The histone deacetylase inhibitor suberic bishydroxamate: a potential sensitizer of melanoma to TNF-related apoptosis-inducing ligand (TRAIL) induced apoptosis
The histone deacetylase inhibitor suberic bishydroxamate: a potential sensitizer of melanoma to TNF-related apoptosis-inducing ligand (TRAIL) induced apoptosis
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DOI：
10.1016/s0006-2952(03)00509-4
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发表时间：
2003-10-15
影响因子：
5.8
通讯作者：
Hersey, P
中科院分区：
文献类型：
--
作者：
Zhang, XD;Gillespie, SK;Hersey, P
TRAIL似乎是一种很有前途的抗癌药物，因为它可以诱导多种癌细胞而不是正常组织的凋亡。黑色素瘤细胞对trail诱导的细胞凋亡的敏感性差异很大，因为它们对细胞凋亡的抵抗机制不同。我们在本报告中讨论了一种历史性的去乙酰化酶抑制剂SBHA对trail诱导的细胞凋亡的潜在影响。历史性去乙酰化酶（HDAC）抑制剂调节组蛋白乙酰化，从而调节某些基因的转录活性，导致细胞生长停滞、细胞分化和凋亡。Suberic bishydroxamate （SBHA）是一种相对较新的HDAC抑制剂，通过线粒体和caspase依赖途径诱导大多数黑色素瘤细胞系凋亡。这是由于它调节多种蛋白的表达，这些蛋白参与线粒体凋亡途径（Bcl-2家族成员）或凋亡的最后阶段（caspase-3和XIAP）。无毒剂量的SBHA和TRAIL联合治疗导致TRAIL诱导的黑色素瘤细胞凋亡显著增加，但对黑色素细胞没有毒性。SBHA似乎通过上调trail诱导的凋亡通路中的促凋亡蛋白如caspase-8、caspase-3、Bid、Bak和Bax，以及上调BH3结构域蛋白Bim，使黑色素瘤对trail诱导的凋亡敏感。这可能与活化的Bid一起协同作用，引起线粒体的变化。SBHA处理还导致Bcl-2家族抗凋亡成员Bcl-X-L和Mcl-1以及IAP成员XIAP的下调，这些变化将进一步促进凋亡信号传导。因此，SBHA似乎是克服黑素瘤对trail诱导的细胞凋亡的抗性的有效药物。(C) 2003 Elsevier Inc.版权所有。
TRAIL appears to be a promising anticancer agent in that it induces apoptosis in a wide range of cancer cells but not normal tissues. sensitivity of melanoma cells to TRAIL-induced apoptosis varied considerably because of their development of various resistance mechanisms against apoptosis. We discuss in this report the potential effect of a historic deacetylase inhibitor SBHA on TRAIL-induced apoptosis. Historic deacetylase (HDAC) inhibitors regulate histone acetylation and thereby modulate the transcriptional activity of certain genes leading to cell growth arrest, cellular differentiation, and apoptosis. Suberic bishydroxamate (SBHA) is a relatively new HDAC inhibitor that induced apoptosis in the majority of melanoma cell lines through a mitochondrial and caspase-dependent pathway. This was due to its regulation of the expression of multiple proteins that are involved in either the mitochondrial apoptotic pathway (Bcl-2 family members) or the final phase of apoptosis (caspase-3 and XIAP). Co-treatment with SBHA at nontoxic doses and TRAIL resulted in a marked increase in TRAIL-induced apoptosis of melanoma, but showed no toxicity to melanocytes. SBHA appeared to sensitize melanoma to TRAIL-induced apoptosis by up-regulation of pro-apoptotic proteins in the TRAIL-induced apoptotic pathway such as caspase-8, caspase-3, Bid, Bak, and Bax, and up-regulation of the BH3 domain only protein, Bim. This, together with activated Bid, may have acted synergistically to cause changes in mitochondria. Treatment with SBHA also resulted in down-regulation of antiapoptotic members of the Bcl-2 family, Bcl-X-L and Mcl-1, and the IAP member, XIAP These changes would further facilitate apoptotic signaling. SBHA appeared therefore to be a potent agent in overcoming resistance of melanoma to TRAIL-induced apoptosis. (C) 2003 Elsevier Inc. All rights reserved.