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Zhou, Hongyan, Sheng Jiang, Jianping Chen, and Shao Bo Su. "Suberoylanilide hydroxamic acid suppresses inflammation-induced neovascularization." Canadian Journal of Physiology and Pharmacology 92, no. 10 (October 2014): 879–85. http://dx.doi.org/10.1139/cjpp-2014-0117.
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Histone deacetylases (HDACs) regulate gene transcription by modifying the acetylation of histone and nonhistone proteins. Deregulated expression of HDACs has been implicated in tumorigenesis and angiogenesis. In this study, we examined the effect of suberoylanilide hydroxamic acid (SAHA), a potent inhibitor of HDACs, on inflammatory corneal angiogenesis. In a mouse model of alkali-induced corneal neovascularization (CNV), topical application of SAHA to the injured corneas attenuated CNV. In addition, in vivo treatment with SAHA downregulated the expression of the pro-angiogenic factors vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), transforming growth factor beta 1 (TGFβ1), and epidermal growth factor (EGF), but upregulated the expression of the anti-angiogenic factors thrombospondin (TSP)-1, TSP-2, and ADAMTS-1 in the injured corneas. Furthermore, SAHA inhibited the expression of pro-angiogenic factors, migration, proliferation, and tube formation by human microvascular endothelial cells (HEMC-1) in vitro. These data indicate that SAHA has therapeutic potential for CNV.
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Cenik, Basar, Chantelle F. Sephton, Colleen M. Dewey, Xunde Xian, Shuguang Wei, Kimberley Yu, Wenze Niu, et al. "Suberoylanilide Hydroxamic Acid (Vorinostat) Up-regulates Progranulin Transcription." Journal of Biological Chemistry 286, no. 18 (March 23, 2011): 16101–8. http://dx.doi.org/10.1074/jbc.m110.193433.
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Progranulin (GRN) haploinsufficiency is a frequent cause of familial frontotemporal dementia, a currently untreatable progressive neurodegenerative disease. By chemical library screening, we identified suberoylanilide hydroxamic acid (SAHA), a Food and Drug Administration-approved histone deacetylase inhibitor, as an enhancer of GRN expression. SAHA dose-dependently increased GRN mRNA and protein levels in cultured cells and restored near-normal GRN expression in haploinsufficient cells from human subjects. Although elevation of secreted progranulin levels through a post-transcriptional mechanism has recently been reported, this is, to the best of our knowledge, the first report of a small molecule enhancer of progranulin transcription. SAHA has demonstrated therapeutic potential in other neurodegenerative diseases and thus holds promise as a first generation drug for the prevention and treatment of frontotemporal dementia.
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Kim, M. J., H. J. Oh, G. A. Kim, H. N. Suh, Y. K. Jo, Y. B. Choi, D. H. Kim, H. J. Han, and B. C. Lee. "36 EFFECT OF SUBEROYLANILIDE HYDROXAMIC ACID TREATED DONOR CELLS ON DOG CLONING." Reproduction, Fertility and Development 27, no. 1 (2015): 110. http://dx.doi.org/10.1071/rdv27n1ab36.
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Although dog cloning technology has been applied to conservation of endangered canids, propagation of elite dogs and production of transgenic dogs, the efficiency of cloning is still very low. To help overcome this problem, we evaluated the effect of treating donor cells with suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor (HDACi), on dog cloning efficiency. Relative mRNA expression of the bax1, bcl2, and Dnmt1 in fibroblasts treated with different concentrations (0, 1, 10, 50 μM) of SAHA and durations (0, 20, 44 h) were assessed using real-time polymerase chain reaction. After determining an optimum concentration and duration, histone acetylation levels (H3K9, H4K5/K8/K12/K16) of SAHA-treated cells were analysed using immunostaining. The SAHA-treated cells were used as donor cells for somatic cell nuclear transfer, and activated reconstructed embryos were transferred to recipients. Pregnancy diagnosis was performed by ultrasonography at least 29 days after the embryo transfer. All experiments were repeated more than 3 times and the data were analysed using Graph Prism software (GraphPad Software Inc., San Diego, CA, USA). An unpaired t-test was used to compare transcripts levels and fluorescence intensities. A chi-squared test was used to compare the implantation rates. The bax1/bcl2 ratio of the 1 μM SAHA group was similar to that of control but significantly increased in the 10 μM and 50 μM groups. Expression of Dnmt1 was decreased in the 1 μM SAHA group, and the 10 μM and 50 μM groups showed the lowest expression compared with the control group. Although the bax1/blc2 ratio was not affected by the SAHA treatment duration, 20-h treatment group showed significantly decreased Dnmt1 levels compared with control group. As a pan-HDAC inhibitor, 1 μM for 20 h of SAHA treatment significantly increased acetylation of H3K9, H4K5, H4K8, and H4K16. For control and SAHA groups, a total of 76 and 64 cloned embryos were produced and transferred to 7 and 5 recipients, respectively. Three fetuses were diagnosed in both groups but there was no significant difference in the pregnancy rate. In conclusion, although SAHA treatment as used in this study significantly decreased bax/bcl2 and Dnmt1 transcripts of donor nuclei, as well as increased H3 and H4 acetylation, it would not enough to increase in vivo developmental competence of cloned dog embryos.This study was supported by RDA (#PJ008975022014), IPET (#311062–04–3SB010), Research Institute for Veterinary Science and the BK21 plus program.
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Cao, Hua, Manfred Jung, and George Stamatoyannopoulos. "Hydroxamic Acids Derivatives Induce γ Globin Gene Expression in Vivo." Blood 104, no. 11 (November 16, 2004): 1224. http://dx.doi.org/10.1182/blood.v104.11.1224.1224.
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Abstract We have previously shown that four hydroxamic acids: butyric and propionic hydroxamic acids, subericbishydroxamic acid (SBHA) and suberoylanilide hydroxamic acid (SAHA) are potent inhibitors of histone deacetylase and strong inducers of fetal hemoglobin expression in vitro (Exp Hematol.31:197, 2003). In the present study we tested their effect on fetal hemoglobin synthesis in vivo. Transgenic mice carrying the human μLCR Aγ construct continue to express the human γ gene in the adult stage of development ( γ/α mRNA ratio ~ 5%, Blood.77:1326, 1991). These mice were crossed to mice heterozygous for a thalassemia gene due to β globin gene deletion (PNAS.92:11608, 1995). The β thalassemia/μLCR Aγ mice represent an appropriate moderately anemic animal model for testing the effects of Hb F inducers. Compounds were administered subcutaneously with a mini-osmotic pump continuously for 7days in a high and a low concentration. Concentrations were: for butyric hydroxamic acid: 500mg/kg/day/100mg/kg/day; for propionic hydroxamic acid: 500mg/kg/day/100mg/kg/day; for SAHA: 100mg/kg/day/20mg/kg/day; and for SBHA: 200mg/kg/day/40mg/kg/day. Two test groups were studied. In group 1, 70μL mice blood was drawn every other day up to 20 days; in group 2, 70μL mice blood was drawn only on days 0 and 21. Reticulocytes and F reticulocytes were measured using flow cytometry, while γ globin gene expression was quantitated by RNase protection assay. Butyric and propionate hydroxamic acids increased reticulocytes by 70.52% (from 13.96% to 23.81%) and 172.52% (from 10.34% to 28.20%) respectively. There was only small increase in reticulocytes in the mice treated with SAHA (from 13.33% to 15.36%), SBHA (from 14.24% to 16.27%) and the PBS control (11.06% to 14.11%). All the compounds increased the level of γ mRNA: butyric hydroxamate by 53.07%; propionic hydroxamate by 40.05%; SAHA by 49.87%, and SBHA by 34.05%. These results suggest first that all the hydroxamic acid derivatives we used increase fetal hemoglobin in vivo in the thalassemia animal model; second butyric and propionic hydroxanic acids are in addition inducers of in vivo erythropoiesis.
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Kim, Da Som, Hong-Ki Min, Eun Kyung Kim, Seung Cheon Yang, Hyun Sik Na, Seon-Yeong Lee, Jeong-Won Choi, et al. "Suberoylanilide Hydroxamic Acid Attenuates Autoimmune Arthritis by Suppressing Th17 Cells through NR1D1 Inhibition." Mediators of Inflammation 2019 (October 24, 2019): 1–11. http://dx.doi.org/10.1155/2019/5648987.
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Rheumatoid arthritis (RA) is a type of systemic autoimmune arthritis that causes joint inflammation and destruction. One of the pathological mechanisms of RA is known to involve histone acetylation. Although the histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) can attenuate arthritis in animal models of RA, the mechanism underlying this effect is poorly understood. This study was performed to examine whether SAHA has therapeutic potential in an animal model of RA and to investigate its mechanism of action. Collagen-induced arthritis (CIA) mice were orally administered SAHA daily for 8 weeks and examined for their arthritis score and incidence of arthritis. CD4+ T cell regulation following SAHA treatment was confirmed in splenocytes cultured under type 17 helper T (Th17) cell differentiation conditions. Clinical scores and the incidence of CIA were lower in mice in the SAHA treatment group compared to the controls. In addition, SAHA inhibited Th17 cell differentiation, as well as decreased expression of the Th17 cell-related transcription factors pSTAT3 Y705 and pSTAT3 S727. In vitro experiments showed that SAHA maintained regulatory T (Treg) cells but specifically reduced Th17 cells. The same results were obtained when mouse splenocytes were cultured under Treg cell differentiation conditions and then converted to Th17 cell differentiation conditions. In conclusion, SAHA was confirmed to specifically inhibit Th17 cell differentiation through nuclear receptor subfamily 1 group D member 1 (NR1D1), a factor associated with Th17 differentiation. The results of the present study suggested that SAHA can attenuate CIA development by inhibition of the Th17 population and maintenance of the Treg population through NR1D1 inhibition. Therefore, SAHA is a potential therapeutic candidate for RA.
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Yu, J., H. Wu, Z. Lin, K. Su, J. Zhang, F. Sun, X. Wang, C. Wen, H. Cao, and L. Hu. "Metabolic changes in rat serum after administration of suberoylanilide hydroxamic acid and discriminated by SVM." Human & Experimental Toxicology 36, no. 12 (January 13, 2017): 1286–94. http://dx.doi.org/10.1177/0960327116688067.
