B4G2 Induces Mitochondrial Apoptosis by the ROS-Mediated Opening of Ca2+-Dependent Permeability Transition Pores

Autor: Nan Yao, Ying-Jie Li, Dong-Mei Zhang, Dao-Lu Liu, Ming-Kuen Tang, Anita Yiu, Yong Li, Wei-Min Chen, Ping Lan, Zhe Yao, Zhe-Sheng Chen, Wen-Cai Ye
Jazyk: angličtina
Rok vydání: 2015
Předmět:
Zdroj: Cellular Physiology and Biochemistry, Vol 37, Iss 3, Pp 838-852 (2015)
Druh dokumentu: article
ISSN: 1015-8987
1421-9778
DOI: 10.1159/000430212
Popis: Background/Aims: Hepatocellular carcinoma (HCC) is the most common type of liver cancer. At present, only sorafenib is approved to treat HCC. In this study, we found that a 23-hydroxybetulinic acid derivative, B4G2, exhibited potent antiproliferative activity in HCC cell lines. Methods: We used four HCC cell lines (HepG2, HepG2/ADM, Hep3B and Bel-7402) to evaluate the anti-tumour activity and explore underlying mechanisms by which B4G2 induces apoptosis. Results: Among these cell lines, HepG2 showed the highest sensitivity to B4G2. HepG2 cells treated with B4G2 showed a depolarized mitochondrial membrane potential, released cytochrome c, activated caspase-9 and caspase-3 and cleaved poly ADP-ribose polymerase (PARP). However, Z-VAD-FMK, a pan-caspase inhibitor, did not attenuate B4G2-induced apoptosis, implying that the induction of mitochondrial apoptosis by B4G2 may be independent of caspases. Moreover, pre-treatment with MgCl2, a blocker of Ca2+-dependent permeability transition (PT) pores, attenuated the depolarization of the mitochondrial potential and decreased the population of apoptotic cells, indicating that B4G2-induced apoptosis was partly dependent on the opening of the Ca2+-dependent PT pores. B4G2 also increased the levels of intracellular calcium and reactive oxygen species (ROS). Furthermore, an ROS scavenger, N-acetyl-cysteine (NAC), markedly decreased the accumulation of intracellular calcium and apoptosis. Conclusion: This is the first demonstration that B4G2 inhibits the growth of HCC cells and induces mitochondrial apoptosis in hepatocellular carcinoma cells by the ROS-mediated opening of Ca2+-dependent permeability transition pores.
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