在人肝癌细胞中，自噬抑制可增强重楼皂苷 I 诱导的细胞凋亡。
Polyphyllin I induced-apoptosis is enhanced by inhibition of autophagy in human hepatocellular carcinoma cells.
作者信息
Shi Ya-Min, Yang Lei, Geng Ya-Di, Zhang Chao, Kong Ling-Yi
机构信息
State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China.
State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China.
出版信息
Phytomedicine. 2015 Dec 1;22(13):1139-49. doi: 10.1016/j.phymed.2015.08.014. Epub 2015 Sep 30.
BACKGROUND
Polyphyllin I (PPI), a bioactive phytochemical isolated from the rhizoma of Paris polyphyllin, exerts preclinical anticancer efficacy in various cancer models. However, the effects of PPI on regulatory human hepatocellular carcinoma (HCC) cell proliferation and its underlying mechanisms remain unknown.
PURPOSE
This study investigated the antiproliferation effect of PPI on HCC cells and its underlying mechanisms.
METHODS
Cell viability was measured by MTT assay. Cell death, apoptosis and acidic vesicular organelles (AVOs) formation were determined by flow cytometry. Protein levels were analyzed by Western blot analysis.
RESULTS
PPI induced apoptosis through the caspase-dependent pathway and activated autophagy through the PI3K/AKT/mTOR pathway. Blockade of autophagy by pharmacological inhibitors or RNA interference enhanced the cytotoxicity and antiproliferation effects of PPI. Moreover, chloroquine (CQ) enhanced the antiproliferation effect of PPI on HCC cells via the caspase-dependent apoptosis pathway by inhibiting protective autophagy. Therefore, the combination therapy of CQ and PPI exhibited synergistic effects on HCC cells compared with CQ or PPI alone.
CONCLUSION
The current findings strongly indicate that PPI can induce protective autophagy in HCC cells, thereby providing a novel target in potentiating the anticancer effects of PPI and other chemotherapeutic drugs in liver cancer treatment. Moreover, the combination therapy of CQ and PPI is an effective and promising candidate to be further developed as therapeutic agents in the treatment of liver cancer.
背景
重楼皂苷 I（PPI）是从重楼根茎中分离出的一种生物活性植物化学物质，在多种癌症模型中具有临床前抗癌功效。然而，PPI 对人肝癌（HCC）细胞增殖调控的影响及其潜在机制尚不清楚。
目的
本研究探讨 PPI 对 HCC 细胞的抗增殖作用及其潜在机制。
方法
采用 MTT 法检测细胞活力。通过流式细胞术检测细胞死亡、凋亡和酸性囊泡细胞器（AVO）形成。采用蛋白质印迹分析法定量分析蛋白质水平。
结果
PPI 通过半胱天冬酶依赖性途径诱导凋亡，并通过 PI3K/AKT/mTOR 途径激活自噬。用药物抑制剂或 RNA 干扰阻断自噬可增强 PPI 的细胞毒性和抗增殖作用。此外，氯喹（CQ）通过抑制保护性自噬，经由半胱天冬酶依赖性凋亡途径增强 PPI 对 HCC 细胞的抗增殖作用。因此，与单独使用 CQ 或 PPI 相比，CQ 与 PPI 的联合治疗对 HCC 细胞具有协同作用。
结论
目前的研究结果有力地表明，PPI 可在 HCC 细胞中诱导保护性自噬，从而为增强 PPI 和其他化疗药物在肝癌治疗中的抗癌作用提供了一个新靶点。此外，CQ 与 PPI 的联合治疗是一种有效且有前景的治疗方案，有望进一步开发成为肝癌治疗的药物。
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