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Suberoylanilide hydroxamic acid (SAHA) exerts marked anticancer effects via promotion of apoptosis, cell cycle arrest, and prevention of oncogene expression. In this study, serum metabolomics and artificial intelligence recognition were used to investigate SAHA toxicity. Forty rats (220 ± 20 g) were randomly divided into control and three SAHA groups (low, medium, and high); the experimental groups were treated with 12.3, 24.5, or 49.0 mg kg−1 SAHA once a day via intragastric administration. After 7 days, blood samples from the four groups were collected and analyzed by gas chromatography–mass spectrometry, and pathological changes in the liver were examined using microscopy. The results showed that increased levels of urea, oleic acid, and glutaconic acid were the most significant indicators of toxicity. Octadecanoic acid, pentadecanoic acid, glycerol, propanoic acid, and uric acid levels were lower in the high SAHA group. Microscopic observation revealed no obvious damage to the liver. Based on these data, a support vector machine (SVM) discrimination model was established that recognized the metabolic changes in the three SAHA groups and the control group with 100% accuracy. In conclusion, the main toxicity caused by SAHA was due to excessive metabolism of saturated fatty acids, which could be recognized by an SVM model.
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Kawamata, Norihiko, John Chen, and H. Phillip Koeffler. "Suberoylanilide hydroxamic acid (SAHA; vorinostat) suppresses translation of cyclin D1 in mantle cell lymphoma cells." Blood 110, no. 7 (October 1, 2007): 2667–73. http://dx.doi.org/10.1182/blood-2005-11-026344.
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Mantle cell lymphoma (MCL) has a chromosomal translocation resulting in the expression of the cyclin D1 gene driven by the powerful enhancer of the immunoglobulin heavy chain gene, leading to uncontrolled, overexpressed cyclin D1 protein. We showed that suberoylanilide hydroxamic acid (SAHA; vorinostat), one of the histone deacetylase inhibitors derived from hydroxamic acid, caused a dramatic decrease (90%) in protein levels of cyclin D1 after 8-hour exposure to SAHA (5 μM) in MCL lines (SP49, SP53, Jeko1). mRNA levels and protein stability of cyclin D1 were minimally affected by SAHA over 8 hours. In contrast, metabolic labeling assays showed that SAHA decreased incorporation of [35S]methionine into cyclin D1 protein. The drug also decreased levels of phosphorylated Akt, mammalian target of Rapamycin (mTOR), and eukaryotic translation initiation factor 4E binding protein (eIF4E-BP) and lowered the cap site binding activity of eIF4E in the MCL cells. In vitro phosphatidyl inositol (PI) kinase assay demonstrated that SAHA directly inhibited kinase activity of PI 3′ kinase. Taken together, SAHA caused a rapid decrease of cyclin D1 in MCL by blocking the translation of cyclin D1 by inhibiting the phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR/eIF4E-BP pathway, probably by PI3K inhibition.
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Ekou, Lynda, Tchirioua Ekou, Javier Garcia, Isabelle Opalinski, and Jean Pierre Gesson. "Design and Synthesis of Small Molecules Based on a Substructural Analysis of the Histone Deacetylase Inhibitors TSA and SAHA." E-Journal of Chemistry 8, no. 3 (2011): 1394–400. http://dx.doi.org/10.1155/2011/403129.
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Inhibitors of histone deacetylases (HDACs) are patent inducers of differentiation and bear considerable potential as drugs for chemoprevention and treatment of cancer. In this paper, we have investigated three synthetic, inhibitors A1a,b, A2a. Analogue hybrid trichostatine A (TSA), suberoylanilide hydroxamic acid SAHA, in order to seek new histone deacetylases (HDACs) inhibitors.
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Qin, Yu, Xuejiao Zhao, and Yong Fang. "PP242 Synergizes With Suberoylanilide Hydroxamic Acid to Inhibit Growth of Ovarian Cancer Cells." International Journal of Gynecologic Cancer 24, no. 8 (October 2014): 1373–80. http://dx.doi.org/10.1097/igc.0000000000000238.
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ObjectivesOverexpression of histone deacetylases and activation of the phosphatidylinositol 3-kinase/mammalian target of rapamycin pathway are common aberrations in ovarian cancer. For this reason, simultaneous inhibition of such targets is a rational therapeutic strategy to treat patients with ovarian cancer. This study aimed to investigate the biological effect of the histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA), in combination with the dual mTOR complex 1 and mTOR complex 2 inhibitor, PP242, against ovarian cancer cells.Materials and MethodsThe effects of SAHA and PP242 on the growth of SKOV3 and A2780 cells were examined using Cell Counting Kit-8. The apoptosis was analyzed through flow cytometry, and the expression of apoptosis-related proteins was investigated through Western blotting. Induction of autophagy was determined through fluorescence microscopy using a stably transfected green fluorescent protein/microtubule-associated protein light chain 3 construct to visualize autophagosome formation. The expression of autophagy-related proteins was determined through Western blot analysis. The effect of SAHA and PP242 on the growth of ovarian cancer was also examined in an orthotopic ovarian cancer model.ResultsThe combination of SAHA and PP242 significantly inhibited cell proliferation and synergistically increased apoptosis and autophagy compared with each agent alone in vitro. In vivo, this combination exhibited greater inhibition on tumor growth than monotreatments did and it significantly prolonged the survival time of the mice.ConclusionsThese results suggest that the combination of SAHA and PP242 may lead to a novel strategy in treating patients with ovarian cancer.
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Wang, Wenwen, Min Yan, Qiuhong Ji, Jinbiao Lu, Yuhua Ji, and Juling Ji. "Suberoylanilide hydroxamic acid suppresses hepatic stellate cells activation by HMGB1 dependent reduction of NF-κB1." PeerJ 3 (November 3, 2015): e1362. http://dx.doi.org/10.7717/peerj.1362.
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Hepatic stellate cells (HSCs) activation is essential to the pathogenesis of liver fibrosis. Exploring drugs targeting HSC activation is a promising anti-fibrotic strategy. In the present study, we found suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, prominently suppressed the activation phenotype of a human hepatic stellate cell line—LX2. The production of collagen type I andα-smooth muscle actin (α-SMA) as well as the proliferation and migration of LX2 cells were significantly reduced by SAHA treatment. To determine the molecular mechanisms underlying this suppression, genome wild gene regulation by SAHA was determined by Affymetrix 1.0 human cDNA array. Upon SAHA treatment, the abundance of 331 genes was up-regulated and 173 genes was down-regulated in LX2 cells. Bioinformatic analyses of these altered genes highlighted the high mobility group box 1 (HMGB1) pathway was one of the most relevant pathways that contributed to SAHA induced suppression of HSCs activation. Further studies demonstrated the increased acetylation of intracellular HMGB1 in SAHA treated HSCs, and this increasing is most likely to be responsible for SAHA induced down-regulation of nuclear factor kappa B1 (NF-κB1) and is one of the main underlying mechanisms for the therapeutic effect of SAHA for liver fibrosis.
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Bhatt, Shruti, Brittany Ashlock, Ngoc Toomey, Enrique Mesri, Juan Carlos Ramos, and Izidore S. Lossos. "Synergistic Preclinical Activity of Bortezomib with Suberoylanilide Hydroxamic Acid (SAHA) in Primary Effusion Lymphoma (PEL)." Blood 118, no. 21 (November 18, 2011): 1650. http://dx.doi.org/10.1182/blood.v118.21.1650.1650.
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Abstract Abstract 1650 Primary effusion lymphoma (PEL) is an aggressive subtype of non-Hodgkin lymphoma typically presenting as effusions in the serous body cavities without a contiguous tumor mass. PEL may develop in elderly immunosuppressed HIV-negative individuals but more commonly affects HIV-positive patients, accounting for 4% of all lymphomas in this population. Kaposi's sarcoma-associated herpesvirus (KSHV) is directly implicated in the pathogenesis of PEL, however in most patients the malignant B cells are also coinfected with Epstein-Barr virus which may facilitate transformation. Current chemotherapeutic approaches result in dismal outcome of PEL patients with a median survival of only 6 months. Consequently, development of new therapeutic approaches is urgently needed. Recently we reported development of the UM-PEL1 direct xenograft mice model reproducing human PEL (Sarosiek, PNAS 2010) in which bortezomib (BORT) induced virus lytic reactivation leading to malignant B cell death and transient remission of the PEL in vivo. Further improvement on this monotherapy is warranted. Recent studies have shown that suberoylanilide hydroxamic acid (SAHA), a histone deacetylase (HDAC) inhibitor is a highly effective viral lytic-cycle inducer. As herpesviruses are dependent on the proteasome for replication and mature viral production, induction of lytic replication with concomitant inhibition of the proteasome may provide a highly targeted strategy for eradicating KSHV infected cells without leading to increased viremia. Consequently, we hypothesized that combining BORT with SAHA may act synergistically in PEL tumors. Incubation of human PEL cell lines, UM-PEL1, BC1, BC3 and BC5 with BORT-SAHA resulted in increased apoptotis compared to individual treatment with BORT or SAHA, as assayed by flow cytometry using YO-PRO/PI staining. Concordantly, a statistically significant decrease in UM-PEL1 cell proliferation and viability, as examined by an MTT assay, was observed at 48 and 72 hours following combination therapy as compared to untreated cells or cells treated individually with BORT or SAHA. Cell cycle analysis demonstrated that BORT-SAHA combination induced more pronounced G1 cell cycle arrest and apoptosis as compared to individual treatments. SAHA induced a more robust KSHV lytic reactivation compared to BORT. Intriguingly, the BORT-SAHA combination led to an increased expression of the master lytic transactivator RTA and thymidine kinase, however the late lytic gene, K8.1, showed reduced mRNA expression relative to the individual SAHA treatment. These findings were further confirmed by immunofluorescence staining of the K8.1 protein suggesting that BORT could inhibit mature virion production in lytically reactivated malignant B-cells. To comprehensively examine the activity of the BORT-SAHA combination compared to individual BORT or SAHA treatments in vivo, we used UM-PEL1 direct xenograft model. Mice receiving intraperitoneal BORT-SAHA combination showed statistically significant prolonged survival compared to all the control treatments (p<0.001). Since PEL cells are known to be highly dependent on NF-κB for survival, we examined whether the apoptosis induced by the combination treatment was due to the inhibition of this pro-survival pathway. In contrast to our previous observations that individual BORT treatment did not alter NF-κB activity, the in vivo addition of SAHA led to NF-κB inhibition as demonstrated by gel shift assay. Moreover, Western blotting demonstrated downregulation of anti-apoptotic genes, upregulation of pro-apoptotic genes along with the rise in the p53, p21 and increased acetylation of histone 3 in the combination treated mice versus BORT alone. Further, RTA and early lytic gene expression confirmed our in vitro findings that KSHV lytic reactivation is enhanced in the BORT-SAHA treated mice compared to individual treatments. However, transcription of all late lytic genes tested (gB, K8.1, gM, ORF38, ORF67, ORF68) was uniformly inhibited in the animals treated with the BORT-SAHA as compared to SAHA alone, suggesting that the virus was unable to complete the full replicative cycle. In conclusion, this study demonstrates strong pre-clinical activity of the combination of proteasome inhibitor with HDAC inhibitor as a potent anti-PEL therapy that triggers apoptosis by prompting KSHV lytic reactivation without increasing infectious virus production. Disclosures: No relevant conflicts of interest to declare.
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Chattopadhyay, Shital K., Subhankar Ghosh, Sarita Sarkar, and Kakali Bhadra. "α,ß-Didehydrosuberoylanilide hydroxamic acid (DDSAHA) as precursor and possible analogue of the anticancer drug SAHA." Beilstein Journal of Organic Chemistry 15 (October 24, 2019): 2524–33. http://dx.doi.org/10.3762/bjoc.15.245.
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An alternate synthetic route to the important anticancer drug suberoylanilide hydroxamic acid (SAHA) from its α,ß-didehydro derivative is described. The didehydro derivative is obtained through a cross metathesis reaction between a suitable terminal alkene and N-benzyloxyacrylamide. Some of the didehydro derivatives of SAHA were preliminarily evaluated for anticancer activity towards HeLa cells. The administration of the analogues caused a significant decrease in the proliferation of HeLa cells. Furthermore, one of the analogues showed a maximum cytotoxicity with a minimum GI50 value of 2.5 µg/mL and the generation of reactive oxygen species (ROS) as some apoptotic features.
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Najem, Sonia Abou, Ghada Khawaja, Mohammad Hassan Hodroj, and Sandra Rizk. "Synergistic Effect of Epigenetic Inhibitors Decitabine and Suberoylanilide Hydroxamic Acid on Colorectal Cancer In vitro." Current Molecular Pharmacology 12, no. 4 (October 15, 2019): 281–300. http://dx.doi.org/10.2174/1874467212666190313154531.
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Background:Colorectal Cancer (CRC) is a common cause of oncological deaths worldwide. Alterations of the epigenetic landscape constitute a well-documented hallmark of CRC phenotype. The accumulation of aberrant DNA methylation and histone acetylation plays a major role in altering gene activity and driving tumor onset, progression and metastasis.Objective:In this study, we evaluated the effect of Suberoylanilide Hydroxamic Acid (SAHA), a panhistone deacetylase inhibitor, and Decitabine (DAC), a DNA methyltransferase inhibitor, either alone or in combination, on Caco-2 human colon cancer cell line in vitro.Results:Our results showed that SAHA and DAC, separately, significantly decreased cell proliferation, induced apoptosis and cell cycle arrest of Caco-2 cell line. On the other hand, the sequential treatment of Caco-2 cells, first with DAC and then with SAHA, induced a synergistic anti-tumor effect with a significant enhancement of growth inhibition and apoptosis induction in Caco-2 cell line as compared to cells treated with either drug alone. Furthermore, the combination therapy upregulates protein expression levels of pro-apoptotic proteins Bax, p53 and cytochrome c, downregulates the expression of antiapoptotic Bcl-2 protein and increases the cleavage of procaspases 8 and 9; this suggests that the combination activates apoptosis via both the intrinsic and extrinsic pathways. Mechanistically, we demonstrated that the synergistic anti-neoplastic activity of combined SAHA and DAC involves an effect on PI3K/AKT and Wnt/β-catenin signaling.Conclusion:In conclusion, our results provide evidence for the profound anti-tumorigenic effect of sequentially combined SAHA and DAC in the CRC cell line and offer new insights into the corresponding underlined molecular mechanism.
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Bingul, Murat, Greg M. Arndt, Glenn M. Marshall, David StC Black, Belamy B. Cheung, and Naresh Kumar. "Synthesis and Characterisation of Novel Tricyclic and Tetracyclic Furoindoles: Biological Evaluation as SAHA Enhancer against Neuroblastoma and Breast Cancer Cells." Molecules 26, no. 19 (September 22, 2021): 5745. http://dx.doi.org/10.3390/molecules26195745.
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The dihydropyranoindole structures were previously identified as promising scaffolds for improving the anti-cancer activity of histone deacetylase inhibitors. This work describes the synthesis of related furoindoles and their ability to synergize with suberoylanilide hydroxamic acid (SAHA) against neuroblastoma and breast cancer cells. The nucleophilic substitution of hydroxyindole methyl esters with α-haloketones yielded the corresponding arylether ketones, which were subsequently cyclized to tricyclic and tetracyclic furoindoles. The furoindoles showed promising individual cytotoxic efficiency against breast cancer cells, as well as decent SAHA enhancement against cancer cells in select cases. Interestingly, the best IC50 value was obtained with the non-cyclized intermediate.
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Qi, Yun-feng, Yan-xin Huang, Yan Dong, Li-hua Zheng, Yong-li Bao, Lu-guo Sun, Yin Wu, Chun-lei Yu, Hong-yu Jiang, and Yu-xin Li. "Systematic Analysis of Time-Series Gene Expression Data on Tumor Cell-Selective Apoptotic Responses to HDAC Inhibitors." Computational and Mathematical Methods in Medicine 2014 (2014): 1–15. http://dx.doi.org/10.1155/2014/867289.
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SAHA (suberoylanilide hydroxamic acid or vorinostat) is the first nonselective histone deacetylase (HDAC) inhibitor approved by the US Food and Drug Administration (FDA). SAHA affects histone acetylation in chromatin and a variety of nonhistone substrates, thus influencing many cellular processes. In particularly, SAHA induces selective apoptosis of tumor cells, although the mechanism is not well understood. A series of microarray experiments was recently conducted to investigate tumor cell-selective proapoptotic transcriptional responses induced by SAHA. Based on that gene expression time series, we propose a novel framework for detailed analysis of the mechanism of tumor cell apoptosis selectively induced by SAHA. Our analyses indicated that SAHA selectively disrupted the DNA damage response, cell cycle, p53 expression, and mitochondrial integrity of tumor samples to induce selective tumor cell apoptosis. Our results suggest a possible regulation network. Our research extends the existing research.
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Ekou, Lynda, Tchirioua Ekou, Isabelle Opalinski, and Jean Pierre Gesson. "Histone Deacetylase Inhibitors: Synthesis of Tetrapeptide Analogue SAHA/TPX." E-Journal of Chemistry 8, s1 (2011): S79—S84. http://dx.doi.org/10.1155/2011/572546.
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The inhibition of HDAC (histone deacetylase) activity by specific inhibitors induces growth arrest, differentiation and apoptosis of transformed or several cancer cells. Some of these inhibitors are in clinical trial at phase I or phase II. The discovery and development of specific HDAC inhibitors are helpful for cancer therapy. In this paper we describe the synthesis of simple inhibitorBhybrid analogue suberoylanilide hydroxamic acid (SAHA), trapoxinB(TPX B) in as little as five steps. This compound is interesting lead for the design of potent inhibitors of histone deacetylase.
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Brodská, Barbora, Petra Otevřelová, and Aleš Holoubek. "Decitabine and SAHA-Induced Apoptosis Is Accompanied by Survivin Downregulation and Potentiated by ATRA in p53-Deficient Cells." Oxidative Medicine and Cellular Longevity 2014 (2014): 1–13. http://dx.doi.org/10.1155/2014/165303.
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While p53-dependent apoptosis is triggered by combination of methyltransferase inhibitor decitabine (DAC) and histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) in leukemic cell line CML-T1, reactive oxygen species (ROS) generation as well as survivin and Bcl-2 deregulation participated in DAC + SAHA-induced apoptosis in p53-deficient HL-60 cell line. Moreover, decrease of survivin expression level is accompanied by its delocalization from centromere-related position in mitotic cells suggesting that both antiapoptotic and cell cycle regulation roles of survivin are affected by DAC + SAHA action. Addition of subtoxic concentration of all-trans-retinoic acid (ATRA) increases the efficiency of DAC + SAHA combination on viability, apoptosis induction, and ROS generation in HL-60 cells but has no effect in CML-T1 cell line. Peripheral blood lymphocytes from healthy donors showed no damage induced by DAC + SAHA + ATRA combination. Therefore, combination of ATRA with DAC and SAHA represents promising tool for therapy of leukemic disease with nonfunctional p53 signalization.
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McGee-Lawrence, Meghan E., Angela L. McCleary-Wheeler, Frank J. Secreto, David F. Razidlo, Minzhi Zhang, Bridget A. Stensgard, Xiaodong Li, Gary S. Stein, Jane B. Lian, and Jennifer J. Westendorf. "Suberoylanilide hydroxamic acid (SAHA; vorinostat) causes bone loss by inhibiting immature osteoblasts." Bone 48, no. 5 (May 2011): 1117–26. http://dx.doi.org/10.1016/j.bone.2011.01.007.
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Yuniarti, Nunung, Berry Juliandi, Tsukasa Sanosaka, and Kinichi Nakashima. "Mid-gestational exposure to histone deacetylase inhibitor suberoylanilide hydroxamic acid influence cortical interneuron and astrocyte in mouse brain." Indonesian Journal of Biotechnology 22, no. 1 (January 18, 2018): 32. http://dx.doi.org/10.22146/ijbiotech.25986.
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Suberoylanilide hydroxamic acid (SAHA) has been reported preclinically to diffuse across the placenta and to be found in fetal plasma, suggesting that it can influence the fetus if taken by a pregnant cancer patient. In utero exposure of SAHA to mouse embryos during mid-gestation was found to perturb corticogenesis. However, the influence of in utero administration of SAHA to mouse embryos during mid-gestation on astrocyte, glial cell, and inhibitory neurons (interneurons) is yet to be reported. Pregnant dams were divided into control and SAHA groups and given methyl cellulose (as control) and SAHA orally once a day for 3 days during mid-gestation, starting from embryonic day (E)12 until E14. Astrocyte, interneuron, and behavior analyses were performed on the pups from postnatal day 7 until adulthood (3 months old). Brains were harvested and immunohistochemistry, Western Blot, and RT-PCR were performed on their cortex area. Transient exposure of SAHA to mouse embryos resulted in a decrease and increase in cortical astrocyte and interneuron, respectively. Meanwhile, adult SAHA mice displayed significantly increased anxiety, decreased memory, altered long-term cognitive functions, and reduced social interactions. Our study suggests that exposure to SAHA during prominent neurogenic periods might imbalance the normal excitatory:inhibitory neuron ratio required for the precise regulation of physiological functions in the brain.
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Kelly, William Kevin, Owen A. O'Connor, Lee M. Krug, Judy H. Chiao, Mark Heaney, Tracy Curley, Barbara MacGregore-Cortelli, et al. "Phase I Study of an Oral Histone Deacetylase Inhibitor, Suberoylanilide Hydroxamic Acid, in Patients With Advanced Cancer." Journal of Clinical Oncology 23, no. 17 (June 10, 2005): 3923–31. http://dx.doi.org/10.1200/jco.2005.14.167.
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Purpose To determine the safety, dosing schedules, pharmacokinetic profile, and biologic effect of orally administered histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) in patients with advanced cancer. Patients and Methods Patients with solid and hematologic malignancies were treated with oral SAHA administered once or twice a day on a continuous basis or twice daily for 3 consecutive days per week. Pharmacokinetic profile and bioavailibity of oral SAHA were determined. Western blots and enzyme-linked immunosorbent assays of histones isolated from peripheral-blood mononuclear cells (PBMNCs) pre and post-therapy were performed to evaluate target inhibition. Results Seventy-three patients were treated with oral SAHA and major dose-limiting toxicities were anorexia, dehydration, diarrhea, and fatigue. The maximum tolerated dose was 400 mg qd and 200 mg bid for continuous daily dosing and 300 mg bid for 3 consecutive days per week dosing. Oral SAHA had linear pharmacokinetics from 200 to 600 mg, with an apparent half-life ranging from 91 to 127 minutes and 43% oral bioavailability. Histones isolated from PBMNCs showed consistent accumulation of acetylated histones post-therapy, and enzyme-linked immunosorbent assay demonstrated a trend towards a dose-dependent accumulation of acetylated histones from 200 to 600 mg of oral SAHA. There was one complete response, three partial responses, two unconfirmed partial responses, and 22 (30%) patients remained on study for 4 to 37+ months. Conclusions Oral SAHA has linear pharmacokinetics and good bioavailability, inhibits histone deacetylase activity in PBMNCs, can be safely administered chronically, and has a broad range of antitumor activity.
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Liu, Jin-Hwang, Yu-Hern Lin, Hon-Wen Liu, and Jyh-Pyng Gau. "Histone Deacetylation Inhibitor Sensitizes T-ALLs to Topoisomerase II Inhibitor By Attenuating G2 Cell Cycle Arrest and Blocking Nuclear Entry of Ctip during DNA Repair." Blood 126, no. 23 (December 3, 2015): 4862. http://dx.doi.org/10.1182/blood.v126.23.4862.4862.
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Abstract Double strand DNA repair can be epigenetically modulated to sensitize the malignant cells to chemotherapy. CTV-1 and Molt-3 were segregated as T-acute lymphoblastic cells (T-ALL) according to their expression profiles. We found in these cells doxorubicin, a topoisomerase II (TOP2) inhibitor, induced expression and phosphorylation of cell cycle checkpoint kinase 1(CHK1) associated with G2 cell cycle arrest before achieving apoptosis; while a histone deacetylation inhibitor (HDACi), suberoylanilide hydroxamic acid (SAHA), synergistically enhanced cell death by attenuation of expression and phosphorylation of CHK1, and by attenuated expression and phosphorylation of a double strand DNA repair protein, C-terminal binding protein (CtBP)-interacting protein [CtIP], and was associated with shortened G2 cell cycle arrest. Very often is Doxorubicin as a topoisomerase II inhibitor enrolled in the treatment of T-ALL. We evidenced with isobologram synergistic cell-killing by doxorubicin and SAHA in CTV-1 and Molt-3 T-ALL cell lines of which expression and phosphorylation of CHK1 were negatively affected by SAHA. In the SAHA-treated T-ALL cells, the repair of doxorubicin-induced double strand DNA break (DSB) was associated with increased γH2AX. However, although SAHA increased expression of γH2AX and acetyl H2AX, apoptosis was enhanced with shortened G2/M arrest and the hampered nuclear entry of CtIP revealed by immunofluorescent confocal microscopy. HDACi thus synergistically impaired the topoisomerase II-induced DSB repair and enhanced apoptosis by eliciting DNA repair with γH2AX expression; however, aborted the DNA repair and induced apoptosis by hampering the nuclear entry of CtIP. Attenuation of activated CHK1 may be potentially a biomarkers of synergistic cytotoxicities of HDACi and DSB-inducing chemotherapeutics. Disclosures Off Label Use: in vitro study only. suberoylanilide hydroxamic acid in combination with topoisomerase II inhibitor may have synergistic effects. .
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Whitworth, K. M., J. M. Teson, K. Lee, J. Mao, K. J. Tessanne, L. D. Spate, and R. S. Prather. "27 THE HISTONE DEACETYLASE INHIBITOR 4-IODO-SUBEROYLANILIDE HYDROXAMIC ACID IMPROVES TOTAL CELL NUMBER IN PIG NUCLEAR TRANSFER BLASTOCYSTS." Reproduction, Fertility and Development 24, no. 1 (2012): 125. http://dx.doi.org/10.1071/rdv24n1ab27.
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Treatment of reconstructed pig clones with the histone deacetylase inhibitor (HDACi) Scriptaid immediately after nuclear transfer (NT) and activation results in increased cloning efficiency. Aberrant gene expression examined in NT blastocyst stage embryos is only partially corrected by Scriptaid use; therefore, 2 other HDACi were examined in this study including the class I and II HDACi, suberoylanilide hydroxamic acid (SAHA) and its hydrophobic derivative 4-iodo-SAHA (I-SAHA). Blastocyst rates and total cell numbers were examined across 6 treatment groups (1 μM SAHA, 10 μM SAHA, 1 μM I-SAHA, 10 μM I-SAHA, 0.5 μM Scriptaid and no HDACi treatment). Nuclear transfer was performed on enucleated MII oocytes using 3 different cell lines. Clones were electrically fused and activated, treated with HDACi for 14 to 16 h and cultured to the blastocyst stage in PZM3 under low oxygen tension for 7 days. Blastocyst number was calculated from the total number of fused oocytes. Blastocysts were then fixed in 4% paraformaldehyde and total cell number was determined by Hoechst staining of nuclei. The results from all 3 cell lines were pooled and 782 embryos were examined for blastocyst development from 7 replicates. All statistical analysis was performed by SAS 9.1 and means were separated by least significant difference (P < 0.05). The treatment group 10 μM SAHA had the highest blastocyst rate of 41.9% (n = 124) and was significantly different than no HDACi treatment (29.2%, n = 161; P < 0.003). There was no significant difference in blastocyst rates between 1 μM SAHA, 10 μM SAHA, 1 μM I-SAHA and 0.5 μM Scriptaid with blastocyst rates of 31.6% (n = 168), 41.9% (n = 124) 34.2% (n = 76) and 40.2% (n = 179), respectively (P < 0.05). Treatment with 10 μM I-SAHA significantly decreased development when compared with the other HDACi treatments (17.6%, n = 74, P < 0.05). There was no interaction between treatment and cell line for blastocyst rates (P > 0.45). Total cell number was significantly higher in blastocysts from the 1 μM I-SAHA (37.9, n = 20) treatment group when compared with Scriptaid (29.9, n = 50) and no HDACi treatment (29.4, n = 42; P < 0.04). There were no significant improvements in total cell number between the other concentrations (P > 0.05). Additionally, there was also a significant interaction between cell line used for nuclear transfer and the total cell number (P < 0.002). Two treatments were selected to determine if 10 μM SAHA and 1 μM I-SAHA treatment postnuclear transfer was compatible with term development. Six embryo transfers were performed and 5 recipient pigs became pregnant and developed to term. The results of this study show that treatment with the HDACi, SAHA and I-SAHA postnuclear transfer has the same blastocyst rates as the commonly used HDACi, Scriptaid. Additionally, treatment with 1 μM I-SAHA improves total cell number when compared with Scriptaid or no HDACi treatment. Funding was provided by Food for the 21st Century.
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Wu, Shao, Zhi Luo, Peng-Jiu Yu, Hui Xie, and Yu-Wen He. "Suberoylanilide hydroxamic acid (SAHA) promotes the epithelial mesenchymal transition of triple negative breast cancer cells via HDAC8/FOXA1 signals." Biological Chemistry 397, no. 1 (January 1, 2016): 75–83. http://dx.doi.org/10.1515/hsz-2015-0215.
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Abstract Inhibitor of histone deacetylases (HDACIs) have great therapeutic value for triple negative breast cancer (TNBC) patients. Interestingly, our present study reveals that suberoyl anilide hydroxamic acid (SAHA), one of the most advanced pan-HDAC inhibitor, can obviously promote in vitro motility of MDA-MB-231 and BT-549 cells via induction of epithelial-mesenchymal transition (EMT). SAHA treatment significantly down-regulates the expression of epithelial markers E-cadherin (E-Cad) while up-regulates the mesenchymal markers N-cadherin (N-Cad), vimentin (Vim) and fibronectin (FN). However, SAHA has no effect on the expression and nuclear translocation of EMT related transcription factors including Snail, Slug, Twist and ZEB. While SAHA treatment down-regulates the protein and mRNA expression of FOXA1 and then decreases its nuclear translocation. Over-expression of FOXA1 markedly attenuates SAHA induced EMT of TNBC cells. Further, silence of HDAC8, while not HDAC6, alleviates the down-regulation of FOXA1 and up-regulation of N-Cad and Vim in MDA-MB-231 cells treated with SAHA. Collectively, our present study reveals that SAHA can promote EMT of TNBC cells via HDAC8/FOXA1 signals, which suggests that more attention should be paid when SAHA is used as anti-cancer agent for cancer treatment.
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DeRyckere, Deborah, Timothy P. Garrington, and Lia Gore. "Pre-Clinical Development of Suberoylanilide Hydroxamic Acid (SAHA, Vorinostat ™) for the Treatment of Pediatric Acute Leukemias." Blood 108, no. 11 (November 1, 2006): 2277. http://dx.doi.org/10.1182/blood.v108.11.2277.2277.
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Abstract Acute leukemia is the most common malignancy of childhood and despite a good outcome for the majority of patients, a proportion of patients has high-risk features, and a very poor prognosis for ultimate cure. As such, novel approaches to therapy and new agents are clearly needed to improve the efficacy and quality of treatment available. We are investigating the utility of several histone deacetylase inhibitors (HDACIs) in the treatment of pediatric acute leukemias. Two HDACIs, suberoylanilide hydroxamic acid (SAHA, Vorinostat™) and MS-275, exhibited broad spectrum anti-tumor activity against a panel of 12 pediatric ALL and 8 AML cell lines representing different cell lineages and stages of development, with clinically achievable IC50 values of approximately 200–900nM. Both agents induced apoptosis in a dose-dependent manner. However, SAHA and MS-275 had differential effects on cell cycle progression and differentiation. Treatment with MS-275 resulted in sustained accumulation of cells in G1 phase and cell line-specific changes in the expression of multiple hematopoietic differentiation markers, including HLA-DR, CD11b, CD13, CD33, and CD61. Differentiation of both AML and ALL cell lines was induced. In contrast, treatment with SAHA either had no effect on cell cycle distribution or caused a transient arrest in G1 phase, which was reversible within 24–48 hours. In addition, only minimal changes in the expression of defined hematopoietic differentiation markers were observed following treatment with SAHA. These data suggest that the anti-leukemia effects mediated by SAHA and MS-275 occur by different biochemical and cellular mechanisms. Consistent with this hypothesis, SAHA and MS-275 exhibited synergistic anti-leukemic activity in vitro in a sequence dependent-manner, with a mean combination index of 0.666 +/− 0.048 based on median effect analysis. Sequence-dependent synergy was noted in a variety of T-cell and pre-B cell lines, including cell lines possessing MLL translocations. Both SAHA and MS-275 exhibited synergistic interactions with drugs representing the topoisomerase II, DNA methyltransferase, and proteosome inhibitor classes based on median effect analysis and/or the universal response surface approach. Detailed data demonstrating the mechanism(s) of HDACI-mediated anti-leukemic synergy and sequence-dependence with these other agents will be presented.
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Dong, Guie, Jia Luo, Vijay Kumar, and Zheng Dong. "Inhibitors of histone deacetylases suppress cisplatin-induced p53 activation and apoptosis in renal tubular cells." American Journal of Physiology-Renal Physiology 298, no. 2 (February 2010): F293—F300. http://dx.doi.org/10.1152/ajprenal.00410.2009.
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Inhibitors of histone deacetylases, including suberoylanilide hydroxamic acid (SAHA) and trichostatin A (TSA), are emerging anticancer agents. In the current study, we examined the cytoprotective effects of these agents. Cisplatin induced 40–50% apoptosis in rat kidney proximal tubular cells in 18 h, which was suppressed to 20–30% by 1–5 μM SAHA or 0.1 μM TSA. Consistently, SAHA partially prevented cisplatin-induced caspase activation. The cytoprotective effects of SAHA and TSA were associated with long-term cell survival. During cisplatin treatment, Bax translocated to mitochondria, leading to cytochrome c release. Both Bax translocation and cytochrome c release were ameliorated by SAHA. Mechanistically, SAHA inhibited and TSA delayed p53 phosphorylation, acetylation, and activation during cisplatin incubation. At the upstream signaling level, SAHA blocked cisplatin-induced phosphorylation of Chk2, a key DNA damage response kinase. Interestingly, in HCT116 colon cancer cells, SAHA suppressed cisplatin-induced p53 activation, but enhanced apoptosis. The results suggest that inhibitors of histone deacetylases can protect against cisplatin nephrotoxicity by attenuating DNA damage response and associated p53 activation.
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Cubitt, C., S. Zhang, and A. Chiappori. "Single-agent and combination activity of suberoylanilide hydroxamic acid (SAHA, vorinostat) in small cell lung cancer (SCLC) cell lines." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): e14586-e14586. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.e14586.
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e14586 Background: SCLC represents a major therapeutic challenge. Histone deacetylase inhibitors (HDAC-I) are a new class of drugs. Exposure to HDAC-Is results in hyperacetylation of core histone proteins, with subsequent chromatin decondensation, and increased topoisomerase inhibitor (TI) DNA binding, with potentiation of DNA damage and apoptosis. This synergy is only observed when the HDAC-I precedes the TI. We investigated the activity of SAHA, an HDAC-I with broad activity in different cancer cell lines, and the potential synergy between SAHA and TIs, in SCLC cell lines. Methods: TIs were obtained from chemical supply companies and SAHA from Merck. Four different cell lines (DMS-114, NCI-H69, NCI-H82, and NCI-H526) were grown and cryopreserved in the recommended media. Drug activity was determined by a high-throughput CellTiter-Blue cell viability assay. A luciferase based assay (Caspase-Glo 3/7) was used to confirm apoptosis as the cause of cell viability reductions. The Chou and Talalay method was used to optimize the drug doses to use in a combination, and to determine the influence of drug sequencing on any additive or synergistic anti- tumor effect. Results: The 72 hours inhibitory concentration 50 (IC50) values corresponding to each drug and cell line is reported in the Table . Using the CellTiter-Blue cell viability assay, the combination index (CI) for SAHA with each of 2 TIs (topotecan and etoposide) was calculated concurrently and sequentially. The strongest synergism was always detected when SAHA and the TI were combined sequentially (SAHA first). This observation was reproduced when the CI was calculated using the Caspase-Glo 3/7 luciferase based assay. Conclusions: The anti-tumor activity of SAHA in SCLC cell lines is comparable to that of common TIs. The synergism observed between SAHA and TIs is sequence specific and highest when drugs are used sequentially (SAHA first). Clinical confirmation of this synergism is warranted in patients with SCLC. [Table: see text] No significant financial relationships to disclose.
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Sanchez-Gonzalez, Blanca, Koyu Hoshino, Carlos Bueso-Ramos, Hui Yang, Emile Youssef, Yanis Boumber, Claritsa Santos-Malave, and Guillermo Garci-Manero. "In Vitro Effects of the Combination of Idarubicin (IDA) with Suberoylanilide Hydroxamic Acid (SAHA) or Valproic Acid (VPA) in Leukemia Cell Lines." Blood 104, no. 11 (November 16, 2004): 1173. http://dx.doi.org/10.1182/blood.v104.11.1173.1173.
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Abstract The nucleosome is the basic structure of chromatin. Changes in the biochemical composition of nucleosome-associated histone tails are associated with specific gene activation states, and are the target of several antineoplastic agents such as histone deacetylase inhibitors (HDI). Nucleosomes are constrained into loops that are flanked by domains known as matrix-attached regions (MARs). MARs contain DNA topoisomerase II (Topo II) consensus sequences. Topo II is responsible for regulating and maintaining DNA topology and is the target of several antineoplastic agents such as the anthracycline IDA, an effect mediated by the induction of double strand DNA breaks (DSB). We hypothesized that the combination of a Topo II inhibitor and a HDI will have synergistic antileukemia activity. VPA and SAHA are two HDIs currently studied in several clinical trials with known antileukemia activity and tolerable toxicity. To test our hypothesis and to develop future clinical studies, we have analyzed the effect of the combination of IDA, a potent Topo II inhibitor, with VPA or SAHA. We treated the leukemic cells lines MOLT4 and HL60 with increasing doses of IDA (0.5-20nM), SAHA (0.3-3μM) or VPA (0.25-3mM) daily for 3 days. First, using trypan blue viability assays, we identified the IC10 of IDA to be 0.5nM for MOLT4 and 1.5nM for HL60. Doses in excess of 2μM of SAHA or 3mM of VPA resulted in more than 90% decrease in cell viability in both cell lines. Subsequently, SAHA at doses of 0.075-1μM and VPA at 1-3mM were used for the combination experiments with IDA at its specific cell line IC10. At low doses of SAHA (0.075-0.45 μM) and VPA (0.25-1 mM) the combination was shown to have synergistic antileukemia activity by the Fractional Product Method of Webb. These results were confirmed using Annexin V assays. Of importance, growth inhibition was independent of the sequence used. To analyze the effects of this combination on DSB generation, we analyzed using immonocytochemistry and western blot, the induction of γH2AX, a histone variant that has been identified as an early event after the DSBs. SAHA alone induced a modest increase in γH2AX compared to baseline, whereas IDA alone had a significant effect that was not potentiated by the addition of SAHA. Histone H3 and H4 acetylation increased in a dose-dependent manner (2.4–15 fold) with both SAHA and VPA, starting at 0.3μM of SAHA and 0.25mM of VPA. The addition of IDA had no significant effect on histone acetylation. Because of previous data indicating that HDIs may down-regulate the expression of Topo II-alpha, the target of IDA, we have studied using real-time PCR its levels prior and during exposure to the different combinations. SAHA or VPA had no effect on Topo II-alpha mRNA levels whereas IDA induced 2.0–3.5 fold its expression in a dose-independent manner, an effect no altered by the addition of SAHA or VPA. Expression of p21CIP1, that is silenced in both cell lines, was restored by single agent VPA, SAHA or IDA. The combination of these drugs resulted in an additive effect in terms of p21CIP1 induction. Despite this phenomenon, no changes in cell cycle status were observed in these cells. In summary, the combination of IDA and SAHA or VPA has potent in vitro antileukemia effect, and should be studied in clinical trials.
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Sun, Xiaoshen, Zainul S. Hasanali, Allshine Chen, Dianzheng Zhang, Xin Liu, Hong-Gang Wang, David J. Feith, Thomas P. Loughran, and Kailin Xu. "Suberoylanilide hydroxamic acid (SAHA) and cladribine synergistically induce apoptosis in NK-LGL leukaemia." British Journal of Haematology 168, no. 3 (October 4, 2014): 371–83. http://dx.doi.org/10.1111/bjh.13143.
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Suffredini, S., L. Gennaccaro, M. C. Florio, P. Pramstaller, and A. Rossini. "Effect of suberoylanilide hydroxamic acid (SAHA) on functional properties of HL-1 cardiomyocytes." Vascular Pharmacology 75 (December 2015): 70. http://dx.doi.org/10.1016/j.vph.2015.11.073.
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Dietrich, Charles S., Victoria L. Greenberg, Christopher P. DeSimone, Susan C. Modesitt, John R. van Nagell, Rolf Craven, and Stephen G. Zimmer. "Suberoylanilide hydroxamic acid (SAHA) potentiates paclitaxel-induced apoptosis in ovarian cancer cell lines." Gynecologic Oncology 116, no. 1 (January 2010): 126–30. http://dx.doi.org/10.1016/j.ygyno.2009.09.039.
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Hendricks, J. Adam, Edmund J. Keliher, Brett Marinelli, Thomas Reiner, Ralph Weissleder, and Ralph Mazitschek. "In Vivo PET Imaging of Histone Deacetylases by18F-Suberoylanilide Hydroxamic Acid (18F-SAHA)." Journal of Medicinal Chemistry 54, no. 15 (August 11, 2011): 5576–82. http://dx.doi.org/10.1021/jm200620f.
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Jang, Boonsil, Ji-Ae Shin, Yong-Soo Kim, Ji-Young Kim, Ho-Keun Yi, Il-Song Park, Nam-Pyo Cho, and Sung-Dae Cho. "Growth-suppressive effect of suberoylanilide hydroxamic acid (SAHA) on human oral cancer cells." Cellular Oncology 39, no. 1 (November 18, 2015): 79–87. http://dx.doi.org/10.1007/s13402-015-0255-3.
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Sangeetha, S. R., Nagendra Singh, John R. Vender, and Krishnan M. Dhandapani. "Suberoylanilide hydroxamic acid (SAHA) induces growth arrest and apoptosis in pituitary adenoma cells." Endocrine 35, no. 3 (March 17, 2009): 389–96. http://dx.doi.org/10.1007/s12020-009-9159-1.
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Futakuchi, Akiko, Toshihiro Inoue, Tomokazu Fujimoto, Utako Kuroda, Miyuki Inoue-Mochita, Eri Takahashi, Saori Ohira, and Hidenobu Tanihara. "Molecular Mechanisms Underlying the Filtration Bleb-Maintaining Effects of Suberoylanilide Hydroxamic Acid (SAHA)." Investigative Opthalmology & Visual Science 58, no. 4 (April 27, 2017): 2421. http://dx.doi.org/10.1167/iovs.16-21403.
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Nimmanapalli, Ramadevi, Lianne Fuino, Corinne Stobaugh, Victoria Richon, and Kapil Bhalla. "Cotreatment with the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) enhances imatinib-induced apoptosis of Bcr-Abl–positive human acute leukemia cells." Blood 101, no. 8 (April 15, 2003): 3236–39. http://dx.doi.org/10.1182/blood-2002-08-2675.
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Abstract Here we demonstrate that treatment with SAHA (suberoylanilide hydroxamic acid), a known inhibitor of histone deacetylases (HDACs), alone induced p21 and/or p27 expressions but decreased the mRNA and protein levels of Bcr-Abl, which was associated with apoptosis of Bcr-Abl–expressing K562 and LAMA-84 cells. Cotreatment with SAHA and imatinib (Gleevec) caused more down-regulation of the levels and auto-tyrosine phosphorylation of Bcr-Abl and apoptosis of these cell types, as compared with treatment with either agent alone (P < .05). This finding was also associated with a greater decline in the levels of phospho-AKT and Bcl-xL. Significantly, treatment with SAHA also down-regulated Bcr-Abl levels and induced apoptosis of CD34+ leukemia blast progenitor cells derived from patients who had developed progressive blast crisis (BC) of chronic myelocytic leukemia (CML) while receiving therapy with imatinib. Taken together, these findings indicate that cotreatment with SAHA enhances the cytotoxic effects of imatinib and may have activity against imatinib-refractory CML-BC.
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Badros, Ashraf, S. Philip, R. Niesvizky, O. Goloubeva, C. Harris, J. Zweibel, J. Wright, et al. "Phase I Trial of Suberoylanilide Hydroxamic Acid (SAHA) + Bortezomib (Bort) in Relapsed Multiple Myeloma (MM) Patients (pts)." Blood 110, no. 11 (November 16, 2007): 1168. http://dx.doi.org/10.1182/blood.v110.11.1168.1168.
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Abstract SAHA, vorinostat, an oral, histone deacetylase inhibitor, affects cell growth by modifying the transcription of cellular proteins such as histones, transcription factors, ubiqutin E3 ligases and stress response proteins (e.g. HSP90). In vitro, SAHA showed synergistic cytotoxicity with the proteasome inhibitor Bort in MM cells by disrupting aggregates of the ubiquitin conjugated aggresomes. The aims of the study were to determine the MTD, pharmacokinetics (PK) and pharmacodynamic (PD) effects and activity of SAHA plus Bort in pts with relapsed/refractory MM. Twenty-one Pts have been treated. Median age was 55 yrs (range 38–79). Median time from MM diagnosis to study entry was 5.3 yrs (range: 1.5–15 yrs). Isotypes included IgG (n=10), IgA (n=5), light chain (n=4), and nonsecretory (n=2). Twelve Pts had complex karyotype. Median number of prior regimens was 6 (range 3–10); including tandem SCT (n=11), one SCT (n=8), thalidomide (n=21) and lenalidomide (n=14). Nineteen pts had received a median of 2 (range: 1–5) Bort-based prior regimens, 14 Pts had PD to last Bort therapy. 19 pts had PD to last therapy, with a median of 20 days (15–39) between last therapy and study entry. Only 2 patients were in first relapse on thalidomide maintenance. Five 3-Pt cohorts were evaluated at various dose levels as outlined in the table below.The MTD of SAHA in cycle 1 was 400 mg daily, as 2 DLTs, grade 4 prolonged QT interval and grade 4-fatigue occurred in the 500 mg daily cohort. Several grade 3–4 toxicities were observed after cycle 2, including myelo-suppression requiring transfusional support and growth factors. Non-hematological toxicities grade 2 and higher included fatigue (n=5), diarrhea (n=3), atrial fibrillation (n=1), shingles (n=1), pneumonia (n=2, bacterial and RSV). In 16 pts evaluable for response, there was 1 nCR and 7 PR (overall response rate of 50%), 6 pts had stable disease and 3 had PD. At last follow up, three pts remain in remission off therapy for 3–5 months, 9 had PD and 5 have died. Dexamethasone was added 4 pts in cycle 2; with no upgrade in response. The PK of SAHA after a single oral dose were linear from 100–500 mg with mean AUC (0.7 + 0.45 to 4.4+ 0.07), Cmax (0.3 + 0.14 to 1.2 + 0.06) and Tmax (1.3 + 0.4 to 2.3 + 2.5). Ten pts had CD-138+ cells isolated from bone marrow on day 1 [median, 1.8 × 106, range: 0.2–42.6] and on day 11 of the first cycle [median, 0.9 × 106: range: 0.4–5.4] for PD studies. The MTD for SAHA plus Bort was 400 mg daily × 8 days plus1.3 mg/ m2 days 1, 4, 8 and 11. SAHA administration after Bort does not affect PK. The regimen showed promising responses in Bort-refractory pts and should be evaluated in a phase II trial. Study schedule/response Cohort Bort (mg/m2) SAHA (mg) No. Pts No Cycles Response Bort days 1, 4, 8, 11 of 21-day cycle + SAHA days 4–11. Pts received 8 cycles. Dexamethasone was added for nonresponders, cycle 2. * Of 10 pts to be treated at MTD. PR, partial response; NE, not evaluable; SD/PD, stable/progressive disease. 1 1.0 100 bid 3 5, 7, 5 SD, SD, SD 2 1.3 100 bid 3 5, 6, 3 SD, PR, PD 3 1.3 200 bid 3 8, 3, 8 VGPR, SD, PR 4 1.3 400 daily 3 5, 3, 3 SD, PD, PR 5 1.3 500 daily 3 7, 1, 1 PR, NE, NE MTD 1.3 400 daily 6* 4, 3, 2, “1, 1, 1” PR, PR, PR, “too early for evaluation”
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Chang, H., S. Y. Rha, H. Jeung, J. Ahn, J. Jung, T. Kim, H. Kwon, B. Kim, and H. C. Chung. "Gene-expression profiles related to a synergistic effect of taxane and suberoylanilide hydroxamic acid combination treatment in gastric cancer cells." Journal of Clinical Oncology 29, no. 4_suppl (February 1, 2011): 50. http://dx.doi.org/10.1200/jco.2011.29.4_suppl.50.
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50 Background: We evaluated the cytotoxic effects of combining of suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, with taxanes in human gastric cancer cell lines, and evaluated the pre-treatment difference of gene profile to identify genes that could potentially mediate the cytotoxic response. Methods: Twenty-five gastric cancer cell lines with 22K gene expression data were treated with SAHA and paclitaxel or docetaxel, and the synergistic interaction between the drugs was evaluated in vitro using the combination index (CI) method. We performed significance analysis of microarray (SAM) to identify chemosensitivity-related genes in gastric cancer cell lines that were concomitantly treated with SAHA and taxane. We generated a correlation-matrix between gene expression and CI values to identify genes whose expression correlated with a combined effect of taxanes and SAHA. Results: Taxane and SAHA combination had a synergistic cytotoxic effect against taxane-resistant gastric cancer cells. We selected 49 chemosensitivity-related genes, which were commonly identified in paclitaxel and docetaxel combined with SAHA, via SAM analysis. Among them, nine common genes (SLIT2, REEP2, EFEMP2, CDC42SE1, FSD1, POU1F1, ZNF79, ETNK1, and DOCK5) were extracted from the subsequent correlation-matrix analysis. Conclusions: Taxane and SAHA combination could be efficacious for the treatment of gastric cancer. The genes which were related with the synergistic response to taxane and SAHA could serve as surrogate biomarkers to predict the therapeutic response in gastric cancer patients. We are researching to determine the expression of the nine genes in malignant human gastric cancer tissue and to correlate them with clinical information. No significant financial relationships to disclose.
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Bogenberger, James, Michelle Kassner, Donald Chow, Holly Yin, and Raoul Tibes. "Phosphatase RNA-Interference Lethality Screening with Suberoylanilide Hyrdoxamic Acid In Myeloid Cell Lines." Blood 116, no. 21 (November 19, 2010): 1851. http://dx.doi.org/10.1182/blood.v116.21.1851.1851.
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Abstract Abstract 1851 Background: In previous work we performed RNAi sensitizer screening of epigenetic modulation with 5-Azacytidine and the human kinome. Few kinase hits were identified. Therefore we asked if phosphatases might be involved in modulating epigenetic therapies. Thus in order to identify potentiators of the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) we performed high-throughput RNA-interference (RNAi) lethality screening using the myeloid cell lines HEL, THP-1 and TF-1 in combination with SAHA. Methods: A small-interfering RNA (siRNA) library targeting 206 phosphatases with 4 sequences per target gene was used for this study. siRNA were transfected in a single-siRNA-per-well format in 384-well plates using commercial lipid-based transfection reagents. Non-silencing siRNA were included as negative controls to access non-specific siRNA toxicity and universal lethal siRNA were included as positive controls to indirectly assess functional transfection efficiency. After a 96 hour incubation period, cell viability/proliferation was measured with Cell Titer Glo. For analysis of screen data, log2 values of (SAHA + siRNA treatment/siRNA treatment only) were calculated. Potentiation was defined as two standard deviations from the median log2 ratio of all siRNA (excluding positive controls) on a plate-by-plate basis. Hits were defined as ≥ 2/4 siRNA sequences meeting potentiation criteria. Results: Transfection efficiency was 95, 90 and 70% for HEL, THP-1 and TF-1, respectively. All three cell lines were similarly sensitive to SAHA with IC50 values of 0.3, 0.4 and 0.6 μM for HEL, THP-1 and TF-1, respectively. Resulting SAHA concentrations for screens were between the IC5 to IC30. For THP-1, 5 phosphatases qualified according to the hit selection criteria applied indicating strong potentiation to SAHA. Of these 5 hits, 3 did not exhibit strong reductions in viability with siRNA alone, suggesting a SAHA-dependent relationship. For HEL and TF-1, although no phosphatases met the strict selection cutoff, there were several phosphatases exhibiting potentiation, suggesting biological relevance. The primary screening data and preliminary analysis will be validated with rigorous secondary experimentation and top hits for all cell lines will be investigated and advanced. Conclusions: While there are numerous kinase inhibitors in the clinic and in preclinical development, phosphatases are much less explored as therapeutic targets. Validated potentiating targets from this RNAi screen can facilitate the development of rational SAHA combination therapies. Disclosures: No relevant conflicts of interest to declare.
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Miksiunas, Rokas, Kestutis Rucinskas, Vilius Janusauskas, Siegfried Labeit, and Daiva Bironaite. "Histone Deacetylase Inhibitor Suberoylanilide Hydroxamic Acid Improves Energetic Status and Cardiomyogenic Differentiation of Human Dilated Myocardium-Derived Primary Mesenchymal Cells." International Journal of Molecular Sciences 21, no. 14 (July 8, 2020): 4845. http://dx.doi.org/10.3390/ijms21144845.
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Background. In this study the effect of histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) on the energetic status and cardiomyogenic differentiation of human healthy and dilated myocardium-derived mesenchymal stromal cells (hmMSC) have been investigated. Methods. The hmMSC were isolated from the healthy and dilated post-operation heart biopsies by explant outgrowth method. Cell proliferation, HDAC activity, mitochondrial membrane potential, and level of adenosine triphosphate (ATP) were evaluated. The effect of SAHA on mitochondrial parameters has been investigated also by Seahorse XF analyzer and cardiomyogenic differentiation was confirmed by the expression of transcription factor NK2 Homeobox 5 (Nkx2.5), cardiac troponin T and alpha cardiac actin at gene and protein levels. Results. Dilated myocardium-derived hmMSC had almost 1.5 folds higher HDAC activity compared to the healthy cells and significantly lower mitochondrial membrane potential and ATP level. HDAC class I and II inhibitor SAHA improved energetic status of mitochondria in dilated myocardium-isolated hmMSC and increased expression of cardiac specific proteins during 14 days of exposure of cells to SAHA. Conclusions. HDAC inhibitor SAHA can be a promising therapeutic for dilated cardiomyopathy (DCM). Dilated hmMSC exposed to SAHA improved energetic status and, subsequently, cardiomyogenic differentiation. Data suggest that human dilated myocardium-derived MSC still have cardio tissue regenerative potential, which might be stimulated by HDAC inhibitors.
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Mitsiades, Nicholas, Constantine S. Mitsiades, Paul G. Richardson, Ciaran McMullan, Vassiliki Poulaki, Galinos Fanourakis, Robert Schlossman, et al. "Molecular sequelae of histone deacetylase inhibition in human malignant B cells." Blood 101, no. 10 (May 15, 2003): 4055–62. http://dx.doi.org/10.1182/blood-2002-11-3514.
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Abstract Histone acetylation modulates gene expression, cellular differentiation, and survival and is regulated by the opposing activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs). HDAC inhibition results in accumulation of acetylated nucleosomal histones and induces differentiation and/or apoptosis in transformed cells. In this study, we characterized the effect of suberoylanilide hydroxamic acid (SAHA), the prototype of a series of hydroxamic acid–based HDAC inhibitors, in cell lines and patient cells from B-cell malignancies, including multiple myeloma (MM) and related disorders. SAHA induced apoptosis in all tumor cells tested, with increased p21 and p53 protein levels and dephosphorylation of Rb. We also detected cleavage of Bid, suggesting a role for Bcl-2 family members in regulation of SAHA-induced cell death. Transfection of Bcl-2 cDNA into MM.1S cells completely abrogated SAHA-induced apoptosis, confirming its protective role. SAHA did not induce cleavage of caspase-8, -9, or -3 in MM.1S cells during the early phase of apoptosis, and the pan-caspase inhibitor ZVAD-FMK did not protect against SAHA. Conversely, poly(ADP)ribose polymerase (PARP) was cleaved in a pattern indicative of calpain activation, and the calpain inhibitor calpeptin abrogated SAHA-induced cell death. Importantly, SAHA sensitized MM.1S cells to death receptor–mediated apoptosis and inhibited the secretion of interleukin 6 (IL-6) induced in bone marrow stromal cells (BMSCs) by binding of MM cells, suggesting that it can overcome cell adhesion–mediated drug resistance. Our studies delineate the mechanisms whereby HDAC inhibitors mediate anti-MM activity and overcome drug resistance in the BM milieu and provide the framework for clinical evaluation of SAHA, which is bioavailable, well tolerated, and bioactive after oral administration, to improve patient outcome.
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Stamatopoulos, Basile, Nathalie Meuleman, Cécile De Bruyn, Alain Delforge, Dominique Bron, and Laurence Lagneaux. "Effect of the Deacetylase Inhibitor Suberoylanilide Hydroxamic Acid (SAHA) On Chronic Lymphocytic Leukemia Cells: Apoptosis, Migration Impairment and Drug Sensitization." Blood 114, no. 22 (November 20, 2009): 3435. http://dx.doi.org/10.1182/blood.v114.22.3435.3435.
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Abstract Abstract 3435 Poster Board III-323 Chronic lymphocytic leukemia (CLL) is a neoplastic disorder that arises largely as a result of defective apoptosis leading to chemoresistance. Furthermore, SDF-1 and its receptor CXCR4 has been shown to play an important role in CLL cell trafficking and survival. Since histone acetylation is involved in the modulation of gene expression, cellular differentiation, and survival, we evaluated the effects of suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, on CLL cells in vitro and in particular on cell survival, CXCR4 expression, migration and in combination with different chemotherapies. Here, we showed that a 48-hour treatment of SAHA induced a dose-dependent decrease in CLL cell viability via apoptosis (n=20, p=0.0032). This effect was also seen in previously untreated and chemoresistant CLL patients. Using specific caspase inhibitors, we demonstrated the participation of caspases-3, -6 and -8, suggesting an activation of the extrinsic pathway. Additionally, SAHA decreased actin polymerization (about 45%) in response to SDF-1 (n=6, p=0.0313). SAHA also significantly decreased CXCR4 mRNA (n=10, p=0.0010) and protein expression (n=25, p<0.0001). Consequently, CLL cell migration in response to SDF-1 (n=17, p=0.0003) or through bone marrow stromal cells (pseudoemperipolesis) was dramatically impaired. Finally, SAHA at low concentration (5μM) could increase sensitivity of CLL cells to fludarabine, flavopiridol, thalidomide or bortezomib. In conclusion, SAHA induces apoptosis in CLL cells via the extrinsic pathway and downregulates CXCR4 expression leading to decreased cell migration. SAHA (alone or in combination with other drugs) represents thus a promising therapeutic approach to inhibiting migration, inducing apoptosis in CLL cell and potentially overcoming drug resistance. Disclosures No relevant conflicts of interest to declare.
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Uchida, Hiroshi, Tetsuo Maruyama, Takashi Nagashima, Hironori Asada, and Yasunori Yoshimura. "Histone Deacetylase Inhibitors Induce Differentiation of Human Endometrial Adenocarcinoma Cells through Up-Regulation of Glycodelin." Endocrinology 146, no. 12 (December 1, 2005): 5365–73. http://dx.doi.org/10.1210/en.2005-0359.
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Histone reversible acetylation, which is controlled by histone acetyltransferases and deacetylases, plays a fundamental role in gene transcription. Histone deacetylase inhibitors (HDACIs), such as trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA), have been characterized not only as anticancer drugs, but also as cytodifferentiation-inducing agents. In human endometrium, postovulatory production of progesterone directs estrogen-primed endometrial glandular cells to differentiate and thereby produce a number of unique bioactive substances, including glycodelin, that are critical for implantation at the secretory phase of the menstrual cycle. In this study, we show that TSA and SAHA, belonging to the hydroxamic acid group of HDACIs, can induce the phenotype of a human endometrial adenocarcinoma cell line, Ishikawa (originally derived from the glandular component of the endometrium), to differentiate to closely resemble normal endometrial epithelium in a time- and dose-dependent manner, as determined by morphological changes, synthesis of glycogen, and expression of secretory phase-specific proteins, including glycodelin. The proliferation- and differentiation-modulating effects elicited by TSA and SAHA at their optimal concentrations were comparable or more potent than those exerted by combined treatment with progesterone and estradiol. Furthermore, the gene silencing of glycodelin by small interference RNA resulted in the blockade of HDACI-induced differentiation in Ishikawa cells, suggesting the requirement for glycodelin for endometrial epithelial differentiation. Our results collectively indicate that TSA and SAHA are potent differentiation inducers for endometrial glandular cells, providing a clue for a possible therapeutic strategy to modulate endometrial function by targeting glycodelin.
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Wu, Kan, Xueqin Chen, Xufeng Chen, Shirong Zhang, Yasi Xu, Bing Xia, and Shenglin Ma. "Suberoylanilide hydroxamic acid enhances the radiosensitivity of lung cancer cells through acetylated wild-type and mutant p53-dependent modulation of mitochondrial apoptosis." Journal of International Medical Research 49, no. 2 (February 2021): 030006052098154. http://dx.doi.org/10.1177/0300060520981545.
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Objective Suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, has shown potential as a candidate radiosensitizer for many types of cancers. This study aimed to explore the radiosensitization mechanism of SAHA in lung cancer cells. Methods Mutations in p53 were generated by site-directed mutagenesis using polymerase chain reaction. Transfection was performed to generate H1299 cells carrying wild-type or mutant p53. The radiosensitizing enhancement ratio was determined by clonogenic assays. Mitochondrial apoptosis was detected using JC-1 staining and flow cytometry analysis. Results Our results showed that SAHA induced radiosensitization in H1299 cells expressing wild-type p53, p53R175H or p53P223L, but this enhanced clonogenic cell death was not observed in parental H1299 (p53-null) cells or H1299 cells expressing p53 with K120R, A161T and V274R mutations. In SAHA-sensitized cells, mitochondrial apoptosis was induced following exposure to irradiation. Additionally, we observed that a secondary mutation at K120 (K120R) could eliminate p53-mediated radiosensitization and mitochondrial apoptosis. Conclusions The results of this study suggest that wild-type and specific mutant forms of p53 mediate SAHA-induced radiosensitization by regulating mitochondrial apoptosis, and the stabilization of K120 acetylation by SAHA is the molecular basis contributing to radiosensitization in lung cancer cells.
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Roostaee, Alireza, Yannick D. Benoit, Amel Guezguez, Aline Simoneau, and Jean-Francois Beaulieu. "Tu1214 The Histone Deacetylase Inhibitor Suberoylanilide Hydroxamic Acid (SAHA) Induces Differentiation of Intestinal Cells." Gastroenterology 146, no. 5 (May 2014): S—785. http://dx.doi.org/10.1016/s0016-5085(14)62835-3.
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Ghayad, Sandra E., Ghina Rammal, Omar Sarkis, Hussein Basma, Farah Ghamloush, Assil Fahs, Mia Karam, et al. "The histone deacetylase inhibitor Suberoylanilide Hydroxamic Acid (SAHA) as a therapeutic agent in rhabdomyosarcoma." Cancer Biology & Therapy 20, no. 3 (October 11, 2018): 272–83. http://dx.doi.org/10.1080/15384047.2018.1529093.
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Sardiu, Mihaela E., Karen T. Smith, Brad D. Groppe, Joshua M. Gilmore, Anita Saraf, Rhonda Egidy, Allison Peak, et al. "Suberoylanilide Hydroxamic Acid (SAHA)-Induced Dynamics of a Human Histone Deacetylase Protein Interaction Network." Molecular & Cellular Proteomics 13, no. 11 (July 29, 2014): 3114–25. http://dx.doi.org/10.1074/mcp.m113.037127.
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Richon, Victoria M., Xianbo Zhou, Richard A. Rifkind, and Paul A. Marks. "Histone Deacetylase Inhibitors: Development of Suberoylanilide Hydroxamic Acid (SAHA) for the Treatment of Cancers." Blood Cells, Molecules, and Diseases 27, no. 1 (January 2001): 260–64. http://dx.doi.org/10.1006/bcmd.2000.0376.
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Bouchecareilh, Marion, Darren M. Hutt, Patricia Szajner, Terence R. Flotte, and William E. Balch. "Histone Deacetylase Inhibitor (HDACi) Suberoylanilide Hydroxamic Acid (SAHA)-mediated Correction of α1-Antitrypsin Deficiency." Journal of Biological Chemistry 287, no. 45 (September 20, 2012): 38265–78. http://dx.doi.org/10.1074/jbc.m112.404707.
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Cao, Hua. "Induction of Human γ Globin Gene Expression by Histone Deacetylase Inhibitors." Blood 108, no. 11 (November 16, 2006): 1583. http://dx.doi.org/10.1182/blood.v108.11.1583.1583.
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In previous studies we have showed that HDAC inhibitors including hydroxamic acid derivatives of short chain fatty acids butyryl hydroxamate, propionyl hydroxamate, subericbis hydroxamic acid (SBHA), and suberoylanilide hydroxamic acid (SAHA), are potent inducers of γ globin gene expression in in vitro luciferase assays and in cultures of human adult erythroid progenitor cells. In this present study, we used μLCR Aγ transgenic mice to test whether these compounds can also induce γ gene expression in vivo. We found that in addition to γ gene induction these compounds have considerable erythropoiesis activity. Thus, Propionyl and butyryl hydroxamate increased reticulocytes of mice by 71% and 139%, the in vivo BFUe counts by 75% and 51% and the in vivo γ gene expression by 33.9% and 71% respectively. SBHA and SAHA had no erythropoietic activity in vivo. We conclude that Hydroxamic acid derivatives can stimulate both the in vivo erythropoiesis and fetal globin production in a thalassemic murine model. Cyclic depsipeptide FK228 is a highly potent histone deacetylase inhibitor, currently in clinical trials in cancer patients. We investigated whether FK228 also functions as inducer of human γ globin gene expression and compared Hb F induction by FK228 to that of four other HDAC inhibitors, including hydroxamic acids (TSA), synthetic benzamides (MS-275), and two cyclic tetrapeptides, Apicidin and HC-Toxin. Our results showed that FK228 is the most potent fetal hemoglobin inducer among all the HDAC inhibitors tested in our laboratory. In a concentration of 0.84 nanomolar, FK228 induces γ gene promoter activity in the dual luciferase assay by 7.81 fold. In the human erythroid progenitor cell cultures it increases the levels of γ mRNA by 8.48 fold in a concentration of 0.143 nM. In contrast, fetal hemoglobin induction by other HDAC inhibitors is achieved in concentrations that are 100 to 1000 fold higher. We conclude that FK228 is a promising compound for induction of Hb F in patients with sickle cell disease and thalassemia.
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Ravandi, Farhad, Stefan Faderl, Deborah Thomas, Jan Burger, Charles Koller, Guillermo Garcia-Manero, Gail Morris, Ritva Torma, Hagop Kantarjian, and Jean-Pierre Issa. "Phase I Study of Suberoylanilide Hydroxamic Acid (SAHA) and Decitabine in Patients with Relapsed, Refractory or Poor Prognosis Leukemia." Blood 110, no. 11 (November 16, 2007): 897. http://dx.doi.org/10.1182/blood.v110.11.897.897.
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Abstract Few effective treatment strategies are available for patients with relapsed and refractory leukemias and their prognosis remains poor. Epigenetic therapy by targeting epigenetic pathways is currently under investigation as a potential strategy to reverse transcriptional silencing of tumor suppressor genes leading to the reversal of the neoplastic phenotype. 5-Aza-2′-deoxycytidine (DAC, Decitabine) and suberoylanilide hydroxamic acid (SAHA, Vorinostat) can affect epigenetic change in leukemic cells through promoter CpG island hypomethylation and inhibition of histone deacetylation, respectively. We have conducted a phase I study of combination of DAC plus SAHA (using a sequential dosing schedule) in patients with relapsed, refractory, or high risk leukemias. Five cohorts (Dose levels 0 – 4) of 6 patients each received escalating doses of decitabine (10, 10, 15, 20 and 25 mg/m2 IV daily x 5) followed by SAHA (100 mg PO tid x 14 in the first cohort and 200 mg PO tid x 14 in all subsequent cohorts). From 7/06 to 8/07, 31 patients (21 M, 10 F) have been accrued with the last cohort receiving DAC 25 mg/m2 daily x 5 followed by SAHA 200 mg tid x 14. Median age was 62 years (range, 22 – 82). Twenty one patients (68%) had refractory AML (5 with prior MDS), 1 (3%) refractory acute biphenotypic leukemia, 3 (10%) relapsed MDS, 3 (10%) refractory ALL, 1 (3%) untreated high risk MDS, and 2 (6%) Philadelphia chromosome-negative myeloproliferative disease. Median number of prior regimens was 2 (range, 0 – 8). One patient did not receive therapy due to rapid disease progression and 30 were evaluable for assessment of toxicity. Median number of cycles of DAC + SAHA administered was 2 (range, 0 – 6). One patient had pulmonary embolism and one grade 3 diarrhea, both considered to be dose limiting. Other adverse events included syncope, neutropenic fever, diarrhea, fatigue, renal failure, rash, nausea, thrombosis, and angioedema. Of the 30 evaluable pts, 1 patient achieved complete remission lasting 5.5 weeks, 4 had significant reductions in the bone marrow blasts, 4 had stable disease, 7 are too early for response evaluation, and 14 had no response/disease progression. We conclude that the sequential combination of DAC and SAHA is safe and has activity in advanced leukemia. Correlative studies evaluating DNA promoter methylation and histone acetylation will be presented.