Faculty of Pharmacy, Lj. (FFALJ)
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Inhibition of p38 MAPK or immunoproteasome overcomes resistance of chronic lymphocytic leukemia cells to Bcl-2 antagonist venetoclax [Elektronski vir]Avsec, Damjan, farmacevt, 1993- ...Chronic lymphocytic leukemia (CLL) is a hematological neoplasm of CD19-positive mature-appearing B lymphocytes. Despite the clinical success of targeted therapies in CLL, the development of ... resistance diminishes their therapeutic activity. This is also true for the Bcl-2 antagonist venetoclax. We investigated the molecular mechanisms that drive venetoclax resistance in CLL, with a clear focus to provide new strategies to successfully combat it. Activation of CLL cells with IFNγ, PMA/ionomycin, and sCD40L diminished the cytotoxicity of venetoclax. We demonstrated that the metabolic activity of cells treated with 1 nM venetoclax alone was 48% of untreated cells, and was higher for cells co-treated with IFNγ (110%), PMA/ionomycin (78%), and sCD40L (62%). As of molecular mechanism, we showed that PMA/ionomycin and sCD40L triggered translocation of NFκB in primary CLL cells, while IFNγ activated p38 MAPK, suppressed spontaneous and venetoclax-induced apoptosis and induced formation of the immunoproteasome. Inhibition of immunoproteasome with ONX-0914 suppressed activity of immunoproteasome and synergized with venetoclax against primary CLL cells. On the other hand, inhibition of p38 MAPK abolished cytoprotective effects of IFNγ. We demonstrated that venetoclax-resistant (MEC-1 VER) cells overexpressed p38 MAPK and p-Bcl-2 (Ser70), and underexpressed Mcl-1, Bax, and Bak. Inhibition of p38 MAPK or immunoproteasome triggered apoptosis in CLL cells and overcame the resistance to venetoclax of MEC-1 VER cells and venetