude mice bearing human HCC using nested RT-PCR and its significance." World Journal of Gastroenterology 4, no. 3 (1998): 268. http://dx.doi.org/10.3748/wjg.v4.i3.268.
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James, Charles, Shi-Yuan Cheng, Craig Horbinski, Jann Sarkaria, Roger Stupp, and Atique Ahmed. "TMOD-35. DEVELOPING RECURRENT GBM PDX, IN VIVO, FROM TREATMENT NAÏVE SOURCES." Neuro-Oncology 22, Supplement_2 (November 2020): ii235. http://dx.doi.org/10.1093/neuonc/noaa215.985.
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Abstract PURPOSE Post-therapy recurrent glioblastoma (GBM) patient-derived xenografts (PDX), developed from corresponding treatment-naïve PDX, could serve as useful resources for identifying therapeutics with activity against recurrent GBM. The goal of this study was to determine whether treatment-naïve intracranial GBM PDX, in mice receiving radiotherapy (RT) and/or temozolomide (TMZ), acquire the same mutations that occur in post-RT+TMZ GBMs from patients. METHODS Luciferase-modified, treatment-naïve GBM PDX were engrafted in the brains of athymic nude mice, followed by treatment with RT only (2 Gy/day x 5), TMZ only (10 mg/kg/day x 5), or RT+TMZ. Bioluminescence imaging was used to monitor intracranial tumor growth, response to treatment, and recurrence from treatment. Some mice with recurrent tumors received additional TMZ treatment. When mice became symptomatic, intracranial tumors were resected and engrafted subcutaneously in a new mouse host, then sequentially propagated subcutaneously into additional host mice. After the third passage, whole-exome sequencing (WES) was done, comparing post-therapy with treatment-naïve PDX sequence variants. RESULTS Analysis of PDX WES showed the following: 1) TMZ consistently caused more genes to incur coding sequence mutations than RT, as much as 13x more; 2) TMZ-treated tumor mutations were mostly G-C to A-T transitions (71-92%), consistent with the known mutagenic effect of TMZ; and 3) post-therapy PDX acquire similar mutations as do recurrent GBMs in patients, for example involving DNA mismatch repair gene MSH6. One of the derivative PDX with MSH6 mutation has been retested for response to RT and TMZ, with results showing its having become TMZ, but not RT resistant. CONCLUSIONS The mutation profiles of RT+TMZ-treated PDX are similar to those reported for GBMs that recur after RT+TMZ in patients. The new PDX resources described here may prove useful for identifying effective treatments against recurrent GBM.
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Liu, Jia-Huang, Qi-Fei Wu, Jun-Ke Fu, Xiang-Ming Che, and Hai-Jun Li. "Obesity Potentiates Esophageal Squamous Cell Carcinoma Growth and Invasion by AMPK-YAP Pathway." Journal of Immunology Research 2020 (December 10, 2020): 1–9. http://dx.doi.org/10.1155/2020/6765474.
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Obesity could increase the risk of esophageal squamous cell carcinoma (ESCC) and affect its growth and progression, but the mechanical links are unclear. The objective of the study was to explore the impact of obesity on ESCC growth and progression utilizing in vivo trials and cell experiments in vitro. Diet-induced obese and lean nude mice were inoculated with TE-1 cells, then studied for 4 weeks. Serum glucose, insulin, leptin, and visfatin levels were assayed. Sera of nude mice were obtained and then utilized to culture TE-1. MTT, migration and invasion assays, RT-PCR, and Western blotting were used to analyze endocrine effect of obesity on cell proliferation, migration, invasion, and related genes expression of TE-1. Obese nude mice bore larger tumor xenografts than lean animals, and were hyperglycemic and hyperinsulinemic with an elevated level of leptin and visfatin in sera, and also were accompanied by a fatty liver. As for the subcutaneous tumor xenograft model, tumors were more aggressive in obese nude mice than lean animals. Tumor weight correlated positively with mouse body weight, liver weight of mice, serum glucose, HOMA-IR, leptin, and visfatin. Obesity prompted significant TE-1 cell proliferation, migration, and invasion by endocrine mechanisms and impacted target genes. The expression of AMPK and p-AMPK protein decreased significantly ( P < 0.05 ); MMP9, total YAP, p-YAP, and nonphosphorylated YAP protein increased significantly ( P < 0.05 ) in the cells cultured with conditioned media and xenograft tumor from the obese group; the mRNA expression of AMPK decreased significantly ( P < 0.05 ); YAP and MMP9 mRNA expression increased significantly ( P < 0.05 ) in the cells exposed to conditioned media from the obese group. In conclusion, the altered adipokine milieu and metabolites in the context of obesity may promote ESCC growth in vivo; affect proliferation, migration, and invasion of ESCC cells in vitro; and regulate MMP9 and AMPK-YAP signaling pathway through complex effects including the endocrine effect.
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Chandrasekaran, Sanjay, Andrew Hollander, Xiangsheng Xu, Joseph L. Benci, James J. Davis, Jay F. Dorsey, and Gary Kao. "18F-Fluorothymidine-Pet Imaging of Glioblastoma Multiforme: Effects of Radiation Therapy on Radiotracer Uptake and Molecular Biomarker Patterns." Scientific World Journal 2013 (2013): 1–12. http://dx.doi.org/10.1155/2013/796029.
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Introduction. PET imaging is a useful clinical tool for studying tumor progression and treatment effects. Conventional18F-FDG-PET imaging is of limited usefulness for imaging Glioblastoma Multiforme (GBM) due to high levels of glucose uptake by normal brain and the resultant signal-to-noise intensity.18F-Fluorothymidine (FLT) in contrast has shown promise for imaging GBM, as thymidine is taken up preferentially by proliferating cells. These studies were undertaken to investigate the effectiveness of18F-FLT-PET in a GBM mouse model, especially after radiation therapy (RT), and its correlation with useful biomarkers, including proliferation and DNA damage.Methods. Nude/athymic mice with human GBM orthografts were assessed by microPET imaging with18F-FDG and18F-FLT. Patterns of tumor PET imaging were then compared to immunohistochemistry and immunofluorescence for markers of proliferation (Ki-67), DNA damage and repair (γH2AX), hypoxia (HIF-1α), and angiogenesis (VEGF).Results. We confirmed that18F-FLT-PET uptake is limited in healthy mice but enhanced in the intracranial tumors. Our data further demonstrate that18F-FLT-PET imaging usefully reflects the inhibition of tumor by RT and correlates with changes in biomarker expression.Conclusions.18F-FLT-PET imaging is a promising tumor imaging modality for GBM, including assessing RT effects and biologically relevant biomarkers.
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Wang, Jishi, Cheng Chen, Yuan Yang, and Qin Fang. "The Effect of Tyrosine Kinase Inhibitor Resistant to CML Cells Which Was Transfected with HO-1 Lentiviral Vector." Blood 118, no. 21 (November 18, 2011): 4716. http://dx.doi.org/10.1182/blood.v118.21.4716.4716.
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Abstract Abstract 4716 Aim: Heme oxygenase-1(HO-1) is well characterized survival factor that inhibits apoptosis in tumor cells. Chronic myeloid leukemia (CML) cells constitutively express HO-1 in chronic phase, but express highly in accelerated phase (AP) and blast phase (BP). However, resistance against tyrosine kinase inhibitor (TKI) can occur during therapy with TKI, particularly in AP and BP. This study was designed to confirm the relationship between HO-1 and drug resistant in CML, and seek ways to reversal of TKI resistant. Method: HO-1 gene was cloned from human liver by RT-PCR. And the lentiviral vector pLenti6-GFP-HO-1 was constructed. K562 cells which was expressed HO-1 highly was seemed as gene-transfected group. At the same time, we set the empty vector transfected group and untransfected group. K562 cells was cultivated with dasatinib in gene-transfected, empty vector transfected and untransfected groups. Expression of HO-1 mRNA was demonstrable by RT-PCR and the HO-1 protein by Western blotting. Gene mutation was detected by high performance liquid chromatography (HPLC) analysis. HO-1, multi-drug resistance gene(MDR1), lung reristance-related protein (LRP), glutathione S-transferase-π (GST-π), topoisomerase-I (Topo-I) in mRNA and protein level were deteceted by RT-PCR and Western blot. Apoptosis and cell cycle were determined by flow cytomertry analysis after treated with dasatinib. The activity of HO-1 against dasatinib for CML cells in vivo was evaluated by using the nude mouse xenograft model. The virus was injected into mouse through tail vein. Result: HO-1 gene was cloned successfully from human liver. The sequences were confirmed by restriction enzyme digestion analysis and sequencing. The virus was packaged in 293 cells and titer of virus was tested by Real-Time PCR, 1.02×109v.p./mL. Following transfer the lentiviral vector into K562, 72 hours after transfection, it showed that HO-1 was expressed highest by fluorescence micrope. The expression of HO-1 was detected by RT-PCR and Western blotting. HPLC results showed that there were not gene mutation after transfection□GRT-PCR and Western blot showed that the expression of MDR1 was significantly higher than transfection (P<0.01), also LRP and Topo-I levels were higher than transfection (P<0.05), there was no obvious changes of GST-π after transfection. At 48 hours after treatment with 10umol/L dasatinib by flow cytometry, the survival rate in transfected group was lowest which is 7.2±0.9% (P<0.05). And in empty vector transfected and untransfected group the survival rate was 38.2±1.6% and 39.3±1.7%. Cell cycle results showed that the cell population in G0/G1 and S phases decreased significantly in empty vector transfected and untransfected group, cell cycle arrest at G2/M checkpoint when treated by dasatinib. Nude mouse xenegraft models bearing carcinoma were established successfully. HO-1 in nude mouse xenegraft models was associated with protection of tumor cell against dasatinib. Conclusion: Up-regulating of HO-1 in chronic myeloid leukemia cell is associated with cell growth and anti-apoptotic effect. At the same time, there was a close relationship between HO-1 and resistance gene. HO-1 expression was accompanied by the expression of resistance genes. Based on these data, it seems desirable to explore the value of the HO-1-targeting drug in clinical trials in patients with leukemia and solid tumors. Disclosures: No relevant conflicts of interest to declare.
