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.