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Li, Wenchao, Bowen Pan, Yang Shi, Meiying Wang, Tianjiao Han, Qing Wang, Guifang Duan, and Hongzheng Fu. "Identification of poly(ADP-ribose)polymerase 1 and 2 (PARP1/2) as targets of andrographolide using an integrated chemical biology approach." Chemical Communications 57, no. 51 (2021): 6308–11. http://dx.doi.org/10.1039/d1cc02272e.
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Andrographolide is the first PARP natural product inhibitor that does not contain an amide structure and has an inhibitory activity in the nanomolar range. This chemical structure is significant for expanding the structural type of PARP inhibitors.
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Li, Jiaguo, Dian Xiao, Lianqi Liu, Fei Xie, Wei Li, Wei Sun, Xiaohong Yang, and Xinbo Zhou. "Design, Synthesis, and In Vitro Evaluation of the Photoactivatable Prodrug of the PARP Inhibitor Talazoparib." Molecules 25, no. 2 (January 18, 2020): 407. http://dx.doi.org/10.3390/molecules25020407.
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In this article, we report the design, synthesis, photodynamic properties, and in vitro evaluation of photoactivatable prodrug for the poly (ADP-ribose) polymerase 1 (PARP-1) inhibitor Talazoparib. In order to yield a photoactivatable, inactive prodrug, photoactivatable protecting groups (PPGs) were employed to mask the key pharmacophore of Talazoparib. Our study confirmed the good stability and photolytic effect of prodrugs. A PARP-1 enzyme inhibition assay and PARylation experiment showed that the inhibitory activity of the prodrug was reduced 380 times and more than 658 times, respectively, which proved that the prodrug’s expected activity was lost after PPG protection. In BRCA1- and BRCA2-deficient cell lines, the inhibitory activity of the compound was significantly restored after ultraviolet (UV) irradiation. The results indicate that the photoactivatable prodrug strategy is an interesting approach for studying PARP inhibitors. Meanwhile, the described photoactivatable prodrug also provided a new biological tool for the mechanism research of PARP.
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Kam, Caleb M., Amanda L. Tauber, Stephan M. Levonis, and Stephanie S. Schweiker. "Design, synthesis and evaluation of potential inhibitors for poly(ADP-ribose) polymerase members 1 and 14." Future Medicinal Chemistry 12, no. 24 (December 2020): 2179–90. http://dx.doi.org/10.4155/fmc-2020-0218.
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Poly(ADP-ribose) polymerase (PARP) members PARP1 and PARP14 belong to an 18-member superfamily of post-translational modifying enzymes. A library of 9 novel non-NAD analog amine compounds was designed, synthesized and evaluated for inhibitory activity against PARP1 and PARP14. Both in silico studies and in vitro assays identified compound 2 as a potential PARP1 inhibitor, inhibiting activity by 93 ± 2% (PARP14 inhibition: 0 ± 6%), and 7 as a potential PARP14 inhibitor, inhibiting activity by 91 ± 2% (PARP1 inhibition: 18 ± 4%), at 10-μm concentration. Key in silico interactions with TYR907 in PARP1 and TYR1620 and TYR1646 in PARP14 have been identified. Compound 2 and compound 7 have been identified as potential leads for the development of selective PARP inhibitors.
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Gurkan-Alp, A. Selen, Mehmet Alp, Arzu Z. Karabay, Asli Koc, and Erdem Buyukbingol. "Synthesis of Some Benzimidazole-derived Molecules and their Effects on PARP-1 Activity and MDA-MB-231, MDA-MB-436, MDA-MB-468 Breast Cancer Cell Viability." Anti-Cancer Agents in Medicinal Chemistry 20, no. 14 (October 14, 2020): 1728–38. http://dx.doi.org/10.2174/1871520620666200502001953.
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Background: Poly (ADP-ribosyl) polymerase-1 (PARP-1) inhibitors are compounds that are used to treat cancers, which are defective in DNA-repair and DNA Damage-Response (DDR) pathways. Objective: In this study, a series of potential PARP-1 inhibitor substituted (piperazine-1-carbonyl)phenyl)-1Hbenzo[ d]imidazole-4-carboxamide compounds were synthesised and tested for their PARP-1 inhibitory and anticancer activities. Methods: Compounds were tested by cell-free colorimetric PARP-1 activity and MTT assay in MDA-MB-231, MDA-MB-436, MDA-MB-468 breast cancer, and L929 fibroblast cell lines. Results: Our results showed that compound 6a inhibited viability in MDA-MB-231 and MDA-MB-468 cells whereas 8a inhibited viability in MDA-MB-468 cells. Compound 6b significantly inhibited cell viability in tested cancer cells. However, 6b exhibited toxicity in L929 cells, whereas 6a and 8a were found to be non-toxic for L929 cells. Compounds 6a, 6b and 8a exhibited significant inhibition of PARP-1 activity. Conclusion: These three compounds exhibited PARP-1 inhibitory activities and anticancer effects on breast cancer cells, and further research will enlighten the underlying mechanisms of their effects.
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Toledano, Elie, Vasily Ogryzko, Antoine Danchin, Daniel Ladant, and Undine Mechold. "3′-5′ Phosphoadenosine phosphate is an inhibitor of PARP-1 and a potential mediator of the lithium-dependent inhibition of PARP-1 in vivo." Biochemical Journal 443, no. 2 (March 27, 2012): 485–90. http://dx.doi.org/10.1042/bj20111057.
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pAp (3′-5′ phosphoadenosine phosphate) is a by-product of sulfur and lipid metabolism and has been shown to have strong inhibitory properties on RNA catabolism. In the present paper we report a new target of pAp, PARP-1 [poly(ADP-ribose) polymerase 1], a key enzyme in the detection of DNA single-strand breaks. We show that pAp can interact with PARP-1 and inhibit its poly(ADP-ribosyl)ation activity. In vitro, inhibition of PARP-1 was detectable at micromolar concentrations of pAp and altered both PARP-1 automodification and heteromodification of histones. Analysis of the kinetic parameters revealed that pAp acted as a mixed inhibitor that modulated both the Km and the Vmax of PARP-1. In addition, we showed that upon treatment with lithium, a very potent inhibitor of the enzyme responsible for pAp recycling, HeLa cells exhibited a reduced level of poly(ADP-ribosyl)ation in response to oxidative stress. From these results, we propose that pAp might be a physiological regulator of PARP-1 activity.
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Cheong, Woo-Chang, Joo-Hee Park, Hye-Ri Kang, and Moon Jung Song. "Downregulation of Poly(ADP-Ribose) Polymerase 1 by a Viral Processivity Factor Facilitates Lytic Replication of Gammaherpesvirus." Journal of Virology 89, no. 18 (July 8, 2015): 9676–82. http://dx.doi.org/10.1128/jvi.00559-15.
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ABSTRACTIn Kaposi's sarcoma-associated herpesvirus (KSHV), poly(ADP-ribose) polymerase 1 (PARP-1) acts as an inhibitor of lytic replication. Here, we demonstrate that KSHV downregulated PARP-1 upon reactivation. The viral processivity factor of KSHV (PF-8) interacted with PARP-1 and was sufficient to degrade PARP-1 in a proteasome-dependent manner; this effect was conserved in murine gammaherpesvirus 68. PF-8 knockdown in KSHV-infected cells resulted in reduced lytic replication upon reactivation with increased levels of PARP-1, compared to those in control cells. PF-8 overexpression reduced the levels of the poly(ADP-ribosyl)ated (PARylated) replication and transcription activator (RTA) and further enhanced RTA-mediated transactivation. These results suggest a novel viral mechanism for overcoming the inhibitory effect of a host factor, PARP-1, thereby promoting the lytic replication of gammaherpesvirus.IMPORTANCEGammaherpesviruses are important human pathogens, as they are associated with various kinds of tumors and establish latency mainly in host B lymphocytes. Replication and transcription activator (RTA) of Kaposi's sarcoma-associated herpesvirus (KSHV) is a central molecular switch for lytic replication, and its expression is tightly regulated by many host and viral factors. In this study, we investigated a viral strategy to overcome the inhibitory effect of poly(ADP-ribose) polymerase 1 (PARP-1) on RTA's activity. PARP-1, an abundant multifunctional nuclear protein, was downregulated during KSHV reactivation. The viral processivity factor of KSHV (PF-8) directly interacted with PARP-1 and was sufficient and necessary to degrade PARP-1 protein in a proteasome-dependent manner. PF-8 reduced the levels of PARylated RTA and further promoted RTA-mediated transactivation. As this was also conserved in another gammaherpesvirus, murine gammaherpesvirus 68, our results suggest a conserved viral modulation of a host inhibitory factor to facilitate its lytic replication.
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Xin, Minhang, Jiajia Sun, Wei Huang, Feng Tang, Zhaoyu Liu, Qiu Jin, and Jia Wang. "Design and synthesis of novel phthalazinone derivatives as potent poly(ADP-ribose)polymerase 1 inhibitors." Future Medicinal Chemistry 12, no. 19 (October 2020): 1691–707. http://dx.doi.org/10.4155/fmc-2020-0009.
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Aim: The development of effective PARP-1 inhibitors has received great enthusiasm in medicinal chemistry communities. Results: A new series of novel phthalazinone derivatives were designed and synthesized. Among these, B1 and B16 displayed more potent PARP-1 inhibitory activities than olaparib. B16 gave an IC50 value of 7.8 nM against PARP-1, and a PF50 value of 3.4 in the sensitizing effect assay. The in vivo pharmacokinetic properties evaluation showed B16 displayed insufficient oral exposure, and it was also not stable in rat blood. Conclusion: The results indicated that our design phthalazinone derivatives were potent PARP-1 inhibitors, and compound B16 was a valuable lead compound with significant in vitro efficacy, deserving further optimization to develop anticancer drug candidate.
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Zhou, Yunjiang, Shi Tang, Tingting Chen, and Miao-Miao Niu. "Structure-Based Pharmacophore Modeling, Virtual Screening, Molecular Docking and Biological Evaluation for Identification of Potential Poly (ADP-Ribose) Polymerase-1 (PARP-1) Inhibitors." Molecules 24, no. 23 (November 22, 2019): 4258. http://dx.doi.org/10.3390/molecules24234258.
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Poly (ADP-ribose) polymerase-1 (PARP-1) plays critical roles in many biological processes and is considered as a potential target for anticancer therapy. Although some PARP-1 inhibitors have been reported, their clinical application in cancer therapy is limited by some shortcomings such as weak affinity, low selectivity and adverse side effects. To identify highly potent and selective PARP-1 inhibitors, an integrated protocol that combines pharmacophore mapping, virtual screening and molecular docking was constructed. It was then used as a screening query to identify potent leads with unknown scaffolds from an in-house database. Finally, four retrieved compounds were selected for biological evaluation. Biological testing indicated that the four compounds showed strong inhibitory activities on the PARP-1 (IC50 < 0.2 μM). MTT assay confirmed that compounds 1–4 inhibited the growth of human lung cancer A549 cells in a dose-dependent manner. The obtained compounds from this study may be potential leads for PARP-1 inhibition in the treatment of cancer.
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Malka, Matthews M., Julia Eberle, Kathrin Niedermayer, Darius P. Zlotos, and Lisa Wiesmüller. "Dual PARP and RAD51 Inhibitory Drug Conjugates Show Synergistic and Selective Effects on Breast Cancer Cells." Biomolecules 11, no. 7 (July 3, 2021): 981. http://dx.doi.org/10.3390/biom11070981.
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The genetic principle of synthetic lethality has most successfully been exploited in therapies engaging Poly-ADP-ribose-polymerase (PARP) inhibitors to treat patients with homologous recombination (HR)-defective tumors. In this work, we went a step further following the idea of a local molecular cooperation and designed hybrid compounds M1–M3. The drug conjugates M1–M3 combine Olaparib, the first PARP inhibitor approved for clinical use, with Cpd 1, an inhibitor of RAD51 that blocks its HR functions and yet permits RAD51 nucleoprotein filament formation on single-stranded DNA. While in M2 and M3, the parental drugs are linked by -CO-(CH2)n-CO-spacers (n = 2 and 4, respectively), they are directly merged omitting the piperazine ring of Olaparib in M1. Monitoring anti-survival effects of M1–M3 in six breast cancer cell lines of different molecular subtypes showed that in each cell line, at least one of the drug conjugates decreased viability by one to two orders of magnitude compared with parental drugs. While triple-negative breast cancer (TNBC) cells with frequent BRCA1 pathway dysfunction were sensitive to spacer-linked hybrid compounds M1 and M2 regardless of their HR capacities, non-TNBC cells were responsive to the merged drug conjugate M1 only, suggesting different spatial requirements for dual inhibition in these two groups of cell lines. These results demonstrate that, depending on chemical linkage, dual PARP1-RAD51 inhibitory drugs can either sensitize non-TNBC and re-sensitize TNBC cells, or discriminate between these groups of cells.
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Keung, Man Yee, Yanyuan Wu, Francesca Badar, and Jaydutt V. Vadgama. "Response of Breast Cancer Cells to PARP Inhibitors Is Independent of BRCA Status." Journal of Clinical Medicine 9, no. 4 (March 30, 2020): 940. http://dx.doi.org/10.3390/jcm9040940.
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Poly (ADP-ribose) polymerase inhibitors (PARPi) have proven to be beneficial to patients with metastatic breast cancer with BRCA1/2 (BReast CAncer type 1 and type 2 genes) mutations. However, certain PARPi in pre-clinical studies have been shown to inhibit cell growth and promote the death of breast cancer cells lacking mutations in BRCA1/2. Here, we examined the inhibitory potency of 13 different PARPi in 12 breast cancer cell lines with and without BRCA-mutations using cell viability assays. The results showed that 5 of the 8 triple-negative breast cancer (TNBC) cell lines were susceptible to PARPi regardless of the BRCA-status. The estrogen receptor (ER) negative/ human epidermal growth factor receptor 2 (HER2) positive (ER-/HER2+) cells, SKBR3 and JIMT1, showed high sensitivity to Talazoparib. Especially JIMT1, which is known to be resistant to trastuzumab, was responsive to Talazoparib at 0.002 µM. Niraparib, Olaparib, and Rucaparib also demonstrated effective inhibitory potency in both advanced TNBC and ER-/HER2+ cells with and without BRCA-mutations. In contrast, a BRCA-mutant TNBC line, HCC1937, was less sensitive to Talazoparib, Niraparib, Rucaparib, and not responsive to Olaparib. Other PARPi such as UPF1069, NU1025, AZD2461, and PJ34HCl also showed potent inhibitory activity in specific breast cancer cells. Our data suggest that the benefit of PARPi therapy in breast cancer is beyond the BRCA-mutations, and equally effective on metastatic TNBC and ER-/HER2+ breast cancers.
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Cotter, Maura B., Aisling Pierce, Patricia M. McGowan, Louise Flanagan, Cecily Quinn, Denis Evoy, John Crown, Enda McDermott, and Michael J. Duffy. "Preclinical evaluation of PARP inhibition in breast cancer: Comparative effectiveness of olaparib and iniparib." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 1042. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.1042.
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1042 Background: The main function of PARP1 is repair of single-strand DNA. Phase I/II clinical trials have shown that the PARP inhibitor, olaparib has efficacy in BRCA1/2-related breast cancer. Due to the similarities between BRCA1/2-associated and triple negative breast cancer (TNBC), we hypothesise that TNBC may also be sensitive to PARP inhibition. In order to assess this we addressed the effects of 2 PARP/PARP-like inhibitors, on a panel of breast cancer cell lines. Methods: PARP1 was measured by immunohistochemistry in 101 TNBC and 116 non-TN cancers. Comparative growth inhibitory capacity of olaparib and iniparib was evaluated using cell viability (MTT) and colony formation assays in 12 breast cancer cell lines (TN=7, non-TN=5). Results: Using immunohistochemistry, PARP1 staining was predominantly nuclear with some cytoplasmic staining. High staining intensity for PARP1 was found more frequently in ER-negative (p = 0.001), in high grade (p = 0.013) and in Ki67-positive ( p = 0.003) samples. Potentially important was the finding that high PARP1 staining intensity was detected more frequently in TN than non-TN samples (p = 0.0001). IC50 concentrations across 12 cell lines ranged from 3.7-31 µM for olaparib and 13-70 µM for iniparib. No difference in sensitivity was observed between the TN and non-TN cell lines (by MTT). Olaparib also reduced the ability of cells to form colonies with IC50 values ranging from <0.01-2.5 µM. Addition of the CDKI inhibitor CDK1i (Calbiochem) to olaparib resulted in formation of significantly fewer colonies compared with either inhibitor alone, in a cell line dependent manner. Conclusions: Our results suggest that although PARP1 is expressed in the majority of breast cancer, significantly higher staining intensity was found in TN than non-TN samples. Furthermore, our work suggests that olaparib is a more potent inhibitor of the in vitro growth of breast cancer cells than iniparib. Combined inhibition of PARP1 with olaparib and CDK1 with CDK1i may be a way forward for the treatment of TNBC. Acknowledgement: The authors thank SFI (SRC award, 08/SRC/B1410 MTCI) for funding this work.
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Hiroki, Haruka, Masatoshi Takagi, Yuko Ishi, Jinhua Piao, and Tomohiro Morio. "PARP Inhibition Sensitize BCR-ABL1 Positive Cel." Blood 134, Supplement_1 (November 13, 2019): 3367. http://dx.doi.org/10.1182/blood-2019-127853.
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Introduction: BCR-ABL1 play a key role in the development of chronic myelogenous leukemia and a part of Ph1 positive acute lymphoblastic leukemia (ALL). BCR-ABL1 functions as a tyrosine kinase. Whereas, BCR-ABL1 induces genomic instability by downregulation of BRCA1. An innate error of BRCA1, a molecule involved in the homologous recombination repair pathway, causes hereditary breast and ovarian cancer. PARP inhibitor (PARPi) induces synthetic lethality in BRCA defective cell. Therefore, PARP inhibitor is expected to induce efficient cell death with BCR-ABL1 positive cell. In addition, in some previous reports, reduction of PARP1 activity leads to the upregulation of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway and BCR-ABL1 tyrosine kinase activates PI3K/AKT pathway. These findings suggest activation of the PI3K/AKT pathway leading to PARPi resistance in BCR-ABL1 positive leukemic cells. Here, we demonstrate that PARP inhibition attenuates BCR-ABL1 mediated leukemogenesis and aberration of factors associated with PARP inhibitor resistance induces cell death to fully transformed leukemic cells. Method: Bone marrow-derived mononuclear cells (MNC) from wild type mice and BCR-ABL1 transgenic (Tg) mice were exposed to PARPi in vivo, and cell death was analyzed Annexin-V positivity. PARPi sensitivity to BCR-ABL1 expressed cell was also investigated in vivo bone marrow transplantation model using mouse hematopoietic stem cell (HCS) infected with BCR-ABL1 expressing retrovirus. To evaluate more precisely the results obtained in vitro and in vivo transplantation model, the genetical approach was also performed. The Parp1 knockout (KO) mice were crossed with BCR-ABL1 Tg mice. Then, Leukemia development and subsequent mouse death were observed. In vitro, HR activity was examined using DR-GFP assay. Genomic instability was investigated using the breakage-fusion-bridge (BFB) generation.Maintenance of HSC as a progenitor of the leukemic cell was analyzed by repopulation activity using colony assay. The growth-inhibitory effect was assessed using BCR-ABL positive cell lines with PARPi and PI3K inhibitor. Results: BCR-ABL1 Tg mice derived MNC showed more hypersensitivity to PARPi. Mouse HCS was infected with BCR-ABL1 expressing retrovirus and transplanted lethally Olaparib or vehicle was administrated intraperitoneal injection one day after transplantation. BCR-ABL1 mediated leukemic death was observed 1 month after transplantation in sham-treated mouse, whereas, Olaparib treated mouse did not develop BCR-ABL1 mediated leukemia. Parp1 KO BCR-ABL1 Tg mice attenuated leukemia development and extended their survival compared with BCR-ABL1 Tg mice. In vitro experiment revealed HR activity was down-regulated by BCR-ABL1 expression in DR-GFP assay. The number of BFB generation was increased in BCR-ABL1 Tg with Parp1 KO background. The colony-forming activity of BCR-ABL1 positive HSC was totally abolished by PARP inhibition after 3 times serial replating, whereas sham-treated HSC retained repopulation activity. However, the effect of PARPi on BCR-ABL positive leukemic cell lines was controversial. Therefore, leukemic cell lines were treated with the PARPi and inhibitors toward the molecules associated with PARPi resistance. As a result, a combination of PARPi with PI3K inhibitor effectively induce cell death in PARPi resistant BCR-ABL1 positive leukemic cell lines. Conclusion and discussion: Tyrosine kinase inhibitor (TKI) is the gold standard of the therapeutic option of BCR-ABL1 positive leukemia. However, TKI monotherapy is not sufficient for complete eradication of leukemic cells. It is highly expected that molecules effectively induce cell death to leukemic cells combined with TKI. PARPi would be one of these candidates. However, PARPi could not induces efficient death in all of the cancer cells that carry the mutation of molecules associated with the HR defect. Comprehensive genetic analysis to reveal PARPi resistance is important for HRR defective cancer cells. Combination therapy of PARPi and inhibitorstoward the molecules associated with PARPi resistance would be a good therapeutic option for Ph1 positive leukemia. Disclosures No relevant conflicts of interest to declare.
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Nikoleousakos, Nikolaos, Panagiotis Dalezis, Aikaterini Polonifi, Elena G. Geromichalou, Sofia Sagredou, Constantinos E. Alifieris, Maria V. Deligiorgi, Vasiliki Sarli, and Dimitrios T. Trafalis. "Cytocidal Antitumor Effects against Human Ovarian Cancer Cells Induced by B-Lactam Steroid Alkylators with Targeted Activity against Poly (ADP-Ribose) Polymerase (PARP) Enzymes in a Cell-Free Assay." Biomedicines 9, no. 8 (August 17, 2021): 1028. http://dx.doi.org/10.3390/biomedicines9081028.
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We evaluated three newly synthesized B-lactam hybrid homo-aza-steroidal alkylators (ASA-A, ASA-B and ASA-C) for their PARP1/2 inhibition activity and their DNA damaging effect against human ovarian carcinoma cells. These agents are conjugated with an alkylating component (POPA), which also served as a reference molecule (positive control), and were tested against four human ovarian cell lines in vitro (UWB1.289 + BRCA1, UWB1.289, SKOV-3 and OVCAR-3). The studied compounds were thereafter compared to 3-AB, a known PARP inhibitor, as well as to Olaparib, a standard third-generation PARP inhibitor, on a PARP assay investigating their inhibitory potential. Finally, a PARP1 and PARP2 mRNA expression analysis by qRT-PCR was produced in order to measure the absolute and the relative gene expression (in mRNA transcripts) between treated and untreated cells. All the investigated hybrid steroid alkylators and POPA decreased in vitro cell growth differentially, according to the sensitivity and different gene characteristics of each cell line, while ASA-A and ASA-B presented the most significant anticancer activity. Both these compounds induced PARP1/2 enzyme inhibition, DNA damage (alkylation) and upregulation of PARP mRNA expression, for all tested cell lines. However, ASA-C underperformed on average in the above tasks, while the compound ASA-B induced synthetic lethality effects on the ovarian cancer cells. Nevertheless, the overall outcome, leading to a drug-like potential, provides strong evidence toward further evaluation.
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Chen, Xian, Dong Yang, Jason P. W. Carey, Cansu Karakas, Constance Albarracin, Aysegul A. Sahin, Banu K. Arun, et al. "Targeting Replicative Stress and DNA Repair by Combining PARP and Wee1 Kinase Inhibitors Is Synergistic in Triple Negative Breast Cancers with Cyclin E or BRCA1 Alteration." Cancers 13, no. 7 (April 1, 2021): 1656. http://dx.doi.org/10.3390/cancers13071656.
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The identification of biomarker-driven targeted therapies for patients with triple negative breast cancer (TNBC) remains a major clinical challenge, due to a lack of specific targets. Here, we show that cyclin E, a major regulator of G1 to S transition, is deregulated in TNBC and is associated with mutations in DNA repair genes (e.g., BRCA1/2). Breast cancers with high levels of cyclin E not only have a higher prevalence of BRCA1/2 mutations, but also are associated with the worst outcomes. Using several in vitro and in vivo model systems, we show that TNBCs that harbor either mutations in BRCA1/2 or overexpression of cyclin E are very sensitive to the growth inhibitory effects of AZD-1775 (Wee 1 kinase inhibitor) when used in combination with MK-4837 (PARP inhibitor). Combination treatment of TNBC cell lines with these two agents results in synergistic cell killing due to induction of replicative stress, downregulation of DNA repair and cytokinesis failure that results in increased apoptosis. These findings highlight the potential clinical application of using cyclin E and BRCA mutations as biomarkers to select only those patients with the highest replicative stress properties that may benefit from combination treatment with Wee 1 kinase and PARP inhibitors.
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Lee, Jong Hyun, Chakrabhavi Dhananjaya Mohan, Salundi Basappa, Shobith Rangappa, Arunachalam Chinnathambi, Tahani Awad Alahmadi, Sulaiman Ali Alharbi, et al. "The IκB Kinase Inhibitor ACHP Targets the STAT3 Signaling Pathway in Human Non-Small Cell Lung Carcinoma Cells." Biomolecules 9, no. 12 (December 13, 2019): 875. http://dx.doi.org/10.3390/biom9120875.
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STAT3 is an oncogenic transcription factor that regulates the expression of genes which are involved in malignant transformation. Aberrant activation of STAT3 has been observed in a wide range of human malignancies and its role in negative prognosis is well-documented. In this report, we performed high-throughput virtual screening in search of STAT3 signaling inhibitors using a cheminformatics platform and identified 2-Amino-6-[2-(Cyclopropylmethoxy)-6-Hydroxyphenyl]-4-Piperidin-4-yl Nicotinonitrile (ACHP) as the inhibitor of the STAT3 signaling pathway. The predicted hit was evaluated in non-small cell lung cancer (NSCLC) cell lines for its STAT3 inhibitory activity. In vitro experiments suggested that ACHP decreased the cell viability and inhibited the phosphorylation of STAT3 on Tyr705 of NSCLC cells. In addition, ACHP imparted inhibitory activity on the constitutive activation of upstream protein tyrosine kinases, including JAK1, JAK2, and Src. ACHP decreased the nuclear translocation of STAT3 and downregulated its DNA binding ability. Apoptosis was evidenced by cleavage of caspase-3 and PARP with the subsequent decline in antiapoptotic proteins, including Bcl-2, Bcl-xl, and survivin. Overall, we report that ACHP can act as a potent STAT3 signaling inhibitor in NSCLC cell lines.
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Mao, Xiaorong, Senrong Du, Zhongxia Yang, Liting Zhang, Xuebin Peng, Ni Jiang, and Haiyu Zhou. "Inhibitors of PARP-1 exert inhibitory effects on the biological characteristics of hepatocellular carcinoma cells in vitro." Molecular Medicine Reports 16, no. 1 (January 2017): 208–14. http://dx.doi.org/10.3892/mmr.2017.6568.
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Xie, Zhouling, Yu Chen, Pengfei Xu, Youli Zhou, Qian Zhao, He Jiao, and Zhiyu Li. "Design, synthesis and bioevaluation of 1H-indole-4-carboxamide derivatives as potent poly(ADP-ribose) polymerase-1 inhibitors." RSC Advances 6, no. 84 (2016): 80784–96. http://dx.doi.org/10.1039/c6ra12591c.
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LX15 is more potent than AG014699 in PARP-1 inhibitory activity and BRCA-1 deficient cell inhibitory activity. It is more effective than AG014699 in potentiating the antitumor activity of TMZin vitro and in vivo.
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Radosova Muchova, Tereza, Eva Reznickova, Zuzana Somikova, Tomas Gucky, Miroslav Strnad, Vladimir Krystof, and Vladimir Divoky. "A Novel Dual Class III/Src Family Tyrosine Kinase Inhibitor Is Highly Active Against FLT3-ITD Leukemia Cells In Vivo." Blood 128, no. 22 (December 2, 2016): 1569. http://dx.doi.org/10.1182/blood.v128.22.1569.1569.
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Abstract Class III receptor tyrosine kinases (RTK), which include c-fms, c-kit, FMS-like tyrosine kinase receptor-3(FLT3) and platelet-derived growth factor receptor (PDGFR) α/β are expressed on acute myelogenous leukemia (AML) cells from the majority of patients and stimulate survival and proliferation of leukemic blasts. FLT3 activation cooperates, for instance, with oncogenic mixed lineage leukemia (MLL) fusion proteins in MLL-induced transformation. The most common FLT3 activation mutation, internal tandem duplication (ITD), is the most frequently observed molecular defect in AML, and it is associated with early relapses and poor prognosis. FLT3-ITD leads to constitutive, ligand-independent activation of the kinase; this results in FLT3 autophosphorylation and induction of several downstream signaling cascades including Ras/MAPK kinase (MEK)/extracellular signal-regulated kinase (ERK) and STAT5 pathways. FLT3 as well as other class III RTK have been widely accepted as suitable drug targets. Several potent inhibitors have been developed, and some of them, such as quizartinib or crenolanib, have demonstrated promising clinical outcomes. However, resistance to these inhibitors remains a significant clinical problem; therefore, development of novel inhibitors is needed. Also Src family tyrosine kinases (SFK) have been proven as therapeutic targets in multiple cancers including leukemia. Here, we developed and tested a novel series of compounds which revealed dual inhibitory activities against class III RTK and SFK, and tested them in vitro against FLT3- and PDGFRα-mutated leukemic cells and in vivo against FLT3-ITD-positive AML. First, we tested kinase selectivity of the novel compounds. Kinase-inhibitory properties were screened at single concentration of 10 nM in biochemical phosphorylation assays against 300 kinases. The compounds revealed strong and specific inhibitory activity especially against class III RTK and SFK. Then, we have used multiple cell lines harboring various oncogenic kinases to test in vitro growth inhibition potential of the compounds. The most potent newly synthesized inhibitor, designated 3922, showed EC50 values at low nanomolar concentrations against FLT3-ITD-positive cell line MV4-11 and FIP1L1-PDGFRα-positive EOL-1 cells. We also used primary cells derived from mouse bone marrow bearing inducible fusion oncogene MLL-ENL-ER (MEER) adapted to growth in cell culture (Takacova et al, 2012, Cancer Cell 21:517). Prior to drug testing, the MEER cells were grown in cell culture media to induce cytokine addiction either to stem cell factor (SCF) or to ligand of FLT3 (FLT3L). The efficacy of 3922 was 5 times more potent against FLT3L-addicted MEER cells than against SCF-addicted cells suggesting that FLT3 is the main target of 3922. We then compared the effect of 3922 on inhibition of FLT3 phosphorylation (pFLT3-Tyr589/591) with quizartinib (Zarrinkar et al, 2009, Blood 114:2984). Both compounds showed to be very efficient inhibitors of FLT3 phosphorylation at nanomolar concentrations, however, 3922 inhibitory effect had longer durability after drug withdrawal when compared with quizartinib. Finally, we determined the activity of 3922 in vivo. A single-dose of 10 mg/kg of 3922 or quizartinib was administered to the mice with subcutaneously implanted MV4-11 xenograft. Quantitation of pFLT3 revealed that the RTK was inhibited by 95% even after 2 hours administration of 3922 and this inhibition sustained 24 hours, in contrast to elevated pFLT3 24 hours after quizartinib administration (Zarrinkar et al, 2009; Gunawardane et al, 2013, Mol Cancer Ther 12:438). After 2 hours, the pERK1/2 levels were reduced by both inhibitors, however, returned to phosphorylation levels comparable to vehicle treated control in 24 hours after administration. The inhibitory effect was more pronounced on phosphorylation of STAT5. Inhibitor 3922 reduced the pSTAT5 level by more than 95% after 24 hours, slightly more effectively than quizartinib. Induction of apoptosis was assessed by PARP cleavage. Cleaved PARP was significantly elevated by 3922 even after 2 hours of treatment, with a pattern similar to the PARP cleavage induced by quizartinib (Gunawardane et al, 2013). In conclusion, we have developed a novel highly potent tyrosine kinase inhibitor effective against AML in vitro and in vivo. Acknowledgment: Supported by NV15-28951A from Ministry of Health, Czech Republic. Disclosures No relevant conflicts of interest to declare.
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Bindra, Ranjit, Parker L. Sulkowski, Christopher D. Corso, Peter Glazer, and Brian M. Shuch. "Induction of a BRCAness state by oncometabolites and exploitation by PARP inhibitors." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 11586. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.11586.
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11586 Background: 2-Hydroxyglutarate (2HG) exists as two enantiomers, R-2HG and S-2HG, and both are implicated in tumor progression via their inhibitory effects on α-ketoglutarate (aKG)-dependent dioxygenases. The former is an oncometabolite induced by isocitrate dehydrogenase-1 and -2 (IDH1/2) mutations, while the latter is produced under pathologic processes such as hypoxia. Recurring IDH1/2 mutations were first identified in gliomas and acute myeloid leukemia (AML). Methods: Our group recently reported that IDH1/2 mutations induce a homologous recombination (HR) defect which renders tumor cells exquisitely sensitive to Poly (ADP-Ribose) polymerase (PARP) inhibitors. Remarkably, this “BRCAness” phenotype can be completely reversed by mutant IDH1/2 inhibitors, and it can be entirely recapitulated by treatment with either 2HG enantiomer in cells with intact IDH1/2. We performed a comprehensive series of studies that directly implicate two aKG-dependent dioxygenases, KDM4A and KDM4B, as key mediators of the observed phenotype. Results: Using the methodology and preliminary data obtained above as a basis for further inquiry, here we have extended these findings to several related gene mutations, which similarly induce profound synthetic lethality with PARP inhibitors in these tumors, and our data suggest a similar mechanism of action via which HR is suppressed. Finally, we provide additional evidence that suppression of 2HG production with small molecule inhibitors of mutant IDH1/2 function does not lead to any detectable decreases in cell growth or viability in several unique models. Conclusions: Small molecule inhibition of oncogenic kinases is a pillar of precision medicine in modern oncology, and this approach has been extrapolated to treat IDH1/2-mutant and other oncometabolite-producing cancers with inhibitors blocking the neomorphic activity of the mutant proteins. The findings present here directly challenge this therapeutic strategy, and they instead provide a novel approach to treat these tumors with DNA repair inhibitors. Based on these findings, we are planning a multi-center Phase II trial testing the efficacy of olaparib for the treatment of recurrent IDH1/2-mutant tumors later this year.
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Andreone, Teresa, Gordon P. Meares, Katherine J. Hughes, Polly A. Hansen, and John A. Corbett. "Cytokine-mediated β-cell damage in PARP-1-deficient islets." American Journal of Physiology-Endocrinology and Metabolism 303, no. 2 (July 15, 2012): E172—E179. http://dx.doi.org/10.1152/ajpendo.00055.2012.
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Poly(ADP)-ribose polymerase (PARP) is an abundant nuclear protein that is activated by DNA damage; once active, it modifies nuclear proteins through attachment of poly(ADP)-ribose units derived from β-nicotinamide adenine dinucleotide (NAD+). In mice, the deletion of PARP-1 attenuates tissue injury in a number of animal models of human disease, including streptozotocin-induced diabetes. Also, inflammatory cell signaling and inflammatory gene expression are attenuated in macrophages isolated from endotoxin-treated PARP-1-deficient mice. In this study, the effects of PARP-1 deletion on cytokine-mediated β-cell damage and macrophage activation were evaluated. There are no defects in inflammatory mediator signaling or inflammatory gene expression in macrophages and islets isolated from PARP-1-deficient mice. While PARP-1 deficiency protects islets against cytokine-induced islet cell death as measured by biochemical assays of membrane polarization, the genetic absence of PARP-1 does not effect cytokine-induced inhibition of insulin secretion or cytokine-induced DNA damage in islets. While PARP-1 deficiency appears to provide protection from cell death, it fails to provide protection against the inhibitory actions of cytokines on insulin secretion or the damaging actions on islet DNA integrity.
