Norcantharidin alone or in combination with crizotinib induces autophagic cell death in hepatocellular carcinoma by repressing c-Met-mTOR signaling
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Chao-Yue Sun1,*, Ying Zhu1,*, Xiao-Feng Li2, Li-Peng Tang1, Zu-Qing Su1, Xie-Qi Wang1, Cai-Yun Li1, Hong-Mei Yang3, Guang-Juan Zheng1 and Bing Feng1
1Guangdong Provincial Hospital of Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510120, China
2Clinical Medical College of Acupuncture and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou Higher Education Mega Center, Guangzhou 510006, China
3School of Chinese Materia Medica, Guangzhou University of Chinese Medicine, Guangzhou Higher Education Mega Center, Guangzhou 510006, China
*These authors contributed equally to this work
Guang-Juan Zheng, email: [email protected]
Bing Feng, email: [email protected]
Keywords: hepatocellular carcinoma; NCTD; autophagy; c-Met; crizotinib
Received: July 22, 2017 Accepted: November 15, 2017 Published: December 04, 2017
There is an urgent need for effective molecular therapies for hepatocellular carcinoma (HCC), the third-leading cause of cancer-related deaths worldwide. Norcantharidin (NCTD), a demethylated derivative of cantharidin, reportedly exhibits anticancer activity against various types of tumors, including HCC, though the mechanisms involved remain largely unknown. Here, we report that NCTD reduces viability of human MHCC-97H (97H) and HepG2 HCC cells, and induces cell death by triggering high levels of autophagy. Moreover, a significant attenuation of tumor growth was observed after NCTD treatment of HepG2 tumors in vivo, and this effect was enhanced by co-treatment with the c-Met inhibitor crizotinib. Interestingly, western blot analyses showed that the cytotoxic autophagy induced by NCTD correlates with a reduction in the phosphorylation status of both c-Met and m-TOR. These results suggest that cytotoxic autophagy resulting from inhibition of c-Met/mTOR signaling may be achieved in HCC by combined NCTD and crizotinib administration. Further studies to validate the therapeutic potential of this approach are warranted.
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