MS-275, a potent orally available inhibitor of histone deacetylases—The development of an anticancer agent

Hess‐Stumpp, Holger; Bracker, Tomke Ute; Henderson, David; Politz, Oliver

doi:10.1016/j.biocel.2007.02.009

Cited by 136 publications

(105 citation statements)

References 73 publications

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“…This combination of RAMBA VN/66-1 and HDACI MS-275 is highly effective in inhibiting PC-3 cell and tumour growth. In the near future, we plan to repeat the in vivo study with oral dosing, since MS-275 is orally bioavailable and is a preferred route of administration (Hess-Stumpp et al, 2007). Additionally, we propose to further investigate the mechanism of induction of DNA damage.…”

Section: Discussionmentioning

confidence: 99%

“…N-(2-aminophenyl)4-[N-(pyridine-3-yl-methoxy-carbonyl) aminomethyl]benzamide has previously been shown to reactivate RARb2 in a variety of cell lines including prostate, renal carcinoma and breast cancer cells (Hess-Stumpp et al, 2007). We found that while MS-275 alone induced more than a three-fold increase in RARb2 expression, the combination induced almost a seven-fold increase as determined by RT -PCR ( Figure 3C).…”

Section: Treatments With Vn/66-1 or Ms-275 Or Their Combination Reactmentioning

confidence: 99%

“…This leads to acetylation of histones, which opens up the chromatin structure allowing transcription of antigrowth and proapoptotic genes to occur. It should be noted that MS-275 is now in phase I/II clinical trials for various solid tumours and haematological malignancies (Hess-Stumpp et al, 2007).…”

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confidence: 99%

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MS-275 synergistically enhances the growth inhibitory effects of RAMBA VN/66-1 in hormone-insensitive PC-3 prostate cancer cells and tumours

2008

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Combining drugs, which target different signalling pathways, often decreases adverse side effects while increasing the efficacy of treatment. The objective of our study was to determine if the combination of our novel atypical retinoic acid metabolism-blocking agent (RAMBA) VN/66-1 and a promising histone deacetylase inhibitor N-(2-aminophenyl)4-[N-(pyridine-3-yl-methoxycarbonyl)aminomethyl]benzamide (MS-275) would show enhanced antineoplastic activity on human PC-3 prostate cancer cells/ tumours and also to decipher the molecular mechanisms of action. The combination of VN/66-1 þ MS-275 was found to be synergistic in inhibiting PC-3 cell growth, caused cell cytostaticity/cytotoxicity and induced marked G2/M phase arrest and apoptosis. In mice with well-established PC-3 tumours, VN/66-1 (5 and 10 mg kg À1 day À1 ) caused significant suppression of tumour growth compared with mice receiving vehicle alone. Furthermore, treatment with VN/66-1 (10 mg kg À1 day À1 ) þ MS-275 (2.5 mg kg À1 day À1 ) for 18 days resulted in an 85% reduction in final mean tumour volume compared with control and was more effective than either agent alone. Mechanistic studies indicated that treatment of PC-3 cells/tumours with VN/66-1 þ MS-275 caused DNA damage (upregulation of gH2AX), hyperacetylation of histones H3 and H4, upregulation of retinoic acid receptor-b, p21 WAF1/CIP1 , E-cadherin, and Bad and downregulation of Bcl-2. These data suggest that the mechanism of action of the combination of agents is DNA damage-induced p21 activation, resulting in inhibition of the Cdc2/cyclin B complex and accumulation of cells in G2/M phase. In addition, the combination caused modulation and induction of apoptosis. These results suggest that VN/66-1 or its combination with MS-275 may be a novel therapy for the treatment of prostate carcinoma.