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Yang, Mei, Wen Jin, Wei Shi, Bo Wang, Qing Li, and Chunfeng Guan. "Effect of α-momordicine on proliferation and apoptosis of liver cancer, and its associated mechanisms of action." Tropical Journal of Pharmaceutical Research 18, no. 9 (June 29, 2021): 1935–41. http://dx.doi.org/10.4314/tjpr.v18i9.22.
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Purpose: To investigate the effect of α-momordicine (α-MMC) on liver cancer cell proliferation and apoptosis, and to elucidate the mechanisms of action involved.
Methods: In in vitro experiments, hepatoma cell lines were used, while nude mice with hepatocellular carcinoma were used for in vivo studies. Cancer cell proliferation was determined using MTT assay while apoptosis was assayed by flow cytometry and TUNNEL staining. Gene expression was determined with real-time polymerase chain reaction (RT-PCR), while protein expression levels were assayed by Western blot, immunohistochemistry and immunofluorescence.
Results: Alpha-MMC decreased HCC cell viability dose-dependently (p < 0.05). In HepG2 cells, G2/M cell cycle was halted after 48 h intervention with 1.24 mg/mL α-MMC. However, at G0/G1 phase, αMMC at doses of 1.06 and 0.92 mg/mL caused cell cycle arrest of HCC-LM3 and SMMC-7721 cells. In vivo studies showed that after establishment of the nude mice liver cancer model, exposure to α-MMC at a dose of 0.70 mg/kg or 2.08mg/kg for 4 weeks reduced the size of liver cancer in the treatment group, relative to control group; mean diameter of liver cancer decreased from 2.16 to 0.51 cm, while mean volume decreased from 1.185 to 0.085 cm3 . Moreover, α-MMC increased apoptosis level in liver cancer tissues in nude mice, and down-regulated the expressions of P-AKT, RAGE, MMP-9 and HMGB1, but upregulated Bax/Bcl2 ratio (p < 0.05).
Conclusion: α-MMC inhibits cancer cell growth and proliferation, and facilitates their apoptosis by positively regulating the ratio of Bax/Bcl2. The anti-liver cancer effect of α-MMC is mediated via HMGB1-RAGE and AKT signaling pathways
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Greve, Tine, Erik Clasen-Linde, Morten T. Andersen, Mette K. Andersen, Stine D. Sørensen, Mikkel Rosendahl, Elisabeth Ralfkiær, and Claus Yding Andersen. "Cryopreserved ovarian cortex from patients with leukemia in complete remission contains no apparent viable malignant cells." Blood 120, no. 22 (November 22, 2012): 4311–16. http://dx.doi.org/10.1182/blood-2012-01-403022.
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Abstract Some women suffering from leukemia require bone marrow transplantation to be cured. Bone marrow transplantation is associated with a high risk of sterility, and some patients are offered fertility preservation by cryopreservation of the ovarian cortex. Transplantation of the ovarian cortex to women cured of leukemia who became menopausal is currently not performed because of the risk of introducing the disease. In this study, individual pieces of ovarian cortex intended for reimplantation from 25 patients with leukemia were transplanted to each of 25 nude mice for 20 weeks. The ovarian cortex was examined before and after transplantation by histology and immunohistochemistry, and RT–quantitative PCR (in the 7 patients with a known marker). Seventeen patients had the ovarian cortex retrieved when they were in complete remission. Before transplantation, 4 of 7 pieces (2 from patients in complete remission) of ovarian cortex had a positive RT–quantitative PCR. After transplantation, none of the mice revealed any sign of disease, neither in the pieces of ovarian cortex transplanted nor in any of the murine organs evaluated. Thus, the ovaries from patients in complete remission do not appear to contain viable malignant cells contrasting ovarian tissue retrieved before treatment.
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Yu, Ji-wei, Shou-lian Wang, Ju-gang Wu, Rui-qi Lu, Xiao-chun Ni, Cheng Cai, and Bo-jian Jiang. "Study on the Biological Characteristics of CD133+ Cells Interfered by RNA Interference in Gastric Cancer." ISRN Gastroenterology 2014 (March 19, 2014): 1–11. http://dx.doi.org/10.1155/2014/329519.
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Background. To detect the changes of biological characteristics in gastric cancer cells interfered by CD133-specific small interfering RNA (siRNA). Methods. First to select the siRNA which has the strongest interference effect among 3 siRNAs (i.e., siRNA1, siRNA2, and siRNA3) in KATO-III cells by RT-PCR and Western blotting assays. Then, CD133+ cells were sorted out from KATO-III cells using an immunomagnetic bead sorting method and transfected with the selected siRNA. Furthermore, the proliferating characteristics, the antichemotherapeutic assessment, Transwell invasion assay, monoclonal sphere formation assay, and subcutaneous transplanted tumor formation assay in nude mice were investigated. Results. siRNA3 showed the strongest interference effect in KATO-III cells. As compared to the uninterfered control group, the CD133+ cells treated by siRNA3 showed significant decreases in the abilities of proliferation, invasion, clone sphere formation, and resistance to antitumour drugs as well as the weight and size of the transplanted tumor, which was nearly similar to that of CD133− cells. Additionally, the protein expression level of the EMT factor E-cadherin increased while those of EMT-related Snail and N-cadherin decreased in CD133+ cells interfered by siRNA3. Conclusion. Inhibition of CD133 gene expression reduces the abilities of gastric cancer cells in proliferation, invasion, clonal sphere formation, and chemoresistance as well as tumor formation in nude mice.
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Schiewer, Matthew Joseph, Robert Scott Gitman, Edouard John Trabulsi, Taziana DeAngelis, William Kevin Kelly, Leonard G. Gomella, Karen E. Knudsen, Adam Dicker, and Nicole Lynn Simone. "Effect of caloric restriction on the efficacy of radiation in both hormone-sensitive and hormone-resistant prostate cancers." Journal of Clinical Oncology 34, no. 2_suppl (January 10, 2016): 16. http://dx.doi.org/10.1200/jco.2016.34.2_suppl.16.
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16 Background: Locally advanced prostate cancers (LAPC) are aggressive, have poor prognosis, and are associated with high recurrence rates and conversion to castrate resistance. The molecular underpinnings of LAPC are being investigated to identify novel therapeutics. Animal models have shown that caloric restriction (CR) can potentially prevent the initiation of prostate cancer. We propose that CR may be used as a novel therapeutic intervention to enhance outcomes of radiation treatment by altering the molecular profile of prostate tumors. Methods: To assess the effect of CR with radiation in vivo, 6 week old male nude mice were injected with LNCaP (hormone sensitive, N = 60) or PC3 (hormone refractory, N = 60) tumor cells. Once tumors were palpable, mice were randomized to be treated with one of 4 conditions: ad libitum (AL) diet, 8Gy of radiation (RT), 30% reduction in caloric intake (CR), or CR+RT. Results: After PC3 tumor injection, compared with AL, the mice had a 22% reduction in tumor size with radiation, 77% with CR (p < 0.01) and an 80% reduction with CR+RT (p < 0.01). After LNCaP tumor injection, compared with ad libitum, the mice had a 49% reduction in tumor size with CR and a 55% reduction with CR+RT (p < 0.01). Tissue evaluation of mice treated with CR or CR+RT from both the LNCaP and PC3 models revealed decreased proliferation via Ki-67 and increased apoptosis with cleaved caspase-3 levels. Furthermore we establish significant changes of the pro-inflammatory IGF-1R pathway hypothesized to play in intricate roll in prostate cancer; down regulation of serum IGF-1R, IRS-1, PI3K, pAKT, and IGF-1:IGF-BP3. Conclusions: For the first time, we have shown that the efficacy of radiation can be increased by decreasing calories by 30% in both hormone-sensitive and hormone-refractory prostate cancer models. Future clinical trials should consider the innovative use of CR to augment standard cancer therapy as it has the potential to change the biology of tumors and enhance the opportunity for clinical benefit.
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Oweida, Ayman J., Laurel Darragh, Andy Phan, David Binder, Shilpa Bhatia, Adam Mueller, Benjamin Van Court, et al. "STAT3 Modulation of Regulatory T Cells in Response to Radiation Therapy in Head and Neck Cancer." JNCI: Journal of the National Cancer Institute 111, no. 12 (March 13, 2019): 1339–49. http://dx.doi.org/10.1093/jnci/djz036.
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Abstract Background Radioresistance represents a major problem in the treatment of head and neck cancer (HNC) patients. To improve response, understanding tumor microenvironmental factors that contribute to radiation resistance is important. Regulatory T cells (Tregs) are enriched in numerous cancers and can dampen the response to radiation by creating an immune-inhibitory microenvironment. The purpose of this study was to investigate mechanisms of Treg modulation by radiation in HNC. Methods We utilized an orthotopic mouse model of HNC. Anti-CD25 was used for Treg depletion. Image-guided radiation was delivered to a dose of 10 Gy. Flow cytometry was used to analyze abundance and function of intratumoral immune cells. Enzyme-linked immunosorbent assay was performed to assess secreted factors. For immune-modulating therapies, anti–PD-L1, anti-CTLA-4, and STAT3 antisense oligonucleotide (ASO) were used. All statistical tests were two-sided. Results Treatment with anti-CD25 and radiation led to tumor eradication (57.1%, n = 4 of 7 mice), enhanced T-cell cytotoxicity compared with RT alone (CD4 effector T cells [Teff]: RT group mean = 5.37 [ 0.58] vs RT + αCD25 group mean =10.71 [0.67], P = .005; CD8 Teff: RT group mean = 9.98 [0.81] vs RT + αCD25 group mean =16.88 [2.49], P = .01) and induced tumor antigen-specific memory response (100.0%, n = 4 mice). In contrast, radiation alone or when combined with anti-CTLA4 did not lead to durable tumor control (0.0%, n = 7 mice). STAT3 inhibition in combination with radiation, but not as a single agent, improved tumor growth delay, decreased Tregs, myeloid-derived suppressor cells, and M2 macrophages and enhanced effector T cells and M1 macrophages. Experiments in nude mice inhibited the benefit of STAT3 ASO and radiation. Conclusion We propose that STAT3 inhibition is a viable and potent therapeutic target against Tregs. Our data support the design of clinical trials integrating STAT3 ASO in the standard of care for cancer patients receiving radiation.
