Inhibition of autophagy enhances the anticancer activity of bortezomib in B-cell acute lymphoblastic leukemia cells

摘要

B-cell acute lymphoblastic leukemia (B-ALL) remains a challenging disease to treat in adults because of the high rates of relapse and refractory. Bortezomib, as a proteasome inhibitor, exerts obvious cytotoxicity against ALL cells and increases the sensitivity of ALL cells to conventional chemotherapeutic agents. We observed that bortezomib inhibited proliferation, induced apoptosis, arrested the cell cycle and induced autophagy in the Nalm-6 cell line and CD34⁺ primary cells. Additionally, we demonstrated that bortezomib promoted the disruption of the Bcl-2/Beclin-1 complex and increased the formation of the Beclin-1/PI3KC3 complex, leading to the initiation of autophagy. Autophagy inhibitors were employed in this study, and we found that autophagy inhibitors enhanced the anti-ALL activity of bortezomib. Taken together, these results revealed that autophagy protected B-ALL cells against the cytotoxicity of bortezomib and, in combination with autophagy inhibitors, can enhance the anticancer effects of bortezomib.