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Section: Discussionmentioning

confidence: 99%

Section: Treatments With Vn/66-1 or Ms-275 Or Their Combination Reactmentioning

confidence: 99%

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MS-275 synergistically enhances the growth inhibitory effects of RAMBA VN/66-1 in hormone-insensitive PC-3 prostate cancer cells and tumours

2008

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“…Because HDIs are known to interfere with the ability of cell lines to mount an IFN response, we examined the possibility that pretreatment of PC3 cells with the HDIs would sensitize them to VSV infection and subsequent virus-induced apoptosis. For these experiments, we used an attenuated strain of VSV encoding the GFP gene (VSV-⌬51-GFP) and 2 distinct HDI-MS-275 and SAHA (Vorinostat)-which have shown promising anti-cancer activity in preclinical (MS-275) and clinical (SAHA/Vorinostat) trials (22)(23)(24)(25)(26)(27)(28)(29)(30)(31). Both HDIs dramatically increased VSV replication in PC3 cells as early as 24 h after infection, at which time robust GFP expression was detected by fluorescence microscopy and FACS analysis.…”

Section: Hdi Treatment Sensitizes Pc3 Prostate Cancer Cells To Vsv-mementioning

confidence: 99%

Chemical targeting of the innate antiviral response by histone deacetylase inhibitors renders refractory cancers sensitive to viral oncolysis

Nguyên

Abdelbary

Arguello

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

161

176

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“…clinical trials (Hess-Stumpp et al, 2007;Lee et al, 2008), it appears feasible that this combination approach of HDACI for chemosensitization of medulloblastoma can be translated into a clinical application.…”

mentioning

confidence: 99%

Histone deacetylase inhibitors prime medulloblastoma cells for chemotherapy-induced apoptosis by enhancing p53-dependent Bax activation

et al. 2011

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Despite aggressive therapies, the prognosis of children with high-risk medulloblastoma is still poor, thus underscoring the need to develop novel treatment strategies. Here, we report that histone deacetylase inhibitors (HDACI), that is, MS-275, valproic acid or SAHA, provide a novel strategy for sensitization of medulloblastoma to DNA-damaging drugs such as Doxorubicin, VP16 and Cisplatin by promoting p53-dependent, mitochondrial apoptosis. Mechanistic studies reveal that single-agent treatment with MS-275 causes acetylation of the non-histone protein Ku70, an event reported to release Bax from Ku70, whereas DNAdamaging drugs trigger p53 acetylation and accumulation. Combined treatment with MS-275 and Doxorubicin or VP16 cooperates to promote binding of p53 to Bax and p53-dependent Bax activation, resulting in enhanced loss of mitochondrial membrane potential, cytochrome c release and caspase-dependent apoptosis. Overexpression of Bcl-2 almost completely abolishes the MS-275-mediated chemosensitization, underlining the importance of the mitochondrial pathway for inducing apoptosis. Also, MS-275 cooperates with chemotherapeutics to inhibit long-term clonogenic survival. Most importantly, MS-275 increases chemotherapeutic drug-induced apoptosis in primary medulloblastoma samples, and cooperates with Doxorubicin to suppress medulloblastoma growth in an in vivo model, which underscores the clinical relevance of the findings. Thus, HDACI such as MS-275 present a promising approach for chemosensitization of medulloblastoma by enhancing mitochondrial apoptosis in a p53-dependent manner. These findings have important clinical implications for the design of experimental treatment protocols for medulloblastoma.

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MS-275, a potent orally available inhibitor of histone deacetylases—The development of an anticancer agent

Cited by 136 publications

References 73 publications

MS-275 synergistically enhances the growth inhibitory effects of RAMBA VN/66-1 in hormone-insensitive PC-3 prostate cancer cells and tumours

MS-275 synergistically enhances the growth inhibitory effects of RAMBA VN/66-1 in hormone-insensitive PC-3 prostate cancer cells and tumours

Chemical targeting of the innate antiviral response by histone deacetylase inhibitors renders refractory cancers sensitive to viral oncolysis

Histone deacetylase inhibitors prime medulloblastoma cells for chemotherapy-induced apoptosis by enhancing p53-dependent Bax activation

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