20.500.12556/RUL-136098 Targeting autophagy triggers apoptosis and complements the action of venetoclax in chronic lymphocytic leukemia cells Continuous treatment of patients with chronic lymphocytic leukemia (CLL) with venetoclax, an antagonist of the anti-apoptotic protein Bcl-2, can result in resistance, which highlights the need for novel targets to trigger cell death 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 the autophagosome–lysosome fusion inhibitor chloroquine demonstrated concentration-dependent and time-dependent cytotoxicity against CLL cells, even in those from hard-to-treat patients who carried del(11q) and del(17p). Dorsomorphin and MRT68921 but not chloroquine triggered caspase-dependent cell death. According to the metabolic activities of CLL cells and PBMCs following treatments with 10 µM dorsomorphin (13% vs. 84%), 10 µM MRT68921 (7% vs. 78%), and 25 µM chloroquine (41% vs. 107%), these autophagy inhibitors are selective toward CLL cells. In these CLL cells, venetoclax induced autophagy, and addition of dorsomorphin, MRT68921, or chloroquine showed potent synergistic cytotoxicities. Additionally, MRT68921 alone induced G2 arrest, but when combined with venetoclax, it triggered caspase-dependent cytotoxicity. These data provide the rationale to target autophagy and for autophagy inhibitors as potential treatments for patients with CLL. chronic lymphocytic leukemia autophagy AMPK/ULK1 venetoclax drug resistance targeted therapy avtofagi odpornost na zdravila tarčna terapija kronična limfocitna levkemija tarčno zdravljenje apoptoza true false true Angleški jezik Slovenski jezik Članek v reviji 2022-04-12 15:19:03 2022-04-12 15:19:05 2022-09-15 04:13:23 0000-00-00 00:00:00 2021 0 0 20 str. iss. 18, art. 4557 Vol. 13 Sep. 2021 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 576.36:616.155.392+616-006-085 2072-6694 10.3390/cancers13184557 76337667 RAZ_Avsec_Damjan_2021.pdf RAZ_Avsec_Damjan_2021.pdf 1 5AE03444E9975B9A96417C17BE3A460C f8026a65e04519553f6f4b12cebed6b4951b087dbbfb4ea68d780e7b212136de 564d8ff8-ba63-11ec-8aca-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=155564 https://www.mdpi.com/2072-6694/13/18/4557 1 13ddfa0b-ba63-11ec-8aca-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=155563 Fakulteta za farmacijo Medicinska fakulteta 0 0 0