Department of Neurosurgery, The First Hospital of Jilin University, Changchun 130-021, PR China.
Oncol Rep. 2010 Apr;23(4):1053-62. doi: 10.3892/or_00000732.
Glioma is the most common type of brain tumors in adults, and treatment of high-grade gliomas is still palliative. Studies to date have revealed only modest effect in attenuating growth of these tumors with single agent therapy, but combination treatment appears to be more effective. Cyclophilin A (CypA), a target of immunosuppressive drugs cyclosporin A (CsA) and sanglifehrin A (SFA), is an intracellular protein that has peptidyl-prolyl cis-trans isomerase (PPIase) enzymatic activity. Previously, we showed that overexpressed CypA induced chemoresistance in cancer cells. Here we provide evidence that combination of cisplatin with either CsA or SFA synergistically enhances apoptotic cell death in C6 glioma cells, compared with single agent treatment. Enhanced apoptotic cell death is a result of an increase in ROS generation and a decrease in intracellular glutathione levels. Consistently, CypA knockdown by siRNA also enhances cisplatin-induced apoptosis. Immunohistochemical analysis showed increased expression of CypA in human glioblastoma multiforme, but not in normal human astrocytes. CypA was also shown to be up-regulated in C6 glioma cells during hypoxia. In conclusion, CsA or SFA in combination with cisplatin synergistically enhances cisplatin-induced apoptosis in C6 glioma cells via inhibition of PPIase activity of CypA, indicating that development of new drugs that selectively inhibit the CypA PPIase activity without immune suppression may facilitate alleviation of chemoresistance in treatment of high-grade glioma.
神经胶质瘤是成年人中最常见的脑肿瘤类型，高级别神经胶质瘤的治疗仍然是姑息性的。迄今为止的研究表明，单一药物治疗只能轻微减缓这些肿瘤的生长，但联合治疗似乎更有效。亲环素 A（CypA）是免疫抑制剂环孢素 A（CsA）和桑利福林 A（SFA）的靶点，是一种细胞内蛋白，具有肽基脯氨酰顺反异构酶（PPIase）的酶活性。以前，我们表明过表达的 CypA 诱导癌细胞产生化疗耐药性。在这里，我们提供的证据表明，与单一药物治疗相比，顺铂与 CsA 或 SFA 的联合使用可协同增强 C6 神经胶质瘤细胞的细胞凋亡。增强的细胞凋亡是由于 ROS 生成增加和细胞内谷胱甘肽水平降低所致。一致地，siRNA 敲低 CypA 也增强了顺铂诱导的细胞凋亡。免疫组织化学分析显示 CypA 在人类多形性胶质母细胞瘤中表达增加，但在正常的人类星形胶质细胞中没有表达。在 C6 神经胶质瘤细胞缺氧期间也显示 CypA 上调。总之，CsA 或 SFA 与顺铂联合使用通过抑制 CypA 的 PPIase 活性协同增强顺铂诱导的 C6 神经胶质瘤细胞凋亡，表明开发选择性抑制 CypA PPIase 活性而不抑制免疫的新药可能有助于缓解高级别神经胶质瘤治疗中的化疗耐药性。
