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Targeting autophagy triggers apoptosis and complements the action of venetoclax in chronic lymphocytic leukemia cells
ID
Avsec, Damjan
(
Author
),
ID
Jakoš Djordjevič, Alma Tana
(
Author
),
ID
Kandušer, Maša
(
Author
),
ID
Podgornik, Helena
(
Author
),
ID
Škerget, Matevž
(
Author
),
ID
Mlinarič-Raščan, Irena
(
Author
)
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MD5: 5AE03444E9975B9A96417C17BE3A460C
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https://www.mdpi.com/2072-6694/13/18/4557
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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 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.
Language:
English
Keywords:
chronic lymphocytic leukemia
,
autophagy
,
AMPK/ULK1
,
venetoclax
,
drug resistance
,
targeted therapy
Work type:
Article
Typology:
1.01 - Original Scientific Article
Organization:
FFA - Faculty of Pharmacy
MF - Faculty of Medicine
Publication status:
Published
Publication version:
Version of Record
Year:
2021
Number of pages:
20 str.
Numbering:
Vol. 13, iss. 18, art. 4557
PID:
20.500.12556/RUL-136098
UDC:
576.36:616.155.392+616-006-085
ISSN on article:
2072-6694
DOI:
10.3390/cancers13184557
COBISS.SI-ID:
76337667
Publication date in RUL:
12.04.2022
Views:
914
Downloads:
134
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Record is a part of a journal
Title:
Cancers
Shortened title:
Cancers
Publisher:
MDPI
ISSN:
2072-6694
COBISS.SI-ID:
517914137
Licences
License:
CC BY 4.0, Creative Commons Attribution 4.0 International
Link:
http://creativecommons.org/licenses/by/4.0/
Description:
This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.
Licensing start date:
10.09.2021
Secondary language
Language:
Slovenian
Keywords:
avtofagi
,
odpornost na zdravila
,
tarčna terapija
,
kronična limfocitna levkemija
,
tarčno zdravljenje
,
apoptoza
Projects
Funder:
ARRS - Slovenian Research Agency
Project number:
P1-0208
Name:
Farmacevtska kemija: načrtovanje, sinteza in vrednotenje učinkovin
Funder:
ARRS - Slovenian Research Agency
Project number:
NC-0004
Name:
NOBIL - Novi biološki označevalci v levkemiji
Funder:
ARRS - Slovenian Research Agency
Project number:
P3-0289
Name:
Značilnosti malignih neoplazem, pomembnih za diagnozo ter napoved poteka bolezni in izida zdravljenja
Funder:
EC - European Commission
Acronym:
EATRIS-TRI.SI
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