Research Centre of Siyuan Natural Pharmacy and Biotoxicology, College of Life Sciences, Zhejiang University, Zijinggang Campus, Hangzhou, 310058, People's Republic of China.
Apoptosis. 2014 May;19(5):871-82. doi: 10.1007/s10495-014-0969-0.
Drug resistance is a major reason for therapy failure in cancer. Clitocine is a natural amino nucleoside isolated from mushroom and has been shown to inhibit cancer cell proliferation in vitro. In this study, we observed that clitocine can effectively induce drug-resistant human cancer cell apoptosis in vitro and inhibit tumor xenograft growth in vivo. Clitocine treatment inhibited drug-resistant human cancer cell growth in vitro in a dose- and time-dependent manner. Biochemical analysis revealed that clitocine-induced tumor growth inhibition is associated with activation of caspases 3, 8 and 9, PARP cleavage, cytochrome c release and Bax, Bak activation, suggesting that clitocine inhibits drug-resistant cancer cell growth through induction of apoptosis. Analysis of apoptosis regulatory genes indicated that Mcl-1 level was dramatically decreased after clitocine treatment. Over-expression of Mcl-1 reversed the activation of Bax and attenuated clitocine-induced apoptosis, suggesting that clitocine-induced apoptosis was at least partially by inducing Mcl-1 degradation to release Bax and Bak. Consistent with induction of apoptosis in vitro, clitocine significantly suppressed the drug-resistant hepatocellular carcinoma xenograft growth in vivo by inducing apoptosis as well as inhibiting cell proliferation. Taken together, our data demonstrated that clitocine is a potent Mcl-1 inhibitor that can effectively induce apoptosis to suppress drug-resistant human cancer cell growth both in vitro and in vivo, and thus holds great promise for further development as potentially a novel therapeutic agent to overcome drug resistance in cancer therapy.
耐药性是癌症治疗失败的主要原因。石杉碱甲是一种从蘑菇中分离出来的天然氨基核苷，已被证明能在体外抑制癌细胞增殖。在这项研究中，我们观察到石杉碱甲能有效诱导体外耐药性人癌细胞凋亡，并抑制体内肿瘤异种移植生长。石杉碱甲处理能以剂量和时间依赖的方式抑制体外耐药性人癌细胞生长。生化分析表明，石杉碱甲诱导的肿瘤生长抑制与 caspase-3、8 和 9 的激活、PARP 切割、细胞色素 c 释放和 Bax、Bak 的激活有关，提示石杉碱甲通过诱导细胞凋亡抑制耐药性癌细胞生长。凋亡调节基因分析表明，石杉碱甲处理后 Mcl-1 水平显著降低。Mcl-1 的过表达逆转了 Bax 的激活，并减弱了石杉碱甲诱导的凋亡，表明石杉碱甲诱导的凋亡至少部分是通过诱导 Mcl-1 降解来释放 Bax 和 Bak。与体外诱导凋亡一致，石杉碱甲通过诱导凋亡和抑制细胞增殖，显著抑制体内耐药性肝癌异种移植生长。综上所述，我们的数据表明，石杉碱甲是一种有效的 Mcl-1 抑制剂，能有效诱导凋亡，抑制体外和体内耐药性人癌细胞生长，因此有望进一步开发为治疗癌症耐药性的潜在新型治疗药物。
