title: Autophagy inhibition enhances pan-Bcl-2 inhibitor AT-101-induced apoptosis in non-small cell lung cancer.
abstract: Overexpression of anti-apoptotic Bcl-2 proteins is commonly observed in a variety of cancers and associated with resistance to conventional chemotherapeutic drugs. Targeting multiple anti-apoptotic proteins is now possible with the small molecule BH3 domain mimetics such as AT-101. Autophagy has been found to function as a resistance mechanism against apoptotic cell death. In this study, we investigated the role of autophagy in the AT-101-induced apoptotic death of human lung cancer cells. It was found that AT-101 dose-dependently induced both apoptosis and autophagy in A549 lung cancer cells. And the apoptotic cell death induced by AT-101 was greatly enhanced after autophagy inhibition. Our findings demonstrated that AT-101-induced autophagy was cytoprotective rather than being part of cell death process in lung cancer cells. Inhibition of autophagy in combination with efforts to enhance apoptosis through targeting the Bcl-2 family of proteins may be a promising strategy to overcome drug resistance.
authors.forename: H
authors.initials: H
authors.lastname: Mei
authors.forename: Z
authors.initials: Z
authors.lastname: Lin
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.forename: G
authors.initials: G
authors.lastname: Wu
authors.forename: Y
authors.initials: Y
authors.lastname: Song
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006072:Gossypol / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; D006072:Gossypol; C028178:gossypol acetic acid
keywords: apoptosis, autophagy, BH3, lung cancer