Molecular Imaging Laboratory, Department of Radiology, Third Affiliated Hospital of Sun Yat-sen University, Interventional Radiology Institute, Guangzhou, PR China.
Oncol Rep. 2011 Feb;25(2):461-8. doi: 10.3892/or.2010.1084. Epub 2010 Dec 8.
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF family of cytokines and has been shown to induce cell apoptosis in many types of tumors, but not in normal cells. This tumor-selective property has made TRAIL a promising approach for the development of cancer therapy. However, hepatocellular carcinoma (HCC) cells display a striking resistance to TRAIL. Although some chemotherapeutic agents can overcome this resistance, safety issues remain a concern because the combination of these agents and TRAIL has been reported to induce toxicity in normal hepatocytes. In this study, we examined whether cisplatin could reverse TRAIL resistance in HCC cells with different p53 status and evaluated the toxicity of combination TRAIL and cisplatin to normal hepatocytes and mesenchymal stem cells (MSCs). We observed that cisplatin could efficiently sensitize HCC cells, but not hepatocytes and MSCs to TRAIL-induced apoptosis within a wide therapeutic window. The apoptosis of HCC cells only partially depended on the upregulation of DR5 and the status of p53. In addition, we provide favorable evidence supporting the feasibility of the combination of chemotherapy and MSCs transduced with TRAIL.
肿瘤坏死因子（TNF）相关凋亡诱导配体（TRAIL）是 TNF 细胞因子家族的一员，已被证明可诱导多种类型肿瘤细胞凋亡，但不会诱导正常细胞凋亡。这种肿瘤选择性特性使 TRAIL 成为癌症治疗开发的一种有前途的方法。然而，肝细胞癌（HCC）细胞对 TRAIL 表现出明显的耐药性。尽管一些化疗药物可以克服这种耐药性，但安全性问题仍然令人关注，因为这些药物与 TRAIL 的联合应用已被报道会导致正常肝细胞毒性。在这项研究中，我们研究了顺铂是否可以逆转不同 p53 状态的 HCC 细胞对 TRAIL 的耐药性，并评估了 TRAIL 和顺铂联合应用对正常肝细胞和间充质干细胞（MSCs）的毒性。我们观察到，顺铂可以在广泛的治疗窗口内有效地增敏 HCC 细胞，但不能增敏 TRAIL 诱导的凋亡。HCC 细胞的凋亡仅部分依赖于 DR5 的上调和 p53 的状态。此外，我们提供了有利的证据，支持化疗药物联合转染 TRAIL 的间充质干细胞的可行性。
