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.
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DOI：
10.1038/sj.bjc.6604295
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发表时间：
2008-04-08
影响因子：
8.8
通讯作者：
Njar, V. C. O.
中科院分区：
文献类型：
--
作者：
Khandelwal, A.;Gediya, L. K.;Njar, V. C. O.
关键词：
针对不同信号通路的联合药物通常可以减少不良副作用，同时提高治疗效果。本研究的目的是确定我们的新型非典型视黄酸代谢阻断剂（RAMBA）VN/66-1和一种有前途的组蛋白脱乙酰基酶抑制剂N-（2-氨基苯基）4-[N-（吡啶-3-基-甲氧基-羰基）氨基甲基]苯甲酰胺（MS-275）的组合是否会对人PC-3前列腺癌细胞/肿瘤显示出增强的抗肿瘤活性，并破译作用的分子机制。VN/66-1+MS-275联合应用可协同抑制PC-3细胞生长，引起细胞抑制/细胞毒性，并诱导明显的G2/M期阻滞和凋亡。在具有良好建立的PC-3肿瘤的小鼠中，与仅接受载体的小鼠相比，VN/66-1（5和10 mg kg−1天−1）引起肿瘤生长的显著抑制。此外，与对照组相比，VN/66-1（10 mg kg−1天−1）+MS-275（2.5 mg kg−1天−1）治疗18天导致最终平均肿瘤体积减少85%，并且比单独使用任何一种药物更有效。机制研究表明，用VN/66-1+MS-275处理PC-3细胞/肿瘤引起DNA损伤（γ H2 AX上调）、组蛋白H3和H4的高度乙酰化、视黄酸受体-β、p21 WAF 1/CIP 1、E-钙粘蛋白和Bad的上调以及Bcl-2的下调。这些数据表明，药物组合的作用机制是DNA损伤诱导的p21活化，导致Cdc 2/细胞周期蛋白B复合物的抑制和细胞在G2/M期的积累。此外，该组合引起细胞凋亡的调节和诱导。提示VN/66-1或联合MS-275治疗前列腺癌可能是一种新的治疗方法。
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-methoxy-carbonyl)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+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−1 day−1) caused significant suppression of tumour growth compared with mice receiving vehicle alone. Furthermore, treatment with VN/66-1 (10 mg kg−1 day−1)+MS-275 (2.5 mg kg−1 day−1) 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+MS-275 caused DNA damage (upregulation of γH2AX), hyperacetylation of histones H3 and H4, upregulation of retinoic acid receptor-β, p21WAF1/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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影响因子：
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