Dept. of Clinical Lab Science, Dongseo University, Busan, 617-716, Korea.
Arch Pharm Res. 2010 Sep;33(9):1401-9. doi: 10.1007/s12272-010-0914-x. Epub 2010 Oct 14.
The fungal cyclic peptide cyclosporin A (CsA) and fungal macrolide compound sanglifehrin A (SFA) have been developed as immunosuppressive drugs and both bind to cyclophilin A (CypA). CypA has been reported to be upregulated in diverse human cancers including hepatocellular carcinomas (HCC). CypA overexpression induces resistance to hypoxia and chemotherapeutic agents such as cisplatin in cancer cells. In this report, it was shown that CsA or SFA can synergistically increase apoptotic cell death in HCC cells, when combined with cisplatin. The increased cytotoxicity was accompanied by enhanced oxidative stress. The effects of CsA and SFA were due to inhibition of CypA activity. It was also shown that CsA and SFA abrogate cisplatin resistance as well as protection against hypoxia that is provided by CypA overexpression. Importantly, the synergistic effect of CsA or SFA with cisplatin was shown even in p53 defective Hep3B cells. Finally, overexpression of CypA was observed in human HCC tissues. In conclusion, CsA or SFA synergistically enhances cisplatin-induced apoptosis in HCC cells including the p53-defective Hep3B.
真菌环肽环孢素 A（CsA）和真菌大环内酯化合物沙利度胺 A（SFA）已被开发为免疫抑制剂，两者都与亲环素 A（CypA）结合。已经报道 CypA 在包括肝细胞癌（HCC）在内的多种人类癌症中上调。CypA 的过表达诱导癌细胞对缺氧和化疗药物如顺铂的耐药性。在本报告中，表明当与顺铂联合使用时，CsA 或 SFA 可以协同增加 HCC 细胞的凋亡细胞死亡。细胞毒性的增加伴随着氧化应激的增强。CsA 和 SFA 的作用是由于抑制 CypA 活性。还表明，CsA 和 SFA 废除了 CypA 过表达提供的顺铂耐药性以及对缺氧的保护。重要的是，即使在 p53 缺陷型 Hep3B 细胞中，也观察到 CsA 或 SFA 与顺铂的协同作用。最后，在人 HCC 组织中观察到 CypA 的过表达。总之，CsA 或 SFA 协同增强了包括 p53 缺陷型 Hep3B 在内的 HCC 细胞中顺铂诱导的细胞凋亡。
