Susceptibility of multidrug resistance tumor cells to apoptosis induction by histone deacetylase inhibitors
Susceptibility of multidrug resistance tumor cells to apoptosis induction by histone deacetylase inhibitors
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DOI：
10.1002/ijc.10998
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发表时间：
2003-05-01
影响因子：
6.4
通讯作者：
Saceda, M
中科院分区：
文献类型：
--
作者：
Castro-Galache, MD;Ferragut, JA;Saceda, M
我们研究的主要目的是分析新的抗癌药物，特别是组蛋白去乙酰化酶抑制剂在具有多药耐药表型的肿瘤细胞中的效率。我们报道组蛋白去乙酰化酶抑制剂Trichostatin A和Suberoylanilide Hydroxamic Acid （SAHA）在不同的耐药细胞中显著降低细胞活力并促进细胞凋亡，而对其亲本药物敏感细胞的影响程度要小得多。Trichostatin A和SAHA对药敏和耐药细胞的差异作用反映在耐药表型的主要特征上。因此，逆转录- pcr和Western免疫印迹证实，这两种组蛋白去乙酰化酶抑制剂均促进内源性p -糖蛋白下调，p -糖蛋白在耐药细胞中过表达。用p -糖蛋白cDNA转染药物敏感细胞，排除了组蛋白去乙酰化酶抑制剂诱导的p -糖蛋白下调与细胞凋亡之间的先验关联。结果表明组蛋白去乙酰化酶抑制剂在治疗获得性耐药癌症方面具有治疗潜力。(C) 2003 Wiley-Liss, Inc。
The main goal of our study has been to analyze the efficiency of new anticancer drugs, specifically histone deacetylase inhibitors, in tumor cells bearing a multidrug resistance phenotype. We report that the histone deacetylase inhibitors, Trichostatin A and Suberoylanilide Hydroxamic Acid (SAHA), dramatically reduce cell viability and promote apoptosis in different drug-resistant cells, affecting in a much lesser extent to their parental drug-sensitive counterparts. The differential effects induced by Trichostatin A and SAHA between drug-sensitive and drug-resistant cells are reflected on the main characteristics of the resistant phenotype. Thus, reverse transcription-PCR and Western immunoblots confirm that both histone deacetylase inhibitors promote endogenous down-regulation of P-glycoprotein, which is overexpressed in the drug-resistant cells. Transfection of drugsensitive cells with the P-glycoprotein cDNA ruled out the a priori possible association between apoptosis and down-regulation of P-glycoprotein induced by the histone deacetylase inhibitors. The results suggest a therapeutic potential of histone deacetylase inhibitors in the treatment of cancers with acquired resistance. (C) 2003 Wiley-Liss, Inc.