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Xu, Xiaofang, Qihong Li, Kaitao Yu, Ghulam Murtaza, and Bin Liu. "Baicalin-induced Cytotoxicity and Apoptosis in Multidrug-resistant MC3/5FU Mucoepidermoid Carcinoma Cell Line." Letters in Drug Design & Discovery 16, no. 12 (November 8, 2019): 1339–47. http://dx.doi.org/10.2174/157018081210151012121717.
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Background: Multidrug Resistance (MDR) is a serious hindrance to cancer chemotherapy and profoundly influences the clinical findings. Many Traditional Chinese Medicines (TCM) have been tested with the aim of developing effective resistance modulators or anticancer drugs to overcome the MDR of human cancers. Methods: The anticancer effect of baicalin on multidrug-resistant MC3/5FU (5-fluorouracil) cells was investigated by MTT test and xenografts in nude mice. Cell apoptosis was studied by transmission electron microscopy, Hoechst-33342 staining, DNA fragmentation detection, and flow cytometry. RT-PCR and Rhodamine 123 efflux assay was also used to detect its effect on ABC drug transporter proteins, ABCB1 (P-glycoprotein, P-gp) and ABCC1 (multidrug resistance protein 1, MRP1). Results: The results indicate that there was no significant effect of baicalin on ABC transporters expression or efflux function, although it induced potent growth inhibition in MC3/5FU cells. Flow cytometry, Hoechst 33342 staining and transmission electron microscope revealed that baicalin caused MC3/5FU cell death through the induction of apoptosis. It is demonstrated that baicalininduced apoptosis could be mediated by up-regulation of Bax and caspase-3 protein levels and downregulation of Bcl-2 protein levels. In addition, daily intraperitoneal injection of baicalin (100 and 200 mg/kg) for 2 weeks significantly inhibited the growth of MC3/5FU cells xenografts in nude mice. Conclusion: Our results suggest that baicalin possesses considerable cytotoxic activity in multidrug resistance MC3/5FU cells in vitro and in vivo.
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Chen, Bao-An, Jue-qiong Wang, Jian Cheng, Feng Gao, Wen-lin Xu, Hui-lin Shen, Jia-hua Ding, et al. "Comparison of the Effects on Reversal of Multi-Drug Resistance of 5-Bromotetrandrine and Tetrandrine in K562/A02 Cell Line in Vivo and in Vitro." Blood 112, no. 11 (November 16, 2008): 5059. http://dx.doi.org/10.1182/blood.v112.11.5059.5059.
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Abstract Objective This study was to compare the reversal effect of 5-bromotetrandrine (BrTet) with Tetrandrine (Tet) when combined with ADM on multidrug resistance cell line K562/A02 and to investigate the reversal mechanism of this new derivative. Methods The protein levels of P-glycoprotein (P-gp) were detected by fluorospectrophotometry and Western blot. The mRNA levels of P-gp were determined by RT-PCR. The in vivo effect of Tet was investigated using nude mice grafted with sensitive human leukemia cell line K562 and MDR cell line K562/A02. Results Flow cytometry assay showed that 1.0 μMol/L BrTet significantly increased the apoptosis percentage. BrTet also enhanced the intracellular accumulation of ADM in K562/A02 cells and its potency was greater than that of Tet at the same concentrations. BrTet inhibited the overexpression of P-gp and down regulated MDR1 mRNA expression in K562/A02 cells in a dose-dependent manner. In nude mice bearing K562 xenografts on the left flank and K562/A02 xenografts on the right flank, i.p. injection of 10 mg/kg BrTet significantly enhanced the antitumor activity of ADM against K562/A02 xenografts with inhibitory rates of 26.1%, while ADM alone inhibited the growth of KBv200 xenografts by only 5.8%. Conclusion BrTet showed significant MDR reversal activity in vitro and in vivo. Its activity may be related to the inhibition of P-gp overexpression and the increase in intracellular accumulation of anticancer drugs, which lead to more K562/A02 cells apoptosis.
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Rick, Ferenc G., Petra Popovics, Norman L. Block, Jinlin He, Xian Yang Zhang, Irving Vidaurre, Karoly Szepeshazi, and Andrew V. Schally. "Treatment of urinary bladder cancers by growth hormone-releasing hormone antagonists: A preclinical report." Journal of Clinical Oncology 34, no. 2_suppl (January 10, 2016): 433. http://dx.doi.org/10.1200/jco.2016.34.2_suppl.433.
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433 Background: Urinary bladder cancer is the fifth most frequent cancer diagnosed and among the most expensive cancers to treat in the United States. The management of muscle-invasive tumors presents a clinical challenge because of the toxicity and limitations in efficacy and durability of current therapeutic modalities. Novel therapeutic strategies for this disease are of paramount importance. Growth hormone-releasing hormone (GHRH) receptors and its splice variant were detected in a series of urothelial malignancies and GHRH has been shown to influence the growth of these tumors. Herein we evaluated the effect of GHRH antagonists on the growth of various experimental human urinary bladder cancers in vitro and in vivo in nude mice. Methods: We investigated the effects of several GHRH antagonists MIA 602, MIA 606 and MIA 690 on growth of urothelial HT-1376, J82, and RT-4 tumors xenografted into nude mice. The presence of GHRH receptors was validated by Western blotting. Results: The receptors for GHRH and their main splice variant, SV1, were detected in tumor samples of all 3 human bladder cancer models. In the HT-1376 tumors, the GHRH antagonists caused a 30-60% reduction in volume and 52-70% decrease in tumor weights (p < 0.05). All three antagonists strongly inhibited growth of J82 cancers as shown by a 62-75% reduction in tumor volume and 54-66% decrease in tumor weights (p < 0.05). Treatment with MIA-602 and MIA-606 resulted in a similar marked inhibition of growth of RT-4 cancers; tumor volume and weights were reduced by about 51-71% in the treated groups (p < 0.05). The mice tolerated this therapy well; body and organ weights were not significantly changed by the treatments. No toxicity from the GHRH antagonists was noted. Conclusions: We demonstrated the efficacy of potent GHRH antagonists and their lack of toxicity in inhibiting the growth of experimental models of bladder cancer in vivo. The expression of GHRH receptors was detected in all 3 models of human primary urothelial bladder carcinomas. Our findings warrant further development of GHRH antagonists for clinical therapy of bladder cancer alone or in combination with current chemotherapeutic agents and Exploration of their mechanism of action.
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Yan, Jun, Ying Jiang, Jianfeng Lu, Jianhui Wu, and Mingfang Zhang. "Inhibiting of Proliferation, Migration, and Invasion in Lung Cancer Induced by Silencing Interferon-Induced Transmembrane Protein 1 (IFITM1)." BioMed Research International 2019 (May 8, 2019): 1–9. http://dx.doi.org/10.1155/2019/9085435.
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Interferon-induced transmembrane protein 1 (IFITM1), a 17-kDa membrane protein, is generally known as a modulator in many cellular functions. Recent studies showed overexpression of IFITM1 in cancers and relationship between IFITM1 overexpression and tumor progression. However, the role of IFITM1 in lung cancer remains unclear. Here, we presented the overexpression of IFITM1 in lung cancer tissues and cell lines A549 and H460 using quantitative Real-Time RT-PCR.In vitroassay indicated IFITM1 silencing inhibited lung cancer cell proliferation, migration, and invasion. Further,in vivoassay showed that IFITM1 silencing markedly suppressed cell growth and metastasis of lung cancer in tumor-bearing BALB/c nude mice. Mechanistically, we found that IFITM1 silencing significantly alleviated the protein levels ofβ-catenin, cyclin D1, and c-Mycin lung cancer cells and tumor samples. Taken together, our study revealed the role of IFITM1 as a tumor promoter during lung cancer development and the possible molecular mechanism.
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Ueno, Yushi, Masaaki Yamamoto, Israel Vlodavsky, Iris Pecker, Kohichi Ohshima, and Takeo Fukushima. "Decreased expression of heparanase in glioblastoma multiforme." Journal of Neurosurgery 102, no. 3 (March 2005): 513–21. http://dx.doi.org/10.3171/jns.2005.102.3.0513.
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Object. The authors investigated the presence of endoglycosidase heparanase in human glioblastoma multiforme (GBM) and metastatic brain tumors as well as in healthy brain tissue to explore the relationship between the biological characteristics of GBM and the role of heparanase. Methods. Heparanase messenger (m)RNA was almost undetectable in GBMs in vivo, whereas it was frequently seen in metastatic brain tumors according to results of reverse transcription—polymerase chain reaction (RT-PCR). Immunohistochemical analysis of paraffin-embedded tissue sections showed that neoplastic cells in metastatic brain tumors, especially in cells that invaded blood vessels, exhibit intense heparanase immunoreactivity. Heparanase was present in two highly invasive glioma cell lines, U87MG and U251MG, in vitro. These cell lines did not have metastatic capability, which was tested in an experimental pulmonary metastases model in mice. The activity of heparanase in these cell lines was almost the same as that in the highly metastatic melanoma cell line B16-F1. After nude mice were inoculated with U87MG cells, however, heparanase was no longer detected in subcutaneous or intracerebral experimental glioma in vivo based on results of immunohistochemical analysis. According to results of real-time quantitative PCR, there was a 10-fold increase in heparanase mRNA in U87MG glioma cells in vitro compared with that in experimental U87MG glioma tissue in vivo in nude mice. Conclusions. These results indicate that the expression of heparanase was downregulated in GBM in vivo, which rarely metastasizes to distant organs outside the central nervous system. Heparanase is not implicated in the invasiveness of GBM to surrounding healthy brain tissue in vivo.
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Wei, Guo-Jun, Gang An, Zuo-Wei Shi, Kai-Fu Wang, Ying Guan, Yan-Song Wang, Bo Han, et al. "Suppression of MicroRNA-383 Enhances Therapeutic Potential of Human Bone-Marrow-Derived Mesenchymal Stem Cells in Treating Spinal Cord Injury via GDNF." Cellular Physiology and Biochemistry 41, no. 4 (2017): 1435–44. http://dx.doi.org/10.1159/000468057.
