Abstract. 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.
IntroductionGlioma is the most common type of brain tumors in adults, and accounts for 25% of all brain tumors (1,2). Despite significant advances in cancer therapy, treatment of high-grade gliomas is still palliative. To date, the median survival for patients with high-grade gliomas, including glioblastoma multiforme (GBM; World Health Organization grade IV), is less than 1 year (3,4). Therefore, improved systemic treatment strategies are urgently required.Cyclophilin A (CypA), the prototypical member of the cyclophilin family, is a highly conserved protein in mammalian cells (5). CypA possesses enzymatic peptidyl-prolyl cis-trans isomerase (PPIase) activity, which is essential for protein folding in vivo. Although little is known about the function of CypA in cancer cells, it was recently reported that CypA is overexpressed in many cancer cells (6-11). In addition, our studies, as well as others, previously showed that overexpressed CypA protects cancer cells against cellular stresses, including hypoxia and cisplatin treatment, at least in part as a result of its antioxidant function (12)(13)(14)(15). These reports show that CypA might be important for tumorigenesis in solid tumors. CypA is also an immunophilin and a cytosolic receptor for the immunosuppressive drugs cyclosporin A (CsA) (5) and sanglifehrin A (SFA) (16). CsA binds to CypA, and this complex inhibits calcineurin, a calcium-dependent phosphatase, that regulates the expression of various cytokine genes ONCOLOGY REPORTS 2...