Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University, Yokohama, Japan.
J Antibiot (Tokyo). 2012 Jun;65(6):295-300. doi: 10.1038/ja.2012.21. Epub 2012 Apr 4.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been considered as a possible therapeutic agent for cancer treatment. This is because of its selective cytotoxicity against various cancer cells without a detrimental effect on normal cells. However, recent studies have reported that the potential application of TRAIL in cancer therapy is limited, as many cancer cells have been found to be resistant to TRAIL. Therefore, small molecule compounds that potentiate the cytotoxicity of TRAIL would be strategic candidates for therapeutic applications in combination with TRAIL. Here we found that a combined treatment of inostamycin and TRAIL synergistically induced caspase-dependent apoptosis in HCT116 cells. Inostamycin upregulated DR5, and a knockdown of DR5 suppressed the apoptosis that was synergistically induced by co-treatment with inostamycin and TRAIL. Moreover, inostamycin increased the expression of DR5 on the cell surface. Therefore, inostamycin-increased cell surface expression of DR5 may have contributed to the enhancement of TRAIL-induced apoptosis. Our study suggests that combined treatment with inostamycin and TRAIL may offer a strategy to overcome TRAIL resistance in tumor cells.
肿瘤坏死因子相关凋亡诱导配体（TRAIL）被认为是一种治疗癌症的潜在治疗剂。这是因为它对各种癌细胞具有选择性细胞毒性，而对正常细胞没有不良影响。然而，最近的研究报告称，TRAIL 在癌症治疗中的潜在应用受到限制，因为许多癌细胞已被发现对 TRAIL 具有抗性。因此，能够增强 TRAIL 细胞毒性的小分子化合物将成为与 TRAIL 联合治疗的治疗应用的战略候选物。在这里，我们发现伊诺霉素和 TRAIL 的联合治疗协同诱导 HCT116 细胞中 caspase 依赖性凋亡。伊诺霉素上调 DR5，并且 DR5 的敲低抑制了伊诺霉素和 TRAIL 共同处理协同诱导的凋亡。此外，伊诺霉素增加了细胞表面 DR5 的表达。因此，伊诺霉素增加的 DR5 细胞表面表达可能有助于增强 TRAIL 诱导的凋亡。我们的研究表明，伊诺霉素和 TRAIL 的联合治疗可能为克服肿瘤细胞中 TRAIL 耐药性提供一种策略。