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Background/Aims: Transplantation of bone-marrow-derived mesenchymal stem cells (MSCs) has been used to treat spinal cord injury (SCI) to enhance tissue repair and neural cell regeneration. Glial cell line derived neurotrophic factor (GDNF) is an identified neural growth and survival factor. Here, we examined whether modification of GDNF levels in MSCs may further increase the potential of MSCs in promoting neural cell regeneration and subsequently the therapeutic outcome. Methods: We examined the mRNA and protein levels of GDNF in human MSCs by RT-qPCR and Western blot, respectively. Bioinformatics analyses were done to predict microRNAs (miRNAs) that target GDNF in MSCs. The functional binding of miRNAs to GDNF mRNA was examined by a dual luciferase reporter assay. MSCs were transduced with adeno-associated virus (AAV) carrying null or antisense for miR-383 (as-miR-383), which were transplanted into nude rats that underwent SCI. The intact tissue, cavity volume, and recovery of locomotor activity were assessed. Results: MSCs expressed very low GDNF protein, but surprisingly high levels of GDNF mRNA. Bioinformatics analyses showed that miR-383 inhibited protein translation of GDNF, through binding to the 3’-UTR of the GDNF mRNA. MSCs transduced with AAV-as-miR-383 further increased the intact tissue percentage, decreased cavity volume, and enhanced the recovery of locomotor activity in nude rats that underwent SCI, compared to MSCs. Conclusions: Suppression of miR-383 may increase the therapeutic potential of human bone-marrow-derived MSCs in treating SCI via augmentation of GDNF protein levels.
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Peng, Xudong, Qingjie Kang, Rui Wan, and Ziwei Wang. "miR-26a/HOXC9 Dysregulation Promotes Metastasis and Stem Cell-Like Phenotype of Gastric Cancer." Cellular Physiology and Biochemistry 49, no. 4 (2018): 1659–76. http://dx.doi.org/10.1159/000493502.
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Background/Aims: Previous studies demonstrated that HOXC9 acts as an oncogene in several tumors. The aim of this study was to explore whether HOXC9 promotes gastric cancer (GC) progression and elucidate the underlying molecular mechanisms. Methods: HOXC9 expression in GC tissues and adjacent non-cancer tissues was detected by quantitative RT-PCR (qRT-PCR) and immunohistochemistry. The functional effects of HOXC9 on proliferation, metastasis and stem cell-like phenotype were evaluated by relevant experiments in GC cells. The effect of miR-26a on HOXC9 was investigated by gain- and loss-of-function assays and luciferase reporter assay. Nude mouse models were established to test the effect of miR-26a and HOXC9 on tumorigenesis and metastasis of GC cells in vivo. Results: Herein, we showed that HOXC9 was upregulated in GC tissues and associated with a poor prognosis. HOXC9 knockdown inhibited the metastasis and stem cell-like phenotype of GC cells without significant effects on cell proliferation. In addition, we identifed HOXC9 as a direct target of miR-26a. Restoration of miR-26a in GC cells downregulated HOXC9 and reversed its promoting effect on metastasis and self-renewal, whereas miR-26a silencing upregulated HOXC9. In vivo experiments showed that HOXC9 knockdown suppressed tumorigenesis and lung metastasis of GC cells in nude mice, and these effects were mimicked by restoration of miR-26a. Conclusion: The present study demonstrates that HOXC9 promotes the metastasis and stem cell-like phenotype of GC cells, and this phenomenon can be reversed by restoration of miR-26a.
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Liu, Xiaobing, Dangling Zhang, Yaxing Hao, Qian Liu, Yuqi Wu, Xin Liu, Jing Luo, et al. "Cyanidin Curtails Renal Cell Carcinoma Tumorigenesis." Cellular Physiology and Biochemistry 46, no. 6 (2018): 2517–31. http://dx.doi.org/10.1159/000489658.
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Background/Aims: Cyanidin is an anthocyanin found in many foods. Although its variable antioxidant levels are well-documented, little is known about its effects on renal cell carcinoma (RCC) tumorigenesis. This study, therefore, investigated the effects of cyanidin on the proliferation, migration, and invasion of renal cell carcinoma lines and demonstrated, for the first time, significant inhibitory effects of cyanidin on RCC tumorigenesis. Methods: RCC cells were treated with different doses of cyanidin and the effects were tested by Cell Counting Kit-8 reagent, clone formation assay, transwell assay, and flow cytometry. Moreover, the cyanidin-mediated mechanism that curtailed tumorigenesis was analyzed by RNA sequencing (RNA-seq). Sequencing data from The Cancer Genome Atlas (TCGA) were used to compare the expression of both early growth response protein 1 (EGR1) and selenoprotein W (SEPW1) in RCC and tumor-free adjacent normal tissue samples. Real-time PCR (RT-PCR) and/or western blot were used to assess the expression of E-cadherin, cleaved-caspase3, Bcl2, p62, and ATG4. Results: We found significantly greater induction of cell-cycle arrest, apoptosis, and suppression of RCC cell invasion and migration at concentrations of 25 µM and 100 µM than at a concentration of 50 µM. It was also discovered, first through RNA-seq then confirmed by RT-PCR, that cyanidin (100 µM) inhibited RCC carcinogenesis through EGR1 and SEPW1. TCGA data indicated that the expression level of EGR1 was lower and that of SEPW1 was higher in RCC tumor tissue than in normal tissues. Moreover, western blot and/or RT-PCR indicated that cleaved-caspase3 was enhanced and E-cadherin was inhibited by cyanidin treatment. Furthermore, western blot and RT-PCR also showed regulation of p62 and ATG4, which are associated with autophagy. Cyanidin in vivo significantly inhibited the growth of xenografts in nude mice. Conclusions: The results of this study showed the therapeutic potential of cyanidin for the treatment of RCC and the prevention of recurrence and metastasis.
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Tuli, R., A. Surmak, E. C. Ford, E. Tryggestad, J. Wong, T. L. DeWeese, and J. M. Herman. "Bioluminescence image-guided irradiation and tumor monitoring in a preclinical pancreatic cancer mouse model." Journal of Clinical Oncology 29, no. 4_suppl (February 1, 2011): 192. http://dx.doi.org/10.1200/jco.2011.29.4_suppl.192.
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192 Background: Preclinical pancreatic cancer animal models for radiation research are far from optimal because they utilize nonlocalized, single-beam irradiation of large fields due to lack of accurate targeting and delivery. We report on a novel preclinical pancreatic cancer research model that utilizes bioluminescence imaging (BLI)-guided irradiation (RT) of orthotopic xenograft tumors, sparing of surrounding normal tissues and quantitative, noninvasive longitudinal assessment of treatment response. Methods: In accordance with institutional guidelines, luciferase-expressing MiaPaCa-2 pancreatic carcinoma cells were used to generate orthotopic pancreatic tumors in nude mice. BLI of tumors were correlated to PET/CT and necropsy specimens using Pearson correlation. BLI was compared to cone-beam CT (CBCT) to determine the location of the tumor centroid and estimate an appropriate margin for radiation planning. Off-line fusion of BLI with CBCT was performed to guide radiation delivery to tumors using our small animal radiation research platform (SARRP). RT-induced DNA damage was assessed by γ-H2Ax and p-ATM foci. BLI was used to longitudinally monitor radiation treatment response and was correlated to necropsy specimen. Results: BLI accurately predicted tumor volume (R2 = 0.9961) and correlated well with PET/CT imaging of tumors (R2 = 0.97). BLI centroid accuracy was 3.5 mm relative to that of the CBCT. Irradiated pancreatic tumors stained positively for γ-H2Ax and p-ATM, while surrounding organs were spared. Longitudinal assessment of irradiated (5 Gy) tumors with BLI revealed a significant tumor growth delay of 20 days relative to untreated controls. This was also confirmed pathologically as mean tumor volume of irradiated mice was 30.2% that of unirradiated mice (p < 0.05). Conclusions: We have developed a bioluminescent, orthotopic preclinical pancreas cancer model that allows noninvasive 1) normalizing of pretreatment tumor burden; 2) treatment planning and image-guided focal RT therapy; and 3) longitudinal assessment of treatment response. This unique translational model offers a means to investigate targeted and systemic agents with focused RT for pancreatic cancer. No significant financial relationships to disclose.
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Hainfeld, James, Sharif M. Ridwan, Yaroslav Stanishevsky, and Henry Smilowitz. "EXTH-03. IODINE NANOPARTICLE RADIOTHERAPY OF HUMAN BREAST CANCER GROWING IN THE BRAINS OF ATHYMIC MICE." Neuro-Oncology 22, Supplement_2 (November 2020): ii87. http://dx.doi.org/10.1093/neuonc/noaa215.357.
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Abstract About 30% of breast cancers metastasize to brain; those widely disseminated are fatal typically in 3–4 months, even with the best available surgery, drugs, and radiotherapy. To address this dire situation, we have developed iodine nanoparticles (INPs) that target brain tumors after intravenous (IV) injection. The iodine then absorbs X-rays during radiotherapy (RT), creating free radicals and local tumor damage, effectively boosting the local RT dose at the tumor. Efficacy was tested using the very aggressive human triple negative breast cancer (TNBC, MDA-MB-231 cells) growing in the brains of athymic nude mice. With a well-tolerated non-toxic IV dose of the INPs (7 g iodine/kg body weight), tumors showed a heavily iodinated rim surrounding the tumor having an average uptake of 2.9% iodine by weight (peaks at 4.5%), calculated to provide dose enhancement factors of ~5.5 (peaks at 8.0) -- the highest ever reported for any radio-sensitizing agents. With 15 Gy, single dose RT, all animals died by 72 days; INP pretreatment resulted in longer-term remissions with 40% of mice surviving 150 days and 30% surviving > 280 days. Fluorescence confocal microscopy revealed most INP staining co-localized with CD31in the tumor center and periphery. Greatest INP/CD31 staining was in the tumor periphery, the region of increased MicroCT contrast. Tumor cells line irregularly-shaped spaces (ISS) with INP, CD31 staining very close to or on the tumor cell surface and PAS stain on their boundary and may represent a unique form of CD31-expressing vascular mimicry in intracerebral 231-tumors. INP/CD31 co-staining is also seen around ISS formed around tumor cells migrating on CD31+blood-vessels. The significant radiation dose enhancement to the prolific INP-binding ISS found throughout the tumor but concentrated in the tumor rim, may contribute significantly to the life extensions observed after INP-RT; VM could represent a new NP, particularly INP, tumor-homing target.
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Li, Zhen-jiang, Zi-xing Chen, Jun Lu, Jian-nong Cen, and Jun He. "Growth and Infiltration of Human Monocytic Leukemia in Immunosuppressed Nude Mice: A Model for CNSL Leukemia." Blood 106, no. 11 (November 16, 2005): 4560. http://dx.doi.org/10.1182/blood.v106.11.4560.4560.
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Abstract Central nervous system leukemia (CNSL) is one of the major complications of acute leukemia which always lead to relapse and imply a poor prognosis. Our study aimed to establish a human monocytic leukemia model with CNS infiltration in Balb/C nude mice, so as to help investigation on pathogenesis of CNSL. 11 and 16 of four and six-week-old Balb/C nu/nu mice, respectively, were treated by splenectomy, cytoxan intraperitoneal injection, and sublethal irradiation, and referred to as SCI-nu/nu mice. SHI-1 monoblasts were derived from an acute monocytic leukemia patient, featured by t(6;11)(q21;q23), P53 dysfunction and a high tumorogenecity. SHI-1 cell were injected into tail vein of mouse. One of the four-week-old mouse was sacrificed in one week’s interval until the mice die of leukemia. 6 of six-week-old mice were also killed 30 days after inoculation. The leukemic cells engrafted in the mice were tracked by RT-PCR, histopathological examination, immunohistochemistry and FCM. All mice were inspected carefully and all tissues from different organs including head and spine were properly processed and sectioned. CNSL was graded as follows: grade 0: no leukemic cell infiltrated in brain; grade I: mild and focally infiltration in subdural space and pia-arachnoid; grade II: moderate to dense infiltration in subdural space and pia-arachnoid without penetrating to brain parenchyma; grade III: extensive infiltration in brain parenchyma. 25–30 days after injection, SCI-nu/nu mice presented anorexia, hunched posture, lethargy, weight loss and died after a median of 41 days (range, 33 to 46 days). All the 4-week-old mice were paralysed in rear legs, while only 30% in six-week-old mice,. Autopsy showed that green solid tumor were grossly formed in stomach, kidney, thoracic and lumbar vertebrae, head, neck, mediastinum, heart, scapula. MLL-AF6 fusion gene products could be amplified in multiple organs by RT-PCR including in the brain. Leukemic infiltrated foci were seen in liver, lung, stomach, kidney, heart, testis. In paralyzed mice the destructed thoracic and lumbar vertebral bone marrow was fully occupied by leukemic cells. Leukemic cells penetrated to the surface of vertebrae, forming neoplasm, and traveled to the subdural space, but seldom involving the parenchyma, indicating that paralysis was most likely caused by the destruction of bone and compression by leukemia cells. Central nervous system involvement were found in all SCI-nu/nu mice: grade I 71.4% (5/7); grade II 28.6 % (2/7) after 30 days, and becoming more seriously [grade II 35.3%(6/17), grade III 64.7%(11/17)] upon death:. Leukemia cells filled in the subdural space and pia-arachnoid, covered the surface of cerebrum, cerebellum and along the virchow-robin space of pia mater. For grade III, leukemic cells focally scattering around the peri-vascula could be seen in deep parenchyma. Brain parenchyma infiltration always accompanied by massive infiltration of adjacent pia-arachnoid and skull. The series of sections from our successful and reproducible experimental model of CNSL and systemic leukemia in SCI-nu/nu mice clearly demonstrated that the leukemia cells in central nervous system came from bone marrow of skull and vertebrae, via subdural space, pia-arachnoid, and the Virchow-Robin spaces, finally penetrated into the nervous parenchyma. This experimental model may provide an useful tool for studies on the pathogenesis of CNSL.
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Exner, Samantha, Claudia Schuldt, Sachindra Sachindra, Jing Du, Isabelle Heing-Becker, Kai Licha, Bertram Wiedenmann, and Carsten Grötzinger. "AGTR1 Is Overexpressed in Neuroendocrine Neoplasms, Regulates Secretion and May Potentially Serve as a Target for Molecular Imaging and Therapy." Cancers 12, no. 11 (October 27, 2020): 3138. http://dx.doi.org/10.3390/cancers12113138.
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This study identified and confirmed angiotensin II (ATII) as a strong activator of signaling in neuroendocrine neoplasm (NEN) cells. Expression analyses of the ATII receptor type 1 (AGTR1) revealed an upregulation of mRNA levels (RT-qPCR) and radioligand binding (autoradiography) in small-intestinal (n = 71) NEN tissues compared to controls (n = 25). NEN cells with high AGTR1 expression exhibited concentration-dependent calcium mobilization and chromogranin A secretion upon stimulation with ATII, blocked by AGTR1 antagonism and Gαq inhibition. ATII also stimulated serotonin secretion from BON cells. AGTR1 ligand saralasin was coupled to a near-infrared fluorescent (NIRF) dye and tested for its biodistribution in a nude mouse model bearing AGTR1-positive BON and negative QGP-1 xenograft tumors. NIRF imaging showed significantly higher uptake in BON tumors. This proof of concept establishes AGTR1 as a novel target in NEN, paving the way for translational chelator-based probes for diagnostic PET imaging and radioligand therapy.
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Krayem, Mohammad, Malak Sabbah, Ahmad Najem, An Wouters, Filip Lardon, Stephane Simon, François Sales, et al. "The Benefit of Reactivating p53 under MAPK Inhibition on the Efficacy of Radiotherapy in Melanoma." Cancers 11, no. 8 (August 1, 2019): 1093. http://dx.doi.org/10.3390/cancers11081093.
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Radiotherapy (RT) in patients with melanoma historically showed suboptimal results, because the disease is often radioresistant due to various mechanisms such as scavenging free radicals by thiols, pigmentary machinery, or enhanced DNA repair. However, radiotherapy has been utilized as adjuvant therapy after the complete excision of primary melanoma and lymph nodes to reduce the rate of nodal recurrences in high-risk patients. The resistance of melanoma cells to radiotherapy may also be in relation with the constitutive activation of the MAPK pathway and/or with the inactivation of p53 observed in about 90% of melanomas. In this study, we aimed to assess the potential benefit of adding RT to BRAF-mutated melanoma cells under a combined p53 reactivation and MAPK inhibition in vitro and in a preclinical animal model. We found that the combination of BRAF inhibition (vemurafenib, which completely shuts down the MAPK pathway), together with p53 reactivation (PRIMA-1Met) significantly enhanced the radiosensitivity of BRAF-mutant melanoma cells. This was accompanied by an increase in both p53 expression and activity. Of note, we found that radiation alone markedly promoted both ERK and AKT phosphorylation, thus contributing to radioresistance. The combination of vemurafenib and PRIMA-1Met caused the inactivation of both MAPK kinase and PI3K/AKT pathways. Furthermore, when combined with radiotherapy, it was able to significantly enhance melanoma cell radiosensitivity. Interestingly, in nude mice bearing melanoma xenografts, the latter triple combination had not only a synergistic effect on tumor growth inhibition, but also a potent control on tumor regrowth in all animals after finishing the triple combination therapy. RT alone had only a weak effect. In conclusion, we provide a basis for a strategy that may overcome the radioresistance of BRAF-mutated melanoma cells to radiotherapy. Whether this will translate into a rational to use radiotherapy in the curative setting in BRAF-mutated melanoma patients deserves consideration.
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Zips, D., M. Krause, J. Westphal, K. Brchner, W. Eicheler, C. Hoinkins, R. Grenman, C. Petersen, A. Dörfler, and M. Baumann. "VEGFR tyrosine kinase inhibition by ZK 222584/PTJ 787 (ZK) combined with fractionated radiotherapy (RT) in human squamous cell carcinomas (hSCC) in nude mice." European Journal of Cancer 37 (April 2001): S143. http://dx.doi.org/10.1016/s0959-8049(01)81020-0.
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Bossolasco, Patrizia, Davide Soligo, Yvan Torrente, Federica Pisati, Mirella Meregalli, Lidia Cova, Cinzia Calzarossa, et al. "In Vitro and In Vivo Mesenchymal Stem Cells Neurotrophin Production but Limited Neuronal Differentiation." Blood 106, no. 11 (November 16, 2005): 1687. http://dx.doi.org/10.1182/blood.v106.11.1687.1687.
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Abstract The aim of the present work was to explore mesenchymal stem cells (MSCs) differentiation potential towards neural phenotype. MSCs are self-renewable multipotent cells shown to be able to support hematopoiesis and to improve functional outcomes in animal models of neurological disorders. MSCs were obtained by plastic adherence from iliac crest bone marrow of healthy donors for allogeneic transplantation and, for the in vitro studies, were cultured on laminin-coated dishes in a B27 Neurobasal medium with 3% to 10% FBS for 3 weeks. Few cell (11%) showing bipolar morphologies, expressed β-tubulin III and GFAP. Furthermore, only GAP43 expression was detected by RT-PCR. Addition of exogenous neurotrophins to cultures did not improve neural differentiation. To investigate the brain microenvironment effect on MSCs, cells were cultured on brain sections and supernatant of the cultures analyzed by ELISA. In this condition, MSCs were shown to release soluble human NT3/NT4 and NGF and to express p75 and TrkC receptors by immunocytochemistry. In order to improve these observations, we analyzed the human neurotrophin and receptor gene expression profile by GEArray technology. The expression patterns of human trkC, NT3, NT4, and NGF mRNA were consistent with the results of immunostaining. To evaluate the in vivo MSCs differentiation potential, 50.000 cells labeled with a fluorescent dye (PKH26) were injected into the right parietal cortex of newborn Balb/C and nude mice (4 and 7 days old). Seven and 45 days later, immunocytochemistry and RT-PCR were performed on brain sections using the following neural specific markers: neurofilament-M, NSE, GFAP, b-tubulin III, MAP-2ab, nestin, Gal-C, and anti TrkC, TrkA and p75NFGR. FISH analysis was also performed using both Cy-3 labeled human Pan Centromeric and FITC labeled mouse Pan Centromeric probes. In 7 out of 52 Balb/C mice analyzed, fluorescent cells were detected 30 days post-injection but only one mouse showed NF and MAP-2ab expression by immunocytochemistry on FISH positive cells thirty days after transplantation. These data were confirmed by RT-PCR for the presence of human GAPDH. In nude mice, fluorescent cells were also detected away from the site of injection indicating cells migration throughout the brain. Moreover, 7 and 45 days post-injection, a high percentage of cells was shown to express the TrkC and p75 receptors. Isolation of the single human MSCs transplanted cells from brain sections was performed by laser microdissection analysis. ELISA analysis from these dissected areas showed the expression of human NT3/NT4 and NGF neurotrophin’s. Finally, several transplanted human MSCs expressing the Ve-cadherin were found close to blood vessels after 45 days of transplantation, whereas these cells were negative for human KDR and CD45. In addition, we determined the capability of conditioned MSCs media to regulate the angiogenesis in a tube formation assay. In conclusion, our data show an in vitro and in vivo capacity of MSCs to express neurotrophins under epigenetic stimuli rather than a real neural differentiation potential.
