title: B-cell lymphoma 2 inhibitor ABT-737 induces Beclin1- and reactive oxygen species-dependent autophagy in Adriamycin-resistant human hepatocellular carcinoma cells.
abstract: ABT-737, a B-cell lymphoma 2 homology 3 mimetic, not only induces cell apoptosis by inhibiting the interaction of B-cell lymphoma 2 and Bax but also induces cell autophagy by interrupting the interaction of B-cell lymphoma 2 and Beclin1. Several recent studies have reported that ABT-737 has antitumor efficacy in diverse cancers. However, another study showed that hepatocellular carcinoma cells with high B-cell lymphoma 2 expression were resistant to ABT-737 compared to hepatocellular carcinoma cells with low B-cell lymphoma 2 expression. It was also found that ABT-737-induced autophagy is crucial for drug resistance. Here, we observed that of B-cell lymphoma 2 expression in Adriamycin-resistant human hepatocellular carcinoma HepG2/ADM cells is higher than that in human hepatocellular carcinoma HepG2 cells. Therefore, we further confirmed the mechanism and effect of autophagy induced by ABT-737 on apoptosis in HepG2/ADM cells with high B-cell lymphoma 2 expression. Our results showed that ABT-737 induced apoptosis and autophagy in time- and dose-dependent manner in HepG2/ADM cells, and this ABT-737-induced autophagy was Beclin1-dependent. In addition, we demonstrated that ABT-737 induced reactive oxygen species-mediated autophagy, and the reactive oxygen species-inhibitor N-acetyl-l-cysteine suppressed the reactive oxygen species-induced autophagy and ABT-737-induced increase in HepG2/ADM cell apoptosis. Furthermore, autophagy inhibitors increased HepG2/ADM cell apoptosis. In conclusion, our study further confirms that Beclin1- and reactive oxygen species-dependent autophagy induced by ABT-737 also plays a protective function in HepG2/ADM cells, which show B-cell lymphoma 2 expression higher than that in HepG2 cells.
authors.affiliation: 1 Department of Hepatobiliary & Pancreatic Surgery, The Second Affiliated Hospital of Jilin University, Changchun, China.
authors.forename: Xiaoxiao
authors.initials: X
authors.lastname: Yao
authors.affiliation: 2 Department of Pathophysiology, School of Basic Medical Sciences, Jilin University, Changchun, China.
authors.forename: Xiaoning
authors.initials: X
authors.lastname: Li
authors.affiliation: 1 Department of Hepatobiliary & Pancreatic Surgery, The Second Affiliated Hospital of Jilin University, Changchun, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Zhang
authors.affiliation: 1 Department of Hepatobiliary & Pancreatic Surgery, The Second Affiliated Hospital of Jilin University, Changchun, China.
authors.forename: Yingjun
authors.initials: Y
authors.lastname: Xie
authors.affiliation: 3 Department of Hepatobiliary & Pancreatic Surgery, China-Japan Union Hospital of Jilin University, Changchun, China.
authors.forename: Baozhen
authors.initials: B
authors.lastname: Sun
authors.affiliation: 3 Department of Hepatobiliary & Pancreatic Surgery, China-Japan Union Hospital of Jilin University, Changchun, China.
authors.forename: Hang
authors.initials: H
authors.lastname: Li
authors.affiliation: 2 Department of Pathophysiology, School of Basic Medical Sciences, Jilin University, Changchun, China.
authors.forename: Liankun
authors.initials: L
authors.lastname: Sun
authors.affiliation: 1 Department of Hepatobiliary & Pancreatic Surgery, The Second Affiliated Hospital of Jilin University, Changchun, China.
authors.forename: Xuewen
authors.initials: X
authors.lastname: Zhang
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D000071186:Beclin-1 / Q000096:biosynthesis* / Q000235:genetics; D001713:Biphenyl Compounds / Q000008:administration & dosage*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D004317:Doxorubicin / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009596:Nitrophenols / Q000008:administration & dosage*; D010879:Piperazines / Q000008:administration & dosage; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000235:genetics*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013449:Sulfonamides / Q000008:administration & dosage*
chemical_list: C501332:ABT-737; D000071186:Beclin-1; D001713:Biphenyl Compounds; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D013449:Sulfonamides; D004317:Doxorubicin
keywords: B-cell lymphoma 2; Beclin1; HepG2/ADM; autophagy; reactive oxygen species