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Todorovic, Lidija, Gorana Stamenkovic, Biljana Vucetic-Tadic, Kazuo Umezawa, Ana Bozovic, Shunichi Yamashita, and Boban Stanojevic. "Synergistic effect of 17-allylamino-17-demethoxygeldanamycin with dehydroxymethylepoxyquinomicin on the human anaplastic thyroid carcinoma cell line KTC2." Archives of Biological Sciences, no. 00 (2020): 55. http://dx.doi.org/10.2298/abs201010055t.
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The use of targeted inhibitors has shown promise as an effective approach in cancer therapy. However, targeted therapies based only on one drug, such as 17-allylamino-17-demethoxygeldanamycin (17-AAG), have limited success, partly because cancer cells engage alternate pathways for survival and proliferation. In the present study, we evaluated whether dehydroxymethylepoxyquinomicin (DHMEQ), a nuclear factor ?B (NF-?B) inhibitor, can enhance the antitumor activities of 17-AAG, a 90 kDa heat shock protein (Hsp90) inhibitor, in the anaplastic thyroid cancer cell line KTC2. We examined the effect of combined drug treatment vs single drug treatment on cell survival. Isobologram analysis was performed to distinguish the additive vs synergistic effects of the drug combination. Western blotting was performed to investigate apoptosis markers: caspase 3, poly(ADP-ribose) polymerase-one (PARP-1), Bcell lymphoma-extra large (Bcl-XL), X-linked inhibitor of apoptosis (XIAP) and cellular inhibitor of apoptosis 2 (cIAP-2). Compared to monotherapy, the combined treatment enhanced growth-inhibitory effects in a synergistic manner and strongly potentiated apoptosis. These results demonstrate the first in vitro evidence that a combination of Hsp90 and NF-?B inhibitors is a more effective modality for inhibiting cell proliferation and survival in anaplastic thyroid carcinoma cells than either agent alone, warranting further investigations.
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Oğuz and Adan. "Resveratrol Targets Sphingolipid Metabolism and BCR-ABL in Ph+ Acute Lymphoblastic Leukemia to Induce Growth Inhibiton." Proceedings 40, no. 1 (December 25, 2019): 3. http://dx.doi.org/10.3390/proceedings2019040003.
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The mechanisms underlying the growth inhibitory effect of resveratrol on Ph+ ALL cells were investigated with regard to targeting of ceramide metabolism and changes in BCR-ABL expression. Growth inhibition and apoptotic effects of resveratrol, SK inhibitor (SKI II), GCS inhibitor (PDMP), SPT inhibitor (myriocin) and resveratrol-inhibitor combinations were investigated by MTT cell proliferation test, Annexin-V/PI staining, caspase-3, PARP expression and cytochrome c release by western blot, while cytostatic effect was investigated by flow cytometry. The effect of resveratrol, inhibitors and combinations on BCR-ABL protein expression was determined by western blot. In addition, the effect of resveratrol on SPT, SK-1/2, GCS protein expression was determined by western blot. In both cell lines resveratrol and resveratrol with SKI II and PDMP suppressed cell growth, triggered apoptosis and arrested the cell cycle at S phase. The combination of resveratrol with myriocin showed cell-specific effects on cell growth and cell cycle, but triggered apoptosis in both cells. In both cell types, resveratrol and combinations generally increased cytochrome-c release, caspase-3 cleavage and PARP cleavage, but cell-specific changes were also detected. Resveratrol decreased the expression of SK-1/SK2 and GCS in both cells and increased SPT expression. While resveratrol, SKI II and PDMP decreased BCR-ABL expression and myriocin increased BCR-ABL expression. Resveratrol together with SKI II and PDMP caused increases in BCR-ABL, while combination with myriocin reduced BCR-ABL expression. As a result, resveratrol suppressed cell growth and triggered apoptosis in Ph+ ALL by regulating ceramide metabolism and BCR-ABL expression.
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Murai, Junko, Christophe Marchand, Sampada A. Shahane, Hongmao Sun, Ruili Huang, Yiping Zhang, Adel Chergui, et al. "Identification of novel PARP inhibitors using a cell-based TDP1 inhibitory assay in a quantitative high-throughput screening platform." DNA Repair 21 (September 2014): 177–82. http://dx.doi.org/10.1016/j.dnarep.2014.03.006.
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Xu, Fangfang, Honggang Guo, Mingyue Shi, Siwei Liu, Min Wei, Kai Sun, and Yuqing Chen. "This Is a Title in Title Case: A Combination of Low-Dose Decitabine and Chidamide Resulted in Synergistic Effects on the Proliferation and Apoptosis of Human Myeloid Leukemia Cell Lines." Blood 134, Supplement_1 (November 13, 2019): 5160. http://dx.doi.org/10.1182/blood-2019-128663.
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Introduction: Myeloid leukemia is a malignant disease caused by both genetic and epigenetic changes. Aberrant DNA methylation and histone modifications are prevalent in cancers including leukemia and the process of epigenetic modifications is reversible, which makes them potential treatment targets using specific inhibitors. In this study, we sought to determine the antileukemic effects of low-dose decitabine (one of the most widely used DNA methyltransferase inhibitor) combined with chidamide (a novel orally active histone deacetylase inhibitor) on myeloid leukemia cells by detecting cell proliferation, cell cycle distribution and cell apoptosis to provide a promising regimen for clinical application. Methods: We conducted CCK-8 assay to determine the effect of low-dose decitabine combinated with chidamide on cell viability, cell cycle distribution analysis by use of flow cytometry accompanied with RT-qPCR and western blotting analysis to reveal its inhibitory mechanism of cell growth, and cell apoptotic analysis also by use of flow cytometry accompanied with RT-qPCR, western blotting analysis, intracellular ROS production and mitochondrial transmembrane potential assay to determine the apoptotic mechanism of combination of low-dose decitabine and chidamide in K562 and THP-1 cells. Result: Low-dose decitabine and chidamide alone played an inhibitory role in the proliferation of K562 and THP-1 cells in a dose- and time-dependent manner, and the combination of the two enhanced this effect, accompanied by induction of p21 expression and cell cycle arrest at G0/G1 phase. Chidamide instead of decitabine had pronounced effects on the histone H3 acetylation levels of leukemia cells. Meanwhile, combination of the two significantly induced cell apoptosis via mitochondrial transmembrane potential loss, resulting in upregulation of the cell apoptosis-related gene Bax and the protein cleaved PARP-1 and downregulation of antiapoptosis gene Bcl-2, and proteins, including pro-caspase 9, pro-caspase 3 and PARP-1. Conclusion: Our results provided evidence for the antileukemia effects of low-dose DNA methyltransferase inhibitor decitabine combinated with histone deacetylase inhibitor chidamide in preclinical myeloid leukemia models and suggested that combination of the two showed therapeutic potential for myeloid leukemia treatment. Disclosures No relevant conflicts of interest to declare.
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Sambucci, M., F. Laudisi, F. Novelli, E. Bennici, M. M. Rosado, and C. Pioli. "Effects of PARP-1 Deficiency on Th1 and Th2 Cell Differentiation." Scientific World Journal 2013 (2013): 1–8. http://dx.doi.org/10.1155/2013/375024.
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T cell differentiation to effector Th cells such as Th1 and Th2 requires the integration of multiple synergic and antagonist signals. Poly(ADP-ribosy)lation is a posttranslational modification of proteins catalyzed by Poly(ADP-ribose) polymerases (PARPs). Recently, many reports showed that PARP-1, the prototypical member of the PARP family, plays a role in immune/inflammatory responses. Consistently, its enzymatic inhibition confers protection in several models of immune-mediated diseases, mainly through an inhibitory effect on NF-κB (and NFAT) activation. PARP-1 regulates cell functions in many types of immune cells, including dendritic cells, macrophages, and T and B lymphocytes. Our results show that PARP-1KO cells displayed a reduced ability to differentiate in Th2 cells. Under both nonskewing and Th2-polarizing conditions, naïve CD4 cells from PARP-1KO mice generated a reduced frequency of IL-4+cells, produced less IL-5, and expressed GATA-3 at lower levels compared with cells from wild type mice. Conversely, PARP-1 deficiency did not substantially affect differentiation to Th1 cells. Indeed, the frequency of IFN-γ+cells as well as IFN-γproduction, in nonskewing and Th1-polarizing conditions, was not affected by PARP-1 gene ablation. These findings demonstrate that PARP-1 plays a relevant role in Th2 cell differentiation and it might be a target to be exploited for the modulation of Th2-dependent immune-mediated diseases.
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Fukuda, Makoto, and Richard Longnecker. "Latent Membrane Protein 2A Inhibits Transforming Growth Factor-β1-Induced Apoptosis through the Phosphatidylinositol 3-Kinase/Akt Pathway." Journal of Virology 78, no. 4 (February 15, 2004): 1697–705. http://dx.doi.org/10.1128/jvi.78.4.1697-1705.2004.
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ABSTRACT Latent membrane protein 2A (LMP2A) blocks B-cell receptor signal transduction in vitro by binding the Syk and Lyn protein tyrosine kinases. As well as blocking B-cell signal transduction, LMP2A has been shown to activate the phosphatidylinositol 3-kinase (PI3-K)/Akt pathway, which acts as a survival signal in both B cells and epithelial cells. Transforming growth factor β1 (TGF-β1) is a multifunctional cytokine that plays important roles in regulating cell growth and differentiation in many biological systems. The loss of the growth-inhibitory response to the TGF-β1 signal is found in many cancers and is widely thought to promote tumor development. In this study, we found that LMP2A induced the phosphorylation of Akt (serine 473) in Burkitt's lymphoma cell line Ramos and in gastric carcinoma cell line HSC-39 and partially enhanced cell viability following TGF-β1 treatment. In addition, LMP2A partially inhibited TGF-β1-induced DNA fragmentation and cleavage of poly(ADP-ribose) polymerase (PARP). In the presence of LY294002, an inhibitor of PI3-K, the LMP2A-mediated inhibitory effects on TGF-β1-induced DNA fragmentation and cleavage of PARP were alleviated. Furthermore, LMP2A did not alter the levels of expression of type I and type II TGF-β1 receptors. Taken together, these results suggest that LMP2A may inhibit TGF-β1-mediated apoptosis through activation of the PI3-K/Akt pathway.
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Williams, Tracy A., Andrea Verhovez, Alberto Milan, Franco Veglio, and Paolo Mulatero. "Protective Effect of Spironolactone on Endothelial Cell Apoptosis." Endocrinology 147, no. 5 (May 1, 2006): 2496–505. http://dx.doi.org/10.1210/en.2005-1318.
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Human umbilical vein endothelial cells (HUVECs) undergo apoptosis in response to serum deprivation. We show that the nonspecific mineralocorticoid receptor antagonist, spironolactone, protects from caspase-3 activation induced by serum deprivation in contrast to the selective mineralocorticoid receptor antagonist, eplerenone, that is nonprotective. We also demonstrate that progesterone, hydrocortisone, and dexamethasone all protect HUVECs from serum-deprivation-induced caspase-3 activation, whereas aldosterone and dihydrotestosterone have no effect. Spironolactone has been demonstrated to display agonist activity only to the progesterone receptor (PR), and we additionally show that spironolactone and progesterone, but not eplerenone, inhibit mitochondrial cytochrome c release and cleavage of nuclear poly (ADP-ribose) polymerase (PARP) and increase cell viability. Additionally, the PR antagonist mifepristone (RU486) partially blocked the inhibitory effect of both spironolactone and progesterone on caspase-3 activation, cytochrome c release, and nuclear PARP cleavage. Nitric oxide (NO) protects HUVECs from apoptosis in response to various stimuli including serum-deprivation; however, the NO synthase inhibitor N-monomethyl-l-arginine, did not abolish inhibition of caspase-3 activation or PARP cleavage by spironolactone. Thus, we demonstrate that spironolactone protects HUVECs from serum-deprivation-induced apoptosis by inhibition of caspase-3 activity, cytochrome c release and PARP cleavage by a NO-independent mechanism; further, this effect is likely mediated by the agonist properties of spironolactone toward the PR.
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Nilov, D. K., V. I. Tararov, A. V. Kulikov, A. L. Zakharenko, I. V. Gushchina, S. N. Mikhailov, O. I. Lavrik, and V. K. Švedas. "Inhibition of Poly(ADP-Ribose) Polymerase by Nucleic Acid Metabolite 7-Methylguanine." Acta Naturae 8, no. 2 (June 15, 2016): 108–15. http://dx.doi.org/10.32607/20758251-2016-8-2-108-115.
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The ability of 7-methylguanine, a nucleic acid metabolite, to inhibit poly (ADP-ribose) polymerase-1 (PARP-1) and poly(ADP-ribose)polymerase-2 (PARP-2) has been identified in silico and studied experimentally.The amino group at position 2 and the methyl group at position 7 were shown to be important substituents for the efficient binding of purine derivatives to PARPs. The activity of both tested enzymes, PARP-1 and PARP-2, was suppressed by 7-methylguanine with IC50 values of 150 and 50 M, respectively. At the PARP inhibitory concentration, 7-methylguanine itself was not cytotoxic, but it was able to accelerate apoptotic death of BRCA1-deficient breast cancer cells induced by cisplatin and doxorubicin, the widely used DNA-damaging chemotherapeutic agents. 7-Methylguanine possesses attractive predictable pharmacokinetics and an adverse-effect profile and may be considered as a new additive to chemotherapeutic treatment.
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Zhu, Hongge, Tianhai Wang, Zhou Xin, Yiyi Zhan, Guoming Gu, Xiaoqin Li, Xiuli Wang, Shune Yang, and Chunling Liu. "An oral second-generation proteasome inhibitor oprozomib significantly inhibits lung cancer in a p53 independent manner in vitro." Acta Biochimica et Biophysica Sinica 51, no. 10 (September 6, 2019): 1034–40. http://dx.doi.org/10.1093/abbs/gmz093.
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Abstract The destruction of proteins via the ubiquitin–proteasome system is a multi-step, complex process involving polyubiquitination of substrate proteins, followed by proteolytic degradation by the macromolecular 26S proteasome complex. Inhibitors of the proteasome promote the accumulation of proteins that are deleterious to cell survival and are promising anticancer agents. Oprozomib (OPZ), an oral second-generation proteasome inhibitor, has been shown to inhibit the growth of several cancers in preclinical and clinical trials, including multiple myeloma and head and neck cancers, but its effects on lung cancer has not yet been determined. In this study, we evaluated the inhibitory effects of OPZ on lung cancer cell lines in vitro. The results showed that OPZ significantly suppressed cell proliferation and strongly induced apoptosis in both tested lung cancer cells independent of p53 expression. OPZ was able to cause obvious caspase 3 and PARP cleavages and stabilize p53 and its transcriptional targets p21, PUMA, and Noxa. Moreover, OPZ was capable of sensitizing lung cancer cells to the conventional chemotherapeutic drug cisplatin. Our study provides preclinical data and sheds light on the potential applications of proteasome inhibitor OPZ in lung cancer treatment.
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Lowery, Maeve A., Fabio Vanoli, Kenneth H. Yu, Maria Jasin, Eileen Mary O'Reilly, and Mary Ellen Moynahan. "Inhibition of poly (ADP-ribose) polymerase-1 (PARP-1) to increase radiosensitivity of human pancreatic cancer (PAC) cell lines proficient in homology-directed repair (HDR)." Journal of Clinical Oncology 30, no. 4_suppl (February 1, 2012): 204. http://dx.doi.org/10.1200/jco.2012.30.4_suppl.204.
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204 Background: Radiation-induced single strand DNA breaks (SSBs) are primarily repaired by base excision repair, of which PARP1 is a key component. Unrepaired SSBs may cause collapse of stalled replication forks during DNA replication generating DNA double-strand breaks (DSBs). PARP inhibition has been shown to potentiate the effect of radiotherapy (RT) in a variety of human cancers in vitro and in vivo. We investigated the ability of the PARP inhibitor olaparib to radiosensitize BRCA1/2 wild-type human PAC cell lines and quantified repair capability of an induced DSB by HDR using the I-SceI-induced DSB DR-GFP assay. Methods: MiaPaCa -2 and ASPC-1 human PAC cells lines were exposed to RT administered in a single fraction by 157-gammacell irradiator at doses of 2, 4, 6 and 8 Gy in the presence or absence of olaparib at a dose of 500nM (4 hours pre and 20 hours post RT). Plates were incubated at 37C for 10-14 days and stained with Giemsa. Clonogenic survival assays following olaparib continuous exposure at concentrations up to 10 µM for 10-14 days were also performed. HDR of an induced DNA DSB was assessed in ASPC1 and MiaPaCa cell lines by co-transfection with an I-SceI expression vector and the DR-GFP reporter plasmid(Pierce et al., 1999), and in BRCA2 deficient CAPAN-1 cells harboring a stably integrated chromosomal DR-GFP gene (Moynahan et al. 2001). Results: Linear quadratic models were fitted to the data sets to generate survival curves. The half maximal inhibitory concentration (IC 50) of RT was 2Gy for both cell lines. The sensitivity enhancement ratio (SER) at 25% survival was 1.44 and 1.53 for MiaPaCa-2 and ASPC-1 cell lines respectively. Both cell lines were resistant to treatment with single agent olaparib to dose of 10µM and were proficient in HDR of DNA DSBs when compared to the BRCA2-deficient Capan-1 cell line. Conclusions: Inhibition of PARP increases radiosensitivity in human PAC cell lines proficient in HDR of DNA DSBs and resistant to treatment with single agent PARP inhibitor. Therapeutic strategies incorporating PARP inhibition and RT offer potential to improve clinical outcomes for patients presenting with localized sporadic and BRCA mutated PAC.
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Alqahtani, Shaherah, Kelly Welton, Jeffrey Gius, Suad Elmegerhi, and Takamitsu Kato. "The Effect of Green and Black Tea Polyphenols on BRCA2 Deficient Chinese Hamster Cells by Synthetic Lethality through PARP Inhibition." International Journal of Molecular Sciences 20, no. 6 (March 14, 2019): 1274. http://dx.doi.org/10.3390/ijms20061274.
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Tea polyphenols are known antioxidants presenting health benefits due to their observed cellular activities. In this study, two tea polyphenols, epigallocatechin gallate, which is common in green tea, and theaflavin, which is common in black tea, were investigated for their PARP inhibitory activity and selective cytotoxicity to BRCA2 mutated cells. The observed cytotoxicity of these polyphenols to BRCA2 deficient cells is believed to be a result of PARP inhibition induced synthetic lethality. Chinese hamster V79 cells and their BRCA2 deficient mutant V-C8, and V-C8 with gene complemented cells were tested against epigallocatechin gallate and theaflavin. In addition, Chinese hamster ovary (CHO) wild-type cells and rad51D mutant 51D1 cells were used to further investigate the synthetic lethality of these molecules. The suspected PARP inhibitory activity of epigallocatechin and theaflavin was confirmed through in vitro and in vivo experiments. Epigallocatechin gallate showed a two-fold increase of cytotoxicity to V-C8 cells compared to V79 and gene complimented cells. Compared to CHO wild type cells, 51D1 cells also showed elevated cytotoxicity following treatment with epigallocatechin gallate. Theaflavin, however, showed a similar increase of cytotoxicity to VC8 compared to V79 and gene corrected cells, but did not show elevation of cytotoxicity towards rad51D mutant cells compared to CHO cells. Elevation of sister chromatid exchange formation was observed in both tea polyphenol treatments. Polyphenol treatment induced more micronuclei formation in BRCA2 deficient cells and rad51D deficient cells when compared against the respective wild type cells. In conclusion, tea polyphenols, epigallocatechin gallate, and theaflavin may present selective cytotoxicity to BRCA2 deficient cells through synthetic lethality induced by PARP inhibition.
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Lee, Jangsoon, Huey Liu, Troy Pearson, Toshiaki Iwase, Jon Fuson, Alshad S. Lalani, Lisa D. Eli, et al. "PI3K and MAPK Pathways as Targets for Combination with the Pan-HER Irreversible Inhibitor Neratinib in HER2-Positive Breast Cancer and TNBC by Kinome RNAi Screening." Biomedicines 9, no. 7 (June 28, 2021): 740. http://dx.doi.org/10.3390/biomedicines9070740.
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Human epidermal growth factor receptor (EGFR) 2 (HER2) is overexpressed/amplified in about 25% of all breast cancers, and EGFR is overexpressed in up to 76% and amplified in up to 24% of triple-negative breast cancers (TNBC). Here, we aimed to identify inhibitors that may enhance the anti-tumor activity of neratinib for HER2+ breast cancer and TNBC. By conducting a non-biased high-throughput RNA interference screening, we identified PI3K/AKT/mTOR and MAPK as two potential inhibitory synergistic canonical pathways. We confirmed that everolimus (mTOR inhibitor) and trametinib (MEK inhibitor) enhances combinatorial anti-proliferative effects with neratinib under anchorage-independent growth conditions (p < 0.05). Compared to single agent neratinib, the combination therapies significantly enhanced tumor growth inhibition in both SUM190 HER2+ breast cancer (neratinib plus everolimus, 77%; neratinib plus trametinib, 77%; p < 0.0001) and SUM149 TNBC (neratinib plus everolimus, 71%; neratinib plus trametinib, 81%; p < 0.0001) xenograft models. Compared to single-agent neratinib, everolimus, or trametinib, both everolimus plus neratinib and trametinib plus neratinib significantly suppressed proliferation marker Ki67 and enhanced antitumor efficacy by activating the apoptosis pathway shown by increased Bim and cleaved-PARP expression. Taken together, our data justify new neratinib-based combinations for both HER2+ breast cancer and TNBC.
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Ghaderi, Amineh, Amir Hossein Daneshmanesh, Ali Moshfegh, Parviz Kokhaei, Jan Vågberg, Johan Schultz, Thomas Olin, et al. "ROR1 is Expressed in Diffuse Large B-Cell Lymphoma (DLBCL) and a Small Molecule Inhibitor of ROR1 (KAN0441571C) Induced Apoptosis of Lymphoma Cells." Biomedicines 8, no. 6 (June 23, 2020): 170. http://dx.doi.org/10.3390/biomedicines8060170.
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The receptor tyrosine kinase ROR1 is absent in most normal adult tissues, but overexpressed in several malignancies. In this study, we explored clinical and functional inhibitory aspects of ROR1 in diffuse large B-cell lymphoma (DLBCL). ROR1 expression in tumor cells was more often observed in primary refractory DLBCL, Richter’s syndrome and transformed follicular lymphoma than in relapsed and non-relapsed DLBCL patients (p < 0.001). A survival effect of ROR1 expression was preliminarily observed in relapsed/refractory patients independent of gender and stage but not of age, cell of origin and international prognostic index. A second generation small molecule ROR1 inhibitor (KAN0441571C) induced apoptosis of ROR1+ DLBCL cell lines, similar to venetoclax (BCL-2 inhibitor) but superior to ibrutinib (BTK inhibitor). The combination of KAN0441571C and venetoclax at EC50 concentrations induced almost complete killing of DLBCL cell lines. Apoptosis was accompanied by the downregulation of BCL-2 and MCL-1 and confirmed by the cleavage of PARP and caspases 3, 8, 9. PI3Kδ/AKT/mTOR (non-canonical Wnt pathway) as well as β-catenin and CK1δ (canonical pathway) were inactivated. In zebra fishes transplanted with a ROR1+ DLBCL cell line, KAN0441571C induced a significant tumor reduction. New drugs with mechanisms of action other than those available for DLBCL are warranted. ROR1 inhibitors might represent a novel promising approach.
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Mini, Enrico, Ida Landini, Laura Lucarini, Andrea Lapucci, Cristina Napoli, Gabriele Perrone, Renato Tassi, Emanuela Masini, Flavio Moroni, and Stefania Nobili. "The Inhibitory Effects of HYDAMTIQ, a Novel PARP Inhibitor, on Growth in Human Tumor Cell Lines With Defective DNA Damage Response Pathways." Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics 25, no. 9 (November 2, 2017): 1441–51. http://dx.doi.org/10.3727/096504017x14926854178616.
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Nieborowska-Skorska, Margaret, Artur Slupianek, Grazyna Hoser, Elisabeth Bolton-Gillespie, Alexei Tulin, Sabine Cerny-Reiterer, Peter Valent, Markus Muschen, Stephen M. Sykes, and Tomasz Skorski. "Oncogene-Induced DNA Repair Defects Promote PARP1-Mediated “Dual Synthetic Lethality” To Eradicate Quiescent and Proliferating Leukemia Stem and Progenitor Cells." Blood 122, no. 21 (November 15, 2013): 810. http://dx.doi.org/10.1182/blood.v122.21.810.810.
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Abstract Leukemia stem cells (LSCs), including quiescent cells, are disease initiating and therapy-refractory cells. Therefore, even if a treatment clears a disease burden consisting mostly of leukemia progenitor cells (LPCs), it usually fails to eradicate LSCs and residual LPCs which developed therapy-resistance. Leukemia cells expressing BCR-ABL1 (CML, Ph+ALL), FLT3(ITD) (AML), and AML1-ETO (AML) accumulate high numbers of spontaneous DNA double strand breaks (DSBs). Leukemia cells can survive numerous DSB, the most lethal DNA lesions, due to enhanced DSB repair activity by homologous recombination (HR; active in S and G2 cell cycle phase) and/or non-homologous end-joining (NHEJ; active in G0/G1 and S cell cycle phase). Altogether, leukemia cells may be “addicted” to DSB repair pathways. Normal cells usually employ BRCA1/2-RAD51 -mediated HRR and Ku70/86-DNA-PKcs -dependent NHEJ. BCR-ABL1 causes BRCA1 and DNA-PKcs deficiency, FLT3(ITD) inhibits Ku86, and AML1-ETO downregulates DNA-PKcs and RAD51. Accordingly, leukemia cells expressing these oncogenes are forced to employ alternative DSB repair pathways, such as PARP-LigIII –mediated NHEJ. Since NHEJ plays a predominant role in quiescent cells and also supports HR in proliferating cells, we postulated that targeting PARP should exert “dual synthetic lethality” to eradicate quiescent LSCs and proliferating LSCs/LPCs, with negligible effect on normal cells. We showed that PARP inhibitor olaparib, which is in clinical trials for the treatment of solid tumors displaying BRCA1/2 mutations, abrogated NHEJ activity in BCR-ABL1 cells. Olaparib reduced the number of imatinib-naïve and imatinib-treated Lin-CD34+CD38-CTVmax quiescent CML-CP LSCs in hypoxia and normoxia mimicking bone marrow niche and arterial peripheral blood, respectively. In addition, olaparib enhanced the anti-proliferative effect of imatinib in Lin-CD34+CML-CP and CML-AP LPCs. These effects are probably due to imatinib-mediated inhibition of BCR-ABL1 kinase-dependent anti-apoptotic activity and olaparib-induced increase of the number of lethal DSBs, resulting in accumulation of annexin V-positive apoptotic quiescent LSCs and hyper-activation of caspase-3 in imatinib+olaparib treated LPCs. Inhibition of PARP almost completely abrogates DSB repair in DNA-PKcs-deficient quiescent LSCs and diminishes resolution of ROS-induced stalled replication forks in BRCA1-deficient proliferating LSCs/LPCs. The combination of imatinib+olaparib did not affect normal quiescent hematopoietic stem cells, but exerted modest inhibitory effect on normal proliferating progenitors. Since olaparib does not discriminate neither between PARP family members nor other enzymatic pathways involving NAD+, its long-term application may generate side-effects. Our genetic studies involving Parp1-/- mice and PARP1(E988K) catalytic-deficient mutant identified PARP1 as major player in NHEJ in BCR-ABL1 cells. Using high throughput screening we identified 5F2, a small molecule which abrogated histone 4-dependent PARP1 activation and exerted synthetic lethality in BRCA1-deficient, but not BRCA1-proficient carcinoma cells. 5F2, similarly to olaparib, reduced the number of imatinib-naïve and imatinib-treated Lin-CD34+CD38-CTVmax quiescent LSCs and inhibited colony formation by Lin-CD34+LPCs. However 5F2, in contrast to olaparib, did not affect normal cells. In addition, olaparib and/or 5F2 reduced the number of imatinib-naïve and imatinib-treated Ph+ALL cells harvested from patients at diagnosis. Moreover, PARP1 inhibitors exerted anti-leukemia effect against ponatinib-naïve and ponatinib-treated Ph+ALL cells carrying BCR-ABL1 T315I mutation, and against lestaurtinib/quizartinib-naïve and lestaurtinib/quizartinib-treated FLT3(ITD)-positive AML cells. PARP1 inhibitors also abrogated the growth of leukemia cells expressing AML1-ETO (AML), but not of these expressing PML-RAR (APL) or overexpressing HOXA9+MEIS1 (AML). In conclusion, targeting PARP1 resulted in the induction of “dual synthetic lethality” and eradication of quiescent and proliferating CML cells displaying specific defects in DSB repair pathways. Similar effect is induced in other leukemias carrying specific, oncogene-induced DSB repair deficiencies. PARP1 inhibitors are currently tested in vivo using primary leukemia xenografts. Disclosures: Valent: Novartis: Consultancy, Honoraria, Research Funding.
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Vahedi, Nafiseh, Majid Mohammadhosseini, and Mehdi Nekoei. "QSAR Study of PARP Inhibitors by GA-MLR, GA-SVM and GA-ANN Approaches." Current Analytical Chemistry 16, no. 8 (October 26, 2020): 1088–105. http://dx.doi.org/10.2174/1573411016999200518083359.
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Background: The poly(ADP-ribose) polymerases (PARP) is a nuclear enzyme superfamily present in eukaryotes. Methods: In the present report, some efficient linear and non-linear methods including multiple linear regression (MLR), support vector machine (SVM) and artificial neural networks (ANN) were successfully used to develop and establish quantitative structure-activity relationship (QSAR) models capable of predicting pEC50 values of tetrahydropyridopyridazinone derivatives as effective PARP inhibitors. Principal component analysis (PCA) was used to a rational division of the whole data set and selection of the training and test sets. A genetic algorithm (GA) variable selection method was employed to select the optimal subset of descriptors that have the most significant contributions to the overall inhibitory activity from the large pool of calculated descriptors. Results: The accuracy and predictability of the proposed models were further confirmed using crossvalidation, validation through an external test set and Y-randomization (chance correlations) approaches. Moreover, an exhaustive statistical comparison was performed on the outputs of the proposed models. The results revealed that non-linear modeling approaches, including SVM and ANN could provide much more prediction capabilities. Conclusion: Among the constructed models and in terms of root mean square error of predictions (RMSEP), cross-validation coefficients (Q2 LOO and Q2 LGO), as well as R2 and F-statistical value for the training set, the predictive power of the GA-SVM approach was better. However, compared with MLR and SVM, the statistical parameters for the test set were more proper using the GA-ANN model.
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Lv, Zhen-Chun, Fei Li, Lan Wang, Qin-Hua Zhao, Gong-Su Gang, Yue Wu, Yu-Qing Miao, and Ping Yuan. "Impact of Parthanatos on the Increased Risk of Onset and Mortality in Male Patients With Pulmonary Hypertension." American Journal of Men's Health 15, no. 3 (May 2021): 155798832110294. http://dx.doi.org/10.1177/15579883211029458.
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There have been no studies as to whether parthanatos, a poly (adenosine diphosphate-ribose) polymerase-1 (PARP-1)-dependent and apoptosis-inducing factor (AIF)-mediated caspase-independent programmed cell death, is present in pulmonary hypertension (PH). Basic studies have, however, been conducted on several of the key molecules in parthanatos, such as PARP-1, AIF, and macrophage migration inhibitory factor (MIF). For this study, we collected blood samples from 88 incident male patients with PH and 50 healthy controls at the Shanghai Pulmonary Hospital. We measured the key factors of parthanatos (PARP-1, PAR, AIF, and MIF) by enzyme-linked immunosorbent assay and performed a logistic regression, Cox proportional hazards analysis, and Kaplan–Meier test to assess the prognostic value of the key molecules in diagnosing and predicting survival. The patients who ultimately died had a significantly poorer clinical status during the study than those who survived. The PARP-1, PAR, AIF, and MIF levels were significantly higher in the patients than in the controls (all p < .0001), and the PARP-1, PAR, and AIF levels were higher in the nonsurvivors than in the survivors (all p < .0001). PARP-1 and AIF levels served as independent predictors of disease onset and mortality in these patients (all p < .005). Patients with PARP-1 levels <11.24 ng/mL or AIF levels <1.459 pg/mL had significantly better survival than those with higher PARP-1 or AIF levels ( p < .0001). Circulating levels of PARP-1 and AIF were independent predictors for PH onset and mortality, which indicated that parthanatos might be associated with the pathogenesis of PH.
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Nong, Liang, Linda Mathews, Mark B. Meads, William Dalton, and Kenneth H. Shain. "Rational Drug Design: Proteasome Inhibitor Mediated Down-Regulation of the FA/BRCA Pathway Is Synergistic with PARP Inhibition in Myeloma Cell Lines." Blood 118, no. 21 (November 18, 2011): 2922. http://dx.doi.org/10.1182/blood.v118.21.2922.2922.
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Abstract Abstract 2922 The development of new and biologically-based therapeutic regimens is critical for the successful control, if not cure, of multiple myeloma. Incorporation of the novel agents, including the proteasome inhibitor bortezomib, harbored large strides in disease modification. However, even with the success of bortezomib containing regimens, drug resistance and disease relapse remain inevitable. As such, it is critical that we use preclinical models to not only develop drugs, but also to consider strategies for co-development of novel drug combinations capitalizing on complementary biological activities. Our investigations in drug resistance recently revealed that increased homologous recombination (HR) potential, via over-expression of the FA/BRCA DNA repair pathway (FA/BRCA pathway), contributed to acquired melphalan-resistance in myeloma cell lines.(Yarde et al 2009) Drug resistance was causally linked to a novel transcriptional regulation of the FA/BRCA by NF-κB. Further examination demonstrated that bortezomib attenuated this component of the HR repair pathway and reversed melphalan resistance. To this end, we anticipated that bortezomib treatment may sensitize cells to inhibitors of complementary DNA repair pathways in a manner similar to the synthetic lethality elicited in by PARP1/2 inhibition in BRCA1 or FANCD1/ BRCA2 mutant cancers.(Farmer 2005, Bryant 2005) Consistent with this rationale, treatment of myeloma cells with bortezomib and the PARP inhibitor AZD2281/olaparib demonstrated synergism in specific myeloma cell lines. Pre-treatment of RPMI8226 myeloma cells with bortezomib for 6 hours greatly enhanced myeloma cell sensitivity to PARP inhibition with AZD2281/olaparib. The inhibitory concentration(IC)-50 was decreased by 17.7-fold (n=3; IC50 AZD2281 alone: 62.7 microM (39.0–84.0) and pretreated with bortezomib 3.54 microM (2.4–4.6)). Combination Index (CI) demonstrated a mean of 0.41 in 8226 and 0.43 in U266 myeloma cells, consistent with a synergistic relationship. Further analysis confirmed that synergism correlated with decreased expression of FANCD2 mRNA and protein by 6 hours. In contrast to sequential treatment, concomitant treatment with these agents did not elicit the synergistic phenotype. Interestingly, sequential treatment of NCIH929 myeloma cells did not demonstrate the same synergistic response (CI :0.89, slight synergism). Consistent with this, treatment of NCIH929 cells with bortezomib did not negatively regulate FANCD2 mRNA or protein expression, suggesting that FA/BRCA pathway can be differentially regulated in myeloma cells. To more specifically determine if FANCD2 was a key factor regulated by bortezomib, we targeted FANCD2 with siRNA. Pretreatment of myeloma cells with FANCD2 siRNA also sensitized cells to AZD2281/olaparib relative to siRNA control (IC50: 19.0 microM vs 35.0 microM n=4; p<0.05). These results show that bortezomib (or other proteosome inhibitors) and AZD2281/olaparib (or other PARP inhibitors) may represent an exciting new combination therapy for myeloma. We are currently examining the applicability of these studies to other proteosome inhibitors and the clinical relevance with ex vivo studies with myeloma patient samples. We believe that data presented here are innovative as they introduce a novel biological rationale, the abrogation complementary pathways in DNA damage repair, for the preclinical development of novel targeted drug combinations in myeloma. Further, we anticipate that although this study has focused on multiple myeloma, the results of the proposed research will be applicable to a wide range of hematologic and solid tumors. Disclosures: No relevant conflicts of interest to declare.
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SHARMA, R. D., S. BAG, N. R. TAWARI, M. S. DEGANI, K. GOSWAMI, and M. V. R. REDDY. "Exploration of 2, 4-diaminopyrimidine and 2, 4-diamino-s-triazine derivatives as potential antifilarial agents." Parasitology 140, no. 8 (April 3, 2013): 959–65. http://dx.doi.org/10.1017/s0031182013000309.
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SUMMARYIn view of the mandate from the World Health Organization (WHO) for developing novel drug candidates against human lymphatic filariasis, dihydrofolate reductase (DHFR) inhibitors are explored as potential antifilarial agents. The in vitro biological evaluation of an in-house library of 12 diverse antifolate compounds with 2,4-diaminopyrimidine and 2,4-diamino-s-triazine structural features against Brugia malayi is reported. To confirm the DHFR inhibitory potential of these compounds, reversal studies using folic acid and folinic acid were undertaken. Inhibition of DHFR can induce apoptosis; in this light, preliminary evidence of apoptosis by test compounds was detected using ethidium bromide–acridine orange staining and the poly(adenosine diphosphate-ribose) polymerase (PARP) inhibition assay. Among the evaluated compounds, 3 showed significant activity against both microfilariae and adult worms. The effects of 2 of these compounds were mostly reversed by folic acid, validating DHFR inhibitory activity. Partial reversal of the effect of 2 compounds by folinic acid and non-reversal of the effect of the third compound both by folic and folinic acids are discussed. This study opens new avenues for the discovery of lead molecules by exploiting the folate pathway against one of the major neglected tropical diseases, filariasis.
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Moertl, Simone, Sarah Payer, Rosemarie Kell, Klaudia Winkler, Natasa Anastasov, and Michael J. Atkinson. "Comparison of Radiosensitization by HDAC Inhibitors CUDC-101 and SAHA in Pancreatic Cancer Cells." International Journal of Molecular Sciences 20, no. 13 (July 2, 2019): 3259. http://dx.doi.org/10.3390/ijms20133259.
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Pancreatic cancer has a poor prognosis. New treatment options are urgently required to improve patient outcomes. One promising new class of anticancer drugs are synthetic histone deacetylase inhibitors (HDACi) which modulate chromatin structure and gene expression by blocking histone deacetylation. In this study, we aimed at comparing the in vitro capacities of the HDACi SAHA and CUDC-101 to increase radiosensitivity of human pancreatic tumor cell lines. Therefore, three pancreatic cancer cell lines (Su.86.86, MIA Paca-2, T3M-4) were treated with SAHA (1.5–5 µM) or CUDC-101 (0.25–3 µM) and after 24 h irradiated. Cell proliferation, clonogenic survival and apoptosis was determined. Additionally, cell lysates were investigated for the expression of apoptosis-related proteins. CUDC-101 and SAHA increased the radiation sensitivity of pancreatic tumor cell lines in a dose-dependent manner. This was evidenced by cell proliferation and clonogenic survival. Furthermore, enhanced radiation sensitivity after CUDC-101 or SAHA treatment was confirmed for Su.86.86 and T3M-4 cells in a 3-D microtissue approach. Increased amounts of subG1 cells and diminished full length PARP-1 suggest increased radiation-induced apoptosis after SAHA or CUDC-101 treatment. The comparison of both inhibitors in these assays manifested CUDC-101 as more potent radiosensitizer than SAHA. In line, western blot quantification of the apoptosis-inhibitory proteins XIAP and survivin showed a stronger down-regulation in response to CUDC-101 treatment than after SAHA application. These proteins may contribute to the synergy between HDAC inhibition and radiation response. In conclusion, these preclinical results suggest that treatment with the HDAC inhibitors CUDC-101 or SAHA can enhance radiation-induced cytotoxicity in human pancreatic cells. However, comparison of both inhibitors identified the multi target inhibitor CUDC-101 as more potent radiosensitizer than the HDAC inhibitor SAHA.
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Magyar, Klara, Laszlo Deres, Krisztian Eros, Kitti Bruszt, Laszlo Seress, Janos Hamar, Kalman Hideg, et al. "A quinazoline-derivative compound with PARP inhibitory effect suppresses hypertension-induced vascular alterations in spontaneously hypertensive rats." Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 1842, no. 7 (July 2014): 935–44. http://dx.doi.org/10.1016/j.bbadis.2014.03.008.
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Atiq, Mohammad Omar, Goutam Chakraborty, Subhiksha Nandakumar, Ying Zhang Mazzu, Konrad Hermann Stopsack, Lina E. Jehane, Yuki Yoshikawa, Nabeela Khan, Gwo-Shu Mary Lee, and Philip W. Kantoff. "Targeting checkpoint kinases in prostate cancer cells resistant to poly ADP-ribose polymerase inhibitors." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e16543-e16543. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e16543.
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e16543 Background: The identification of DNA damage response (DDR) gene abnormalities in various cancers has provided potential therapeutic targets including the poly ADP-ribose polymerase enzyme (PARP). PARP inhibitors are now approved for use in ovarian, breast, and prostate cancer (PC). Olaparib and rucaparib have been given Breakthrough Therapy designation by the FDA for use in patients with metastatic castration-resistant prostate cancer and germline BRCA1/2 or ATM mutations. However, drug resistance limits the efficacy of PARPi. Somatic reversion mutations of BRCA1/2 have been described as one potential mechanism of resistance to PARPi in patients with germline BRCA1/2 mutations. However, in PC, the BRCA2 gene is frequently deleted, in contrast to other cancers, where it is mutated. Thus, we hypothesize that resistance to PARPi in PC may involve alternative molecular mechanisms. Methods: We performed cell viability assays to determine the inhibitory growth (IG) concentrations of olaparib and talazoparib on human castration-resistant PC cell lines (PC-3 and LNCaP-Abl) that have heterozygous genomic deletions of BRCA2. Parental PC-3 cells were cultured in sublethal concentrations (IG 50% and IG 90%) of talazoparib-supplemented media for approximately 2 months to develop talazoparib-resistant cells. We then performed an analysis of phosphorylation status in untreated and treated parental PC-3 and talazoparib-resistant clones with a phosphokinase array. We confirmed this with Western blot. Results: Talazoparib-resistant PC-3 clones showed significantly enhanced cell growth compared to parental cells when cultured in media supplemented with the IG 90% concentration of talazoparib or olaparib. The phosphokinase array revealed a significant increase in the phosphorylation of CHEK2 in talazoparib-resistant clones compared to parental PC-3 cells. Interestingly, a similar increase was seen after 72 hours of treatment with talazoparib, indicating an early connection between PARP inhibition and CHEK2 phosphorylation in PC cells. Moreover, a pan-CHEK inhibitor, prexasertib, led to significant cell growth inhibition in talazoparib-resistant PC-3 clones and a significantly lower IG 50% concentration compared to parental PC-3 cells. Conclusions: We speculate that early activation of CHEK2 may be a primary mechanism of resistance to PARPi in PC cells with deletion of BRCA2. Furthermore, our preliminary data showed that CHEK inhibition can overcome PARPi resistance, indicating a potential for CHEK inhibitor-based therapy for PC patients.
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Tinhofer, Inge, Mariya Boyko-Fabian, Franziska Niehr, Ulrich Keilholz, and Volker Budach. "The PARP inhibitor olaparib (AZD2281) as potent radiosensitizer of head and neck cancer cells." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): e16018-e16018. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.e16018.
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e16018 Background: Current combined radiotherapy regimens for squamous cell carcinoma of the head and neck (SCCHN) are frequently not curative, necessitating novel therapeutic strategies. Inhibitors of poly(ADP-ribose) polymerases (PARPi), either alone or in combination with chemo- and radiotherapy have been shown to be highly active in tumor cells with intrinsic defects in DNA repair. Despite the frequent occurrence of genomic alterations in SCCHN cells also affecting their capacity of DNA repair the radiosensitizing potential of PARPi has not been addressed in detail so far. In this study, the efficacy of PARPi as radiosensitizer in SCCHN and possible mechanisms of cross-resistance between PARPi and cisplatin were evaluated. Methods: Usingthe clonogenic survival assay and a panel of 10 SCCHN cell lines the sensitivity of SCCHN cells to olaparib alone (0 to 500 nM) or in combination with irradiation (0 to 4 Gy) was determined. Survival fractions for given treatments were calculated on the basis of survival of untreated cells. In addition, the activity of cisplatin to inhibit clonogenic growth and its radiosensitizing potential was determined. From the dose-effect curves the IC50 values and the combinatory indices were calculated using the CalcuSyn Software. Results: In 9 of 10 cell lines, olaparib monotherapy showed significant inhibitory activity on clonogenic survival. Synergistic activity of olaparib in combination with irradiation was observed in all cell lines. No correlation between sensitivity of cells to olaparib and cisplatin (IC50 cisplatin vs IC50 olaparib: r2=0.042, p=.57; IC50 cisplatin vs CI [IR+olaparib]: r2=0.005, p=.95) was observed. Furthermore, the activity of olaparib was not dependent on the p53 genotype. Conclusions: The combination of PARPi with radiotherapy represents an active therapeutic regimen in SCCHN. The observed high activity of this combination even in cells with reduced sensitivity to cisplatin and p53 dysfunction suggests its clinical usefulness also in the group of patients with more aggressive disease and the second-line setting. Currently, detailed molecular characterization for identification of potential biomarker for tumor susceptibility to PARP inhibition is ongoing.
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Muñoz Acuña, Ulyana, Peter J. Blanco Carcache, Susan Matthew, and Esperanza J. Carcache de Blanco. "New acyclic bis phenylpropanoid and neolignans, from Myristica fragrans Houtt., exhibiting PARP-1 and NF-κB inhibitory effects." Food Chemistry 202 (July 2016): 269–75. http://dx.doi.org/10.1016/j.foodchem.2016.01.060.
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Fernández-Tomé, Samuel, Fei Xu, Yanhui Han, Blanca Hernández-Ledesma, and Hang Xiao. "Inhibitory Effects of Peptide Lunasin in Colorectal Cancer HCT-116 Cells and Their Tumorsphere-Derived Subpopulation." International Journal of Molecular Sciences 21, no. 2 (January 14, 2020): 537. http://dx.doi.org/10.3390/ijms21020537.
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The involvement of cancer stem-like cells (CSC) in the tumor pathogenesis has profound implications for cancer therapy and chemoprevention. Lunasin is a bioactive peptide from soybean and other vegetal sources with proven protective activities against cancer and other chronic diseases. The present study focused on the cytotoxic effect of peptide lunasin in colorectal cancer HCT-116 cells, both the bulk tumor and the CSC subpopulations. Lunasin inhibited the proliferation and the tumorsphere-forming capacity of HCT-116 cells. Flow cytometry results demonstrated that the inhibitory effects were related to apoptosis induction and cell cycle-arrest at G1 phase. Moreover, lunasin caused an increase in the sub-GO/G1 phase of bulk tumor cells, linked to the apoptotic events found. Immunoblotting analysis further showed that lunasin induced apoptosis through activation of caspase-3 and cleavage of PARP, and could modulate cell cycle progress through the cyclin-dependent kinase inhibitor p21. Together, these results provide new evidence on the chemopreventive activity of peptide lunasin on colorectal cancer by modulating both the parental and the tumorsphere-derived subsets of HCT-116 cells.
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Freysoldt, Bianca, Andrea Schnaiter, Luca Fischer, Michael O'Neill, Yvonne Zimmermann, Grit Hutter, Wolfgang Hiddemann, and Martin H. Dreyling. "Cotargeting of PIM, PI3K and Mtor in Mantle Cell Lymphoma (MCL)." Blood 126, no. 23 (December 3, 2015): 5120. http://dx.doi.org/10.1182/blood.v126.23.5120.5120.
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Abstract Introduction: Mantle cell lymphoma (MCL) comprises about 6% of all non-Hodgkin's lymphoma with a median survival of 3-5 years. Constitutional activation of the mTOR/AKT pathway has been identified in the majority of cases (Rudelius, Blood 2006). The pro-viral insertion in murine (PIM) lymphoma proteins are serine/threonine kinases which play a critical role in cell survival as well as proliferation and identifies a high risk patient cohort with MCL (Hsi, Leuk Lymphoma 2008). In this study we evaluated the efficiency and mode of action of a dual PIM/PI3K (IBL-202) and a triple PIM/PI3K/mTOR inhibitor (IBL-301) in MCL cell lines and primary cells. Methods: MCL cell lines (Granta 519, Jeko-1, Rec-1 and Mino), as well as primary MCL cells were exposed to the combined PIM-kinase/PI3K (IBL-202) and the PIM-kinase/PI3K/mTOR Inhibitor (IBL-301). Cell proliferation (trypan blue staining), cell apoptosis (Annexin V PE/7-AAD staining) and cell cycle (FACS) were investigated. Protein expression and phosphorylation status of different downstream proteins (Akt, GSK-3β, 4EBP1) as well as markers of apoptosis (PARP, Caspase 9) were analysed after 1h, 4h, 8h and 24h. Cell viability was assessed by CellTiter-Glo® assay after 48h. Results: Both inhibitors led to G1 arrest. At 500 nM, the triple inhibitor IBL-301 (19,8%) is in average slightly more efficacious than the dual-inhibitor IBL-202 (13,5%). Accordingly, IBL-301 had a much higher impact on cell proliferation than IBL-202 in all tested MCL cell lines (reduction by 48 - 93% vs 22 - 87%), possibly due to its mTOR inhibitory potential, although it may be also a more potent inhibitor of PIM and PI3K kinases. In addition, treatment with IBL-202 and IBL-301 induced cell apoptosis in Jeko-1, Rec-1 and Mino. Again, rate of apoptosis by IBL-301 was much higher (e.g. JEKO: 56% vs 13%) and could be achieved at lower concentrations in comparison to IBL-202. The differential impact on apoptosis could be confirmed based on PARP and Caspase 9 cleavage, which was higher after treatment with IBL-301 after 24h. In Jeko-1, Granta-519 and Mino both agents led to de-phosphorylation of Akt. Interestingly, this effect was more prominent in IBL-301 treated cell lines, supporting the mode of action via the PI3K-AKT pathway of both inhibitors. De-phosphorylation of GSK-3β was observed in all tested MCL cell lines with both inhibitors already during the first hour of exposure and was reversible thereafter. Primary MCL cells of 2 patients were treated with 62.5 nM IBL-202, 31.25 nM IBL-301 and single inhibitors of PIM (2.5 µM AZD1208), PI3K (1.25 µM idelalisib) and mTOR (5 nM temsirolimus). Viability after 48h was reduced by about 70% following IBL-301 exposure compared to 39% in IBL-202 treated samples. Both combined inhibitors were more potent than any of the single inhibitors. IBL-301 and IBL-202 decreased viability in a similar way as the combination of AZD1208, idelalisib +/- temsirolimus. Normal lymphocytes tolerated both inhibitors in various concentrations (62,5 - 500 nM). Conclusions: Triple inhibition of PIM kinases, PI3K and mTOR is very efficient in MCL cell lines as well as in primary MCL cells, exceeding dual inhibition of PIM kinases and PI3K. Thus, cotargeting PIM kinases, PI3K and mTOR may be a promising novel approach for clinical development in MCL. Disclosures O'Neill: Inflection Biosciences: Employment.
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Veldurthy, Aditya, Michaela Patz, Christian P. Pallasch, Clemens M. Wendtner, Michael Hallek, and Gunter F. Krause. "The Src-Abl Kinase Inhibitor Dasatinib (BMS-354825) Shows Anti-Proliferative and Anti-Apoptotic Effects in Chronic Lymphocytic Leukemia (CLL) Cells In Vitro." Blood 110, no. 11 (November 16, 2007): 3101. http://dx.doi.org/10.1182/blood.v110.11.3101.3101.
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Abstract Introduction: Dasatinib is an ATP competitive, dual-specific Src-Abl kinase inhibitor used for the treatment of imatinib-resistant Bcr-Abl-positive leukemias. Originally it was developed from the aminothiazole scaffold as an inhibitor of Src family kinases (SFKs). Since the aberrant expression and activity of the SFK Lyn seems to enhance the survival of CLL cells, dasatinib is currently tested in clinical studies for CLL. In order to explore the anti-leukemic potential of dasatinib we tested its effects on freshly isolated CLL cells and on CLL cell lines. Methods and Results: In freshly isolated CLL cells, dasatinib showed a dose and time dependent reduction of global tyrosine phosphorylation which was paralleled by a decreased phosphorylation of the activating tyrosine residue of SFKs. The comparison of the inhibitory effect of several protein tyrosine kinase inhibitors on overall tyrosine phosphorylation in cellular lysates of freshly isolated CLL cells showed that 0.1 μM dasatinib had a more pronounced effect than 5 μM of nilotinib, or 10 μM of PP1 or imatinib. In the CLL cell lines, Mec1 and JVM-3, 0.1 μM of dasatinib appeared to interfere with survival signaling, since decreased levels of the activated phosphorylated forms of Akt, Erk1/2 and p38 were observed after exposure to dasatinib for 2 hours. In these cell lines, dasatinib treatment increased p53 protein levels and induced PARP cleavage and caspase activity. Pro-apoptotic effects of dasatinib were observed by an increase of annexin V-positive cells and a decrease of metabolic activity measured as XTT reduction, alone and in combination with fludarabine. Among six patient samples, two clones were particularly sensitive to dasatinib and fludarabine-resistant. While in these two samples the apoptosis induction by 5 μM dasatinib surpassed that by 5 μM fludarabine, the same dose of the two drugs led to similar apoptosis induction in the fludarabine-sensitive samples. Dasatinib treatment sensitized CLL cells for fludarabine-induced apoptosis. This enhancement of apoptosis induction was more pronounced in fludarabine-resistant patient samples and JVM-3 cells than in Mec1 and fludarabine-sensitive CLL cells. Conclusion: The Src-Abl kinase inhibitor dasatinib shows potent inhibitory effects on the survival of CLL cells in vitro.
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Tuli, R., A. Surmak, A. Blackford, A. Leubner, E. M. Jaffee, T. L. DeWeese, and J. M. Herman. "Effect of inhibition of poly-(ADP ribose) polymerase on gemcitabine and radiation-induced cytotoxicity of pancreatic cancer cells." Journal of Clinical Oncology 29, no. 4_suppl (February 1, 2011): 203. http://dx.doi.org/10.1200/jco.2011.29.4_suppl.203.
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203 Background: Poly-(ADP ribose) polymerases (PARPs) are DNA-binding proteins involved in DNA repair. PARP inhibition has resulted in excellent antitumor activity when used with other cytotoxic therapies. ABT-888 is a promising PARP inhibitor with excellent potency against the PARP-1/2 enzymes and good oral bioavailability. We attempt to determine whether PARP-1/2 inhibition alone, or in combination with gemcitabine, will enhance the effects of irradiation (RT) of pancreatic cancer cells. Methods: The pancreatic carcinoma cell lines, MiaPaCa-2 and Panc02, were treated with ABT-888, gemcitabine, RT, or combinations thereof. RT was delivered with a 137-Cs Gammacell in a single fraction. Cells were pre-treated once with ABT-888 and/or gemcitabine 30 minutes prior to RT. Viability was assessed through reduction of resazurin into fluorescent resorufin. Levels of apoptosis were determined by measuring caspase-3/7 activity using a luminescent assay. PARP activity was determined using a chemiluminescent PAR elisa. Results: The half maximal inhibitory concentration (IC50) of RT was 5 Gy; IC10 for ABT-888 and gemcitabine were 10 uM and 5 nM, respectively. Treatment with ABT-888 (10 uM), gemcitabine (5 nM), or combinations of the two with RT led to increasingly higher rates of cell death 8 days after treatment (p<0.001). RT dose enhancement factors were 1.5, 1.82 and 2.36 for 1, 10 and 100 uM ABT-888, respectively. Minimal cytotoxicity was noted when cells were treated with ABT-888 alone up to 100 uM. Caspase activity was not significantly increased when treated with ABT-888 (10 uM) alone (1.28 fold, p=0.077), but became significant when RT (2 Gy) was added (2.03 fold, p=0.006). This difference was further enhanced by the addition of gemcitabine (2.95 fold, p=0.004). Conclusions: ABT-888 is a potent radiosensitizer of pancreatic cancer cells with minimal cytotoxicity when used alone. Cell death is further potentiated by cotreatment with gemcitabine. Radiation-induced apoptosis was significantly enhanced by ABT-888 and gemcitabine, suggesting a synergistic mechanism of interference with DNA repair. These data are currently being validated in an orthotopic pancreatic cancer mouse model. No significant financial relationships to disclose.
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Uto, Takuhiro, Nguyen Huu Tung, Regina Appiah-Opong, Abigail Aning, Osamu Morinaga, Dominic Edoh, Alexander K. Nyarko, and Yukihiro Shoyama. "Antiproliferative and Pro-Apoptotic Activity of Diarylheptanoids Isolated from the Bark of Alnus japonica in Human Leukemia Cell Lines." American Journal of Chinese Medicine 43, no. 04 (January 2015): 757–67. http://dx.doi.org/10.1142/s0192415x15500470.
Full textAbstract:
Alnus japonica Steud is a tree that grows in damp areas of mountain valleys and has been used as a traditional medicine in Asia. We investigated the antiproliferative activity of hirsutanone (Hir) and oregonin (Ore) in human cancer cell lines and elucidated their mechanisms of action. A cytotoxicity study using a panel of 12 human cancer and 4 normal cell lines indicated that Hir exhibited potent antiproliferative activity against 4 leukemia (Jurkat, U937, THP-1, and HL-60) and 2 colon cancer cell lines (HCT-15 and Colo205). Although Ore suppressed the cell growth of Jurkat and THP-1, its inhibitory potency was weaker than that of Hir. The IC50 values of Hir and Ore in Jurkat were 11.37 μM and 22.16 μM, respectively. Further analysis on Jurkat cells demonstrated that Hir caused a sequence of events involved in apoptosis, including nuclear morphological changes and accumulation of cells with sub-G1 DNA content. Hir led to the cleavage of poly(ADP-ribose) polymerase (PARP) and activation of caspase-3, -8, and -9. In addition, Hir-induced PARP cleavage was completely abolished by specific inhibitors to these caspases. Our data suggested that Hir is a potent antiproliferative compound against the 4 leukemia cell lines and the 2 colon cancer cell lines tested. Furthermore, Hir exerts antiproliferative actions via caspase-dependent apoptotic cell death.
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Kandalaft, Lana E., Kunle Odunsi, and George Coukos. "Immune Therapy Opportunities in Ovarian Cancer." American Society of Clinical Oncology Educational Book, no. 40 (May 2020): e228-e240. http://dx.doi.org/10.1200/edbk_280539.
Full textAbstract:
Immunotherapy has emerged as a highly promising approach in the treatment of epithelial ovarian cancer (EOC). Immune checkpoint blockade (ICB) therapy, PARP inhibitors (PARPis), neoantigen vaccines, and personalized T-cell therapy have been associated with encouraging clinical activity in a small subset of patients. To increase the proportion of patients who are likely to derive benefit, it will be important not only to generate sufficient numbers of antitumor T cells but also to overcome multiple inhibitory networks in the ovarian tumor microenvironment (TME). Therefore, a major direction is to develop biomarkers that would predict responsiveness to different types of immunotherapies and allow treatment selection based on the results. Moreover, such biomarkers would allow rational combination of immunotherapies while minimizing toxicities. In this review, we provide progress on immune therapies and future directions for maximally exploiting immune-based strategies for the treatment of ovarian cancer.