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Cuesta-Domínguez, Álvaro, Mara Ortega, Cristina Ormazabal, Matilde Santos-Roncero, Marta Galán-Díez, Juan Luis Steegmann, Eva Arranz, et al. "Transforming and Tumorogenic Activity of JAK2 by Fusion to BCR: Molecular Mechanisms of Action of a Novel BCR-JAK2 Tyrosin-Kinase." Blood 114, no. 22 (November 20, 2009): 4683. http://dx.doi.org/10.1182/blood.v114.22.4683.4683.
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Abstract Abstract 4683 Chromosomal translocations in human tumors frequently produce fusion genes whose chimeric protein products play an essential role in oncogenesis. Recent reports have found a BCR-JAK2 fusion gene in cases of chronic or acute myeloid leukemia, but the protein had not been characterized. We describe a BCR-JAK2 fusion gene by fluorescence in situ hybridization and RT-PCR amplification from bone marrow at diagnosis of a patient with acute lymphoblastic leukemia. After induction therapy, real time PCR showed persistent molecular response correlating with hematological remission maintained up to present. BCR-JAK2 is a 110 KDa chimeric protein containing the BCR oligomerization domain fused to the JAK2 tyrosine-kinase domain. In vitro analysis showed that BCR-JAK2 was constitutively phosphorylated and was located to the cytoplasm. BCR-JAK2 transformed the IL-3-dependent murine hematopoietic cell line Ba/F3 into IL-3 independent growth and induced STAT5b phosphorylation and translocation into the cell nuclei. The treatment with a JAK2 inhibitor abrogated BCR-JAK2 and STAT5b phosphorylation, leading to apoptosis of transformed Ba/F3 cells. To test whether BCR-JAK2 has tumorogenic ability in vivo, we performed experiments with nude mice, in which we injected subcutaneously cells transduced with the control vector and cells expressing BCR-JAK2. Notably, we only obtained tumors in the flank injected with BCR-JAK2 expressing cells, thus confirming the tumorogenic activity of the BCR-JAK2 fusion protein. We conclude that BCR-JAK2 is a new tyrosine-kinase that induces proliferation and cell survival, which can be abrogated by JAK2 inhibitors. In vitro studies demonstrate that BCR-JAK2 displays transforming activity. Moreover, the nude mice model reveals its ability to cause tumors. Disclosures: No relevant conflicts of interest to declare.
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Roux, S., B. Al Sakere, C. Bernat, P. Opolon, J. Garbay, V. Billard, L. Zitvogel, A. Carpentier, L. Mir, and C. Robert. "Combining tumor destruction by electrochemotherapy and innate immunity by CpG-ODN: Toward a new combination treatment for melanoma with skin metastases." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 12507. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.12507.
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12507 Background: Electrochemotherapy (ECT), consisting of electroporating cytotoxic agents (bleomycin or cisplatinum) in tumors, is effective in inducing destruction of cutaneous or subcutaneous tumors and can be used as a palliative treatment for patients with skin melanoma metastases. Our objective was to combine the antigen release induced by ECT with a potent and adapted stimulation of the innate immune system in order to induce a systemic anti-tumor response. Methods: The preclinical work was performed on murine models of skin tumors: fibrosarcoma (LPB) and melanoma (B16F10). We found that electrochemotherapy induced the recruitment of immune cells expressing CD11-c and Mac-1 in the first 48h after the treatment. By quantitative RT-PCR, we showed that this immune cell infiltrate was associated with an increase of TLR9 RNA expression. Therefore, we decided to combine ECT with intra-tumoral injection of TLR9 ligands: unmethylated CpG oligodeoxynucleotides (CpG-ODN). The distant and local antitumoral effect of this association (ECT + CpG-ODN) were tested in mice bearing a tumour on the two flanks (fibrosarcoma or melanoma). Animals were treated on the left flank only by a unique ECT course followed by intratumoral injection of CpG-ODN. Tumor growth rates were monitored on both treated (left) and non-treated (right) sides in order to assess direct and systemic antitumor effects of the association respectively. Experiments were also performed on nude mice, in order to investigate the role of lymphocytes in the systemic antitumor effect. Results: Compared to the separated treatments alone we found an increased local efficacy of the ECT-CpG-ODN, but, more importantly, we demonstrated a clear systemic effect of the combination on the controlateral tumors. In nude mice, no effect was observed in controlateral tumors suggesting a mechanism mediated by T lymphocytes. No significant financial relationships to disclose.
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Reeves, Mark E., Robert J. Aragon, Mariana Alfakhouri, Shin-Tai Chen, Nancy Lowen, Subburaman Mohan, and Yousef G. Amaar. "Ras-Association Domain Family 1C Protein Enhances Breast Tumor Growth in Vivo." Cancer Growth and Metastasis 5 (January 2012): CGM.S9845. http://dx.doi.org/10.4137/cgm.s9845.
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The Ras association domain family 1 (RASSF1) gene is a Ras effector that plays an important role in carcinogenesis. We have previously shown that silencing of RASSF1C decreases and over-expression of RASSF1C increases cell proliferation, migration, and attenuates apoptosis of breast cancer cells in vitro. To further confirm our working hypothesis that RASSF1C may play a role as a growth promoter, we have tested the growth of human breast cancer cells stably over-expressing RASSF1A or RASSF1C in nude mice. Our studies show that breast cancer cells over-expressing HA-RASSF1A developed significantly smaller tumors and cells over-expressing HA-RASSF1C developed significantly larger tumors compared to control cells expressing the vector back bone. We have confirmed the expression of HA-RASSF1A and HA-RASSF1C in tumor tissue using RT-PCR, western blotting and immunohistochemical analyses using HA-antibody. Together, our previous in vitro and current in vivo findings further support our hypothesis that RASSF1C, unlike RASSF1A, is not a tumor suppressor and rather it appears to function as tumor growth promoter in breast cancer cells.
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Ahmad, Anis, Tulasigeri M. Totiger, Ana Paula Benaduce, Brian Marples, and Ivaylo Bodganov Mihaylov. "Establishing Correlations between Breast Tumor Response to Radio-Immunotherapy and Radiomics from Multi-Parametric Imaging: An Animal Study." Applied Sciences 10, no. 18 (September 17, 2020): 6493. http://dx.doi.org/10.3390/app10186493.
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Triple-negative breast cancer (TNBC), which is a type of invasive breast cancer, is characterized by severe disease progression, poor prognosis, high recurrence rate, and short survival. We sought to gain new insight into TNBC by applying computed tomography (CT) and magnetic resonance (MR) quantitative imaging (radiomics) approaches to predict the outcome of radio-immunotherapy treatments in a syngeneic subcutaneous murine breast tumor model. Five Athymic Nude mice were implanted with breast cancer cell lines (4T1) tumors on the right flank. The animals were CT- and MRI-imaged, tumors were contoured, and radiomics features were extracted. All animals were treated with radiotherapy (RT), followed by the administration of PD1 inhibitor. Approximately 10 days later, the animals were sacrificed, tumor volumes were measured, and histopathology evaluation was performed through Ki-67 staining. Linear regression modeling between radiomics and Ki-67 results was performed to establish a correlation between quantitative imaging and post-treatment histochemistry. There was no correlation between tumor volumes and Ki-67 values. Multiple CT- and MRI-derived features, however, correlated with histopathology with correlation coefficients greater than 0.8. MRI imaging helps in tumor delineation as well as an additional orthogonal imaging modality for quantitative imaging purposes. This is the first investigation correlating simultaneously CT- and MRI-derived radiomics to histopathology outcomes of combined radio-immunotherapy treatments in a preclinical setting applied to treatment naïve tumors. The findings indicate that imaging can guide discrimination between responding and non-responding tumors for the combined RT and ImT treatment regimen in TNBC.
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Zips, D., S. Junghanns, W. Eicheler, K. Brüchner, C. Petersen, and M. Baumann. "Does selection of rapidly proliferating clonogenic tumour cells contribute to accelerated repopulation during fractionated RT? A study on human squamous cell carcinoma in nude mice." European Journal of Cancer 37 (April 2001): S203—S204. http://dx.doi.org/10.1016/s0959-8049(01)81237-5.
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Lin, Ruoting, Bowei Ma, Na Liu, Lu Zhang, Tiantian He, Xiongying Liu, Tongsheng Chen, et al. "Targeted radioimmunotherapy with the iodine-131-labeled caerin 1.1 peptide for human anaplastic thyroid cancer in nude mice." Annals of Nuclear Medicine 35, no. 7 (May 4, 2021): 811–22. http://dx.doi.org/10.1007/s12149-021-01618-3.
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Abstract Objective The combination of two or more drugs with different mechanisms is a promising strategy for cancer treatment, and radioimmunotherapy (RIT) is a trending antitumor strategy. Radiotherapy (RT) can promote and activate antitumor immune effects, and immunotherapy can strengthen the effects of selective internal radiotherapy (SIRT); the RIT combination is synergistic and can overcome the adverse side effects of monotherapy. In this study, we developed a radioimmunoconjugate (RIC)—the iodine-131 (131I)-labeled caerin 1.1 peptide—to treat human anaplastic thyroid cancer (ATC). Methods Antitumor activity of caerin 1.1 peptide was determined by MTT assay, plate colony formation and cell wound scratch assays, and the mechanism of the inhibition of carein 1.1 peptide on the growth of CAL-62 cells was identified by cell cycle and western blot. Then, we investigated the efficacy of the caerin 1.1 peptide as a single drug and the 131I-labeled caerin 1.1 peptide for ATC. H&E and TUNEL staining was performed to detect dead cells in the tumor tissue sections. Results We found that caerin 1.1 arrested cells in the S phase to induce apoptosis and inhibited tumor growth to inhibit phosphorylation of Akt. In vivo, the iodine-131 (131I)-labeled caerin 1.1 peptide achieved better antitumor efficacy than radiotherapy alone and showed a good biosafety profile. Conclusions Our study demonstrates for the first time that the iodine-131 (131I)-labeled caerin 1.1 peptide can inhibit CAL-62 tumor growth and migration. The iodine-131 (131I)-labeled caerin 1.1 peptide, which represents a radioimmunotherapy strategy based on the combination of SIRT with a peptide–drug conjugate, could provide a treatment means for the radical cure of ATC.
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Zhang, Zhiping, Zhou Wang, Xiangyan Liu, Jie Wang, Feng Li, Changling Li, and Baozhong Shan. "Up-regulation of p21WAF1/CIP1 by small activating RNA inhibits the in vitro and in vivo growth of pancreatic cancer cells." Tumori Journal 98, no. 6 (November 2012): 804–11. http://dx.doi.org/10.1177/030089161209800620.
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Aims and background To study the inhibitory effect of p21WAF1/CIP1 activation by saRNA on the growth of human pancreatic cancer cells PANC-1 in vitro and in vivo. Methods and study design A dsRNA (dsP21) targeting the p21WAF1/CIP1 gene promoter at position-322 relative to the transcription start site was transfected into PANC-1 cells. Expression of mRNA and protein was evaluated by semiquantitative RT-PCR and Western blotting. Proliferation of PANC-1 cells was measured by the MTT method, and the apoptosis rate was detected by flow cytometry. PANC-1 cells were transplanted subcutaneously in nude mice, and the inhibitory effect of dsP21 on tumor growth was observed. Results The introduction of dsP21 was shown to efficiently up-regulate expression of the p21WAF1/CIP1 gene in PANC-1 cells according to the results of RT-PCR and Western blotting (P <0.01, compared with controls). The inhibitory effect on cell proliferation was confirmed by the MTT test (P <0.05, compared with controls). The apoptosis rate of PANC-1 cells treated with dsP21 was significantly higher than that of the control cells (P <0.01). Our experimental data showed that dsP21-mediated up-regulation of p21 expression exerted an apparent growth inhibitory effect on PANC-1 cells in vivo. Conclusions dsP21 targeting the p21WAF1/CIP1 gene promoter can specifically up-regulate expression of the p21WAF1/CIP1 gene in PANC-1 cells. It therefore has a substantially inhibitory effect on cell proliferation in vitro and in vivo and can be used as a new method and material for the gene therapy of pancreatic cancer.
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Li, Nan, Chuan-Chuan Nan, Xue-Yun Zhong, Jun-Quan Weng, Hai-Dong Fan, Hai-Peng Sun, Su Tang, Lei Shi, and Sheng-Xing Huang. "miR-182-5p Promotes Growth in Oral Squamous Cell Carcinoma by Inhibiting CAMK2N1." Cellular Physiology and Biochemistry 49, no. 4 (2018): 1329–41. http://dx.doi.org/10.1159/000493411.
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Background/Aims: Emerging evidence suggests that the propagation of oral squamous cell carcinoma (OSCC) is influenced by the abnormal expression of microRNAs (miRNAs). This study aimed to characterize the involvement of miR-182-5p in OSCC by targeting the calcium/ calmodulin-dependent protein kinase II inhibitor CAMK2N1. Methods: miR-182-5p expression was quantified in OSCC tissues and cell lines with reverse transcription polymerase chain reaction (RT-PCR). Cell colony formation, Cell Counting Kit-8 (CCK-8), Ki-67, and nude mouse xenograft assays were used to characterize the role of miR-182-5p in the proliferation of OSCC. A miR-182-5p target gene was identified with western blotting, RT-PCR, and luciferase activity assays. OSCC patient survival based on CAMK2N1 expression was also analyzed. Results: miR-182-5p was up-regulated in in vitro cell lines and in vivo clinical OSCC samples. CCK-8, colony formation, and Ki-67 assays revealed that miR-182-5p promoted the growth and proliferation of OSCC cells. miR-182-5p directly targeted CAMK2N1, as evidenced by luciferase assays and target prediction algorithms. CAMK2N1 operated as a tumor suppressor gene in patients with OSCC. Down-regulating miR-182-5p expression in the CAL-27 cell line restored CAMK2N1-mediated OSCC cell proliferation. miR-182-5p expression inhibited the activation of AKT, ERK1/2, and NF-κB. Mice injected with CAL-27 cells transfected with miR-182-5p-inhibitor demonstrated a significant increase in tumor size and weight and increased CAMK2N1 mRNA and protein expression compared with the miR-negative control group. Conclusion: The miR-182-5p-CAMK2N1 pathway can be potentially targeted to regulate the proliferation of OSCC cells.
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Zheng, Xiaobin, Huashan Liu, Xiaoli Zhong, Xuanhui Liu, Zerong Cai, Yufeng Chen, Xiaosheng He, Ping Lan, and Xiaojian Wu. "LDL receptor related protein 2 to promote colorectal cancer metastasis via enhancing GSK3β/β-catenin signaling." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): e15507-e15507. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e15507.
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e15507 Background: LDL receptor related protein 2 (LRP2), a multi-ligand endocytic receptor, has been implicated in the tumourigenesis of various human cancers. However, the biological roles and underlying regulatory mechanism of LRP2 in CRC remain unclear. Methods: Real-time PCR (RT-PCR), western blot, and immunohistochemistry were used to examine LRP2 expression. Gene silencing and overexpressing efficiencies of LRP2 were confirmed by RT-PCR and western blot. Then wound-healing, migration assay and invasion assay were used to investigate the function of LRP2 in CRC cells. The protein expression and cellular localization of LRP2 and β-catenin were characterized by immunofluorescence staining. The nude mice tail vein metastasis model was established to observe the effect of LRP2 on the lung metastasis of CRC cells in vivo. In addition, gene set enrichment analysis was carried out to explore the potential mechanism of LRP2 in CRC. Results: LRP2 expression was highly upregulated in CRC compared with matched adjacent normal tissue. LRP2 overexpression was positively correlated with shorter overall survival in CRC patients. The biological function observation indicated that LRP2 promoted CRC metastasis in vitro and in vivo. Further molecular mechanism investigation demonstrated that LRP2 protein interacted with glycogen synthase kinase-3β (GSK-3β) and led to decreased expression of GSK3β at ser9, followed by enhanced β-catenin signaling pathway in CRC cells. Conclusions: Our study demonstrated that LRP2 could enhance the metastatic abilities of CRC cells in vitro and in vivo by inhibiting the expression of GSK3β and enhancing the activity of β-catenin signaling pathway, providing that LRP2 might be a novel therapeutic target for metastasis in CRC.
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Xu, Meimei, and Yan Zhang. "Morin Inhibits Ovarian Cancer Growth through the Inhibition of NF-κB Signaling Pathway." Anti-Cancer Agents in Medicinal Chemistry 19, no. 18 (February 7, 2020): 2243–50. http://dx.doi.org/10.2174/1871521409666191014164742.
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Background &Objective: Ovarian cancer has the highest mortality in gynecological tumors without effective therapeutic drugs as a result of drug-resistance for long-term utilization. Morin has been reported to possess powerful anti-tumor effects in several cancers. The present study aims to investigate whether Morin could influence ovarian cancer growth and underlying mechanisms. Methods: Morin was administered to cultured cells in vitro and formed tumors in vivo. MTT and colony formation assays were performed to explore the effects of Morin on the proliferation and colony formation of OVCAR3 and SKOV3 ovarian cancer cells. Western blot, RT-qPCR, immunofluorescence as well as ELISA were used to detect protein and mRNA expression of target factors. Tumor formation was performed to investigate tumorigenesis ability of drug-treated cells. Results: The proliferation and colony size of OVCAR3 and SKOV3 were significantly decreased after Morin administration. The expression of NF-κB and inflammatory cytokine IL6/8 induced by TNF-α can be inhibited by Morin. Furthermore, Morin inhibited the volume of ovarian cancer tumors in nude mice. Conclusion: Morin effectively alleviates ovarian cancer growth, inhibits the inflammatory response, and reduces tumor size via modulation of the NF-κB pathway.
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Wang, Junyi, Haiou Yang, Yiran Si, Dongzhi Hu, Yang Yu, Yan Zhang, Ming Gao, and Haiyang Zhang. "Iodine Promotes Tumorigenesis of Thyroid Cancer by Suppressing Mir-422a and Up-Regulating MAPK1." Cellular Physiology and Biochemistry 43, no. 4 (2017): 1325–36. http://dx.doi.org/10.1159/000481844.
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Background/Aims: Iodine may trigger tumorigenesis and development of thyroid carcinoma, but the mechanisms involved remained elusive. MicroRNA (MiRNAs) are known to be involved in each stage of cancer development; however, the role of miRNAs in iodine-induced tumorigenesis of thyroid carcinoma remained unknown. In this study, we aimed at investigating miRNA related signaling pathway in thyroid cancer cells. Methods: Levels of miRNAs and mRNAs were determined using RT-qPCR and proteins were quantified by western blotting. Cell migration and proliferation were checked using Transwell assay and CCK8 assay respectively. Tumor xenografts in nude mice were established by subcutaneous injection of cancer cells. Results: Mitogen activated protein kinase 1 (MAPK1) was significantly up-regulated, while miR-422a was down-regulated in thyroid cancer cells cultured with high iodine; miR-422a directly bound to the 3’UTR of MAPK1 mRNA. Moreover, miR-422a negatively regulated MAPK1 expression, and down-regulated miR-422a promoted proliferation and migration of TPC-1 cells. In vivo studies also confirmed that iodine promoted tumor growth by suppressing miR-422a and up-regulating MAPK1. Conclusions: Our study illustrates a new pathway comprising iodine, miRNA and MAPK1, and defines a novel mechanism in thyroid cancer.
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Ye, Ying, Lai-Xing Wang, Dan-Ping Zhang, Yi-Jia Yan, and Zhi-Long Chen. "Studies on photodynamic mechanism of a novel chlorine derivative (TDPC) and its antitumor effect for photodynamic therapy in vitro and in vivo." Journal of Innovative Optical Health Sciences 08, no. 01 (January 2015): 1540001. http://dx.doi.org/10.1142/s1793545815400015.
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Photodynamic therapy (PDT) represents a promising method for treatment of cancerous tumors. The chemical and physical properties of used photosensitizer (PS) play key roles in the treatment efficacy. In this study, a novel PS, 5,10,15,20-tetrakis((5-dipropylamino)pentyl)-chlorin (TDPC) which displayed a characteristic long wavelength absorption peak at 650 nm were synthesized. It also shows a singlet oxygen generation rate of 4.257 min-1. Generally, TDPC is localized in mitochondria and nucleus of cell. After light irradiation with 650 nm laser, it can kill many types of cell, in addition, TDPC–PDT can destroy ECA-109 tumor in nude mice and a necrotic scab was formed eventually. The expression levels of many genes which regulated cell growth and apoptosis were determined by RT-PCR following TDPC–PDT. The results showed that it either increased or decreased, among which, the expression level of TNFSF13, a member of tumor necrosis factor superfamily, increased significantly. In general, TDPC is an effective antitumor PS in vitro and in vivo and is worthy of further study as a new drug candidate. TNFSF13 will be an important molecular target for the discovery of new PSs.
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Hu, Wei, and ZengMing Xiao. "Formononetin Induces Apoptosis of Human Osteosarcoma Cell Line U2OS by Regulating the Expression of Bcl-2, Bax and MiR-375 In Vitro and In Vivo." Cellular Physiology and Biochemistry 37, no. 3 (2015): 933–39. http://dx.doi.org/10.1159/000430220.
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Background/Aims: Phytoestrogens are known to prevent tumor progression by inhibiting proliferation and inducing apoptosis in cancer cells. Formononetin is one of the main components of red clover plants, and is considered as a typical phytoestrogen. This study investigates formononetin induction of apoptosis of human osteosarcoma cell line U2OS by regulating Bcl-2 and Bax expression in vitro and in vivo. Methods: U2OS cells were treated with different concentrations of formononetin and the proliferation of the cells was measured using an MTT assay. Cell apoptosis was examined by flow cytometry. The levels of miR-375, Bax and Bcl-2 protein expression in treated cells were determined by Western blot and RT-PCR. The antitumor activity of formononetin was also evaluated in vivo in nude mice bearing orthotopic tumor implants. Results: High concentrations of formononetin significantly suppress the proliferation of U2OS cells and induce cell apoptosis. Moreover, compared to control group the expression of Bcl-2 and miR-375 decreases with formononetin in the U2OS cells, while Bax increases. Conclusion: Formononetin has inhibitory effects on the proliferation of U2SO cells, both in vitro and in vivo. This antitumor effect is directly correlated with formononetin concentration.
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Xu, Hongyan, Minghuan Mao, Rui Zhao, and Qing Zhao. "Enoxacin Exerts Anti-Tumor Effects Against Prostate Cancer Through Inducing Apoptosis." Technology in Cancer Research & Treatment 20 (January 1, 2021): 153303382199528. http://dx.doi.org/10.1177/1533033821995284.
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Background: Prostate cancer is the most commonly diagnosed cancer and second leading cause of cancer death in men. Enoxacin, a third-generation fluoroquinolone antibiotic, was found with anti-proliferative effects against many cancer types. This study was to further investigate its effects against prostate cancer and explore the underlying molecular mechanisms. Methods: PC-3 cells were treated with Enoxacin at different concentrations. Tumor model was established by subcutaneously injecting PC-3 cells into nude mice. MTT assay was used to detect cell viability. ELISA assay, Annexin V/PI staining and TUNEL assay were used to detect apoptosis. RT-qPCR and western blot were used to detect the gene and protein expression, respectively. Results: Our data showed that Enoxacin inhibited PC-3 cell proliferation and induced the apoptosis through up-regulating the expression of pro-apoptotic proteins, while down-regulating expression levels of anti-apoptotic proteins. Moreover, Enoxacin increased the gene and protein expression of the autophagy and endoplasmic reticulum stress markers. Treating tumor-bearing mice with Enoxacin significantly inhibited tumor growth in xenograft tumor model. Conclusion: Our results suggested that Enoxacin could be developed as a potential anti-tumor agent against prostate carcinoma.
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Tan, Mengqun, Zhenqing Liu, Juan Zhang, Zhiyan Li, Liujiang Song, Xiaolin Yin, and Xinhua Zhang. "Hybrid AAV6/2-Mediated Human β-Globin Expression in β-Thalassemia Patient Hematopoietic Stem Cells Transplanted Into Irradiated BALB/c Nude Mouse." Blood 118, no. 21 (November 18, 2011): 4715. http://dx.doi.org/10.1182/blood.v118.21.4715.4715.
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Abstract Abstract 4715 β -Thalassemia is one of the most common worldwide monogenic human diseases,caused by molecular defects in the human β -globin gene cluster leading to decrease or absence of β-globin. Loss of β -globin chains causes ineffective production of oxygen-carrying hemoglobin and therefore results in severe anemia. The treatment for β -Thalassemia major usually includes lifelong blood transfusions but chronic blood transfusion often causes iron overload, and accumulated iron produces tissue damage in multiple organs, so that iron chelating treatment is also needed. Bone marrow transplantation is another effective therapy, which can eliminate a patient's dependence on blood transfusions, however, it is difficult to find a matching donor for most patients; therefore it is only available for a minority of patients. Gene therapy is one potential novel therapy for treatment of inherited monogenic disorders. The long–term therapeutic strategy for this disease is to replace the defective β-globin gene via introduction of a functional gene into hematopoietic stem cells (HSCs). Adeno-associated virus type 2 (AAV), a nonpathogenic human parvovirus, has gained attention as a potentially useful vector for human gene therapy. AAV can infect both dividing and non-dividing cells and wild AAV integrates preferentially at a specific site on human chromosome 19. In the absence of helper virus, recombinant AAV will stably integrate into the host cell genome, mediating long-term and stable expression of the transgene. In this study, we used a hybrid rAAV6/2 vector carrying the human β-globin gene to transduce HSCs from a β -Thalassemia patient, followed by transplantation into irradiated BALB/c nude mice. One month post-transplantation, Hb was prepared from peripheral blood and analyzed by Western Blot and HPLC respectively. RNA and DNA were isolated from bone marrow cells (BMCs) from recipient mice transplanted with mock-infected or hybrid rAAV–globin-infected cells and analyzed by RT-PCR and PCR respectively. The results showed: 1. Human β-actin and β-globin transcripts were detected by RT-PCR in BMCs from all recipient mice, indicating that human HSCs were successfully transplanted in these mice and that the human β-globin gene was transcriptionally active in the donor cells. 2. The level of human hemoglobin expressed in peripheral red blood cells of recipient mice as measured by HPLC (ratio of β/α) was increased to 0.3 from 0.05 of pre-transplantation levels. Expression of human β-globin was also confirmed in recipient mice by Western Blot; a 2–3-fold increase compared with that of controls. Our results indicate that human HSCs from a β-Thalassemia patient can be efficiently transduced by a hybrid rAAV6/2-β-globin vector followed by expression of normal human β-globin protein. This study provides a proof-of-concept that rAAV6/2-mediated gene transfer into human HSCs might be a potential approach for gene therapy of β-Thalassemia. Disclosures: No relevant conflicts of interest to declare.
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Colombo, Jucimara, Bruna V. Jardim-Perassi, João P. S. Ferreira, Cristine Z. Braga, Nathália M. Sonehara, Rubens P. Júnior, Marina G. Moschetta, Ana P. Girol, and Debora A. P. C. Zuccari. "Melatonin Differentially Modulates NF-кB Expression in Breast and Liver Cancer Cells." Anti-Cancer Agents in Medicinal Chemistry 18, no. 12 (January 29, 2019): 1688–94. http://dx.doi.org/10.2174/1871520618666180131112304.
Full textAbstract:
Background: NF-kB (nuclear factor kappa B) is a transcription factor composed of two subunits, p50 and p65, which plays a key role in the inflammatory process. Melatonin has oncostatic, antiangiogenic and antimetastatic properties, and some recent studies have indicated an inhibitory effect of melatonin on NF-kB in some types of cancer. This work aims to investigate the effects of melatonin treatment on the expression of NFkB in breast and liver cancer models. Method: The breast cancer xenographic model was performed using female Balb/c nude athymic mice injected with MDA-MB-231 cells. The animals were treated with 40 mg/Kg of melatonin for 21 days. Volume of the tumors was measured with a digital caliper. Hepatocarcinoma model was developed by using the HepG2 cells in vitro, treated with 1 mM melatonin for 24 h. The expression of NF-kB protein was verified by immunohistochemistry and immunocytochemistry and quantified by optical densitometry, in vivo study and in vitro study, respectively. NF-kB gene expression was performed by quantitative RT-PCR. Results: The breast cancer xenografts nude mice treated with melatonin showed reduced tumor size (P=0.0022). There was a decrease in NF-kB protein staining (P=0.0027) and gene expression (P=0.0185) in mice treated with melatonin. The opposite results were observed for the hepatocarcinoma model. HepG2 cells treated with melatonin showed an increase in the NF-kB immunostaining when compared to control cells (P=0.0042). Conclusion: Our results indicated that the treatment with melatonin was able to decrease both gene and protein expressions of NF-kB in breast cancer cells and, conversely, increase the transcription factor protein expression in hepatocarcinoma cells. These data highlighted a double role in the expression of NF-kB, depending on the cell type. Further studies are needed to better elucidate the action of melatonin in NF-kB, since this transcription factor acts on different signaling pathways that are fundamental for carcinogenesis.