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Targeting autophagy triggers apoptosis and complements the action of venetoclax in chronic lymphocytic leukemia cells [Elektronski vir]Avsec, Damjan, farmacevt ...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.Vir: Cancers [Elektronski vir]. - ISSN 2072-6694 (Vol. 13, iss. 18, Jul. 2021, str. 1-20)Vrsta gradiva - e-članek ; neleposlovje za odrasleLeto - 2021Jezik - angleškiCOBISS.SI-ID - 76337667
Avtor
Avsec, Damjan, farmacevt |
Jakoš Djordjevič, Alma Tana |
Kandušer, Maša |
Podgornik, Helena |
Škerget, Matevž |
Mlinarič-Raščan, Irena
Teme
Kronična limfocitna levkemija |
Tarčno zdravljenje |
Apoptoza |
avtofagi |
odpornost na zdravila |
tarčna terapija |
chronic lymphocytic leukemia |
autophagy |
AMPK/ULK1 |
venetoclax |
drug resistance |
targeted therapy
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Avtor | Avsec, Damjan, farmacevt ... |
Naslov | Targeting autophagy triggers apoptosis and complements the action of venetoclax in chronic lymphocytic leukemia cells [Elektronski vir] |
Datum objave | 2021-09-29 |
COBISS.SI-ID | 76337667 |
Verzija objave v repozitoriju | Založnikova različica |
Licenca objave v repozitoriju | Creative Commons Priznanje avtorstva 4.0 Mednarodna |
Embargo | Takojšnja javna objava |
Projekti, iz katerih je bila financirana objava
Naziv | Akronim | Številka projekta | Financer |
---|---|---|---|
NOBIL - Novi biološki označevalci v levkemiji | NC-0004-2018 |
Javna agencija za znanstvenoraziskovalno in inovacijsko dejavnost Republike Slovenije |
|
Značilnosti malignih neoplazem, pomembne za diagnozo ter napoved poteka bolezni in izida zdravljenja | P3-0289-2019 |
Javna agencija za znanstvenoraziskovalno in inovacijsko dejavnost Republike Slovenije |
|
Farmacevtska kemija: načrtovanje, sinteza in vrednotenje učinkovin | P1-0208-2015 |
Javna agencija za znanstvenoraziskovalno in inovacijsko dejavnost Republike Slovenije |
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Povezave do osebnih bibliografij avtorjev | Povezave do podatkov o raziskovalcih v sistemu SICRIS |
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Avsec, Damjan, farmacevt | 52092 |
Jakoš Djordjevič, Alma Tana | ![]() |
Kandušer, Maša | 18619 |
Podgornik, Helena | 12684 |
Škerget, Matevž | 39671 |
Mlinarič-Raščan, Irena | 12443 |
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