Статья

Arenobufagin, a natural bufadienolide from toad venom, induces apoptosis and autophagy in human hepatocellular carcinoma cells through inhibition of PI3K/Akt/mTOR pathway

Dongmei ZhangInstitute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan University, Guangzhou 510632, ChinaJun-Shan LiuGuangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University , Guangzhou 510632 , China ,Lijuan DengGuangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University , Guangzhou 510632 , China ,Minfeng ChenGuangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University , Guangzhou 510632 , China ,Anita YiuSchool of Biomedical Sciences , The Chinese University of Hong Kong , Hong Kong , China andHuihui CaoGuangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University , Guangzhou 510632 , China ,Hai‐Yan TianGuangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University , Guangzhou 510632 , China ,Kwok‐Pui FungSchool of Biomedical Sciences , The Chinese University of Hong Kong , Hong Kong , China andHiroshi KuriharaGuangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University , Guangzhou 510632 , China ,Jingxuan PanDepartment of Pathophysiology , Zhongshan School of Medicine , Sun Yat-Sen University , Guangzhou 510632 , ChinaWen‐Cai YeGuangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University , Guangzhou 510632 , China ,

2013en

ABI

Аннотация

Hepatocellular carcinoma (HCC) is a deadly form of cancer without effective chemotherapy so far. Currently, only sorafenib, a multitargeted tyrosine kinase inhibitor, slightly improves survival in HCC patients. In searching for natural anti-HCC components from toad venom, which is frequently used in the treatment of liver cancer in traditional Chinese medicine, we discovered that arenobufagin, a bufadienolide from toad venom, had potent antineoplastic activity against HCC HepG2 cells as well as corresponding multidrug-resistant HepG2/ADM cells. We found that arenobufagin induced mitochondria-mediated apoptosis in HCC cells, with decreasing mitochondrial potential, as well as increasing Bax/Bcl-2 expression ratio, Bax translocation from cytosol to mitochondria. Arenobufagin also induced autophagy in HepG2/ADM cells. Autophagy-specific inhibitors (3-methyladenine, chloroquine and bafilomycin A1) or Beclin1 and Atg 5 small interfering RNAs (siRNAs) enhanced arenobufagin-induced apoptosis, indicating that arenobufagin-mediated autophagy may protect HepG2/ADM cells from undergoing apoptotic cell death. In addition, we observed the inhibition of phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway by arenobufagin. Interestingly, inhibition of mTOR by rapamycin or siRNA duplexes augmented arenobufagin-induced apoptosis and autophagy. Finally, arenobufagin inhibited the growth of HepG2/ADM xenograft tumors, which were associated with poly (ADP-ribose) polymerase cleavage, light chain 3-II activation and mTOR inhibition. In summary, we first demonstrated the antineoplastic effect of arenobufagin on HCC cells both in vitro and in vivo. We elucidated the underlying antineoplastic mechanisms of arenobufagin that involve cross talk between apoptosis and autophagy via inhibition of the PI3K/Akt/mTOR pathway. This study may provide a rationale for future clinical application using arenobufagin as a chemotherapeutic agent for HCC.

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Идентификаторы

DOI: 10.1093/carcin/bgt060

Цитирования и источники

Цитирований: 2Использованных источников: 0

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