Damjan Avsec (Author), Alma Tana Jakoš Djordjevič (Author), Maša Kandušer (Author), Helena Podgornik (Author), Matevž Škerget (Author), Irena Mlinarič-Raščan (Author)

Abstract

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 [micro]M dorsomorphin (13% vs. 84%), 10 [micro]M MRT68921 (7% vs. 78%), and 25 [micro]M 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.

Keywords

avtofagi;odpornost na zdravila;tarčna terapija;chronic lymphocytic leukemia;autophagy;AMPK/ULK1;venetoclax;drug resistance;targeted therapy;

Data

Language: English
Year of publishing:
Typology: 1.01 - Original Scientific Article
Organization: UL FFA - Faculty of Pharmacy
UDC: 576.36:616.155.392+616-006-085
COBISS: 76337667 Link will open in a new window
ISSN: 2072-6694
Views: 121
Downloads: 49
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Other data

Secondary language: Slovenian
Secondary keywords: Kronična limfocitna levkemija;Tarčno zdravljenje;Apoptoza;
Type (COBISS): Article
Pages: str. 1-20
Volume: ǂVol. ǂ13
Issue: ǂiss. ǂ18
Chronology: Jul. 2021
DOI: 10.3390/cancers13184557
ID: 15013810