Targeting Autophagy Triggers Apoptosis and Complements the Action of Venetoclax in Chronic Lymphocytic Leukemia Cells
Continuous management of patients with chronic lymphocytic leukemia (CLL) with venetoclax, an antagonist from the anti-apoptotic protein Bcl-2, can lead to resistance, which highlights the requirement for novel targets to trigger cell dying in CLL. Venetoclax also induces autophagy by perturbing the Bcl-2/Beclin-1 complex, so autophagy might represent a target in CLL. Diverse autophagy inhibitors were assessed for cytotoxic activities against patient-derived CLL cells. The AMPK inhibitor dorsomorphin, the ULK1/2 inhibitor MRT68921, and also the autophagosome-lysosome fusion inhibitor chloroquine shown concentration-dependent and time-dependent cytotoxicity against CLL cells, even just in individuals from hard-to-treat patients who transported del(11q) and del(17p).
Dorsomorphin and MRT68921 although not chloroquine triggered caspase-dependent cell dying. Based on the metabolic activities of CLL cells and PBMCs following treatments with 10 µM dorsomorphin (13% versus. 84%), 10 µM MRT68921 (7% versus. 78%), and 25 µM chloroquine (41% versus. 107%), these autophagy inhibitors are selective toward CLL cells. During these CLL cells, venetoclax caused autophagy, and inclusion of dorsomorphin, MRT68921, or chloroquine demonstrated potent synergistic cytotoxicities. Furthermore, MRT68921 alone caused G2 arrest, however when coupled with venetoclax, it triggered MRT68921 caspase-dependent cytotoxicity. These data supply the rationale to focus on autophagy as well as for autophagy inhibitors as potential treating patients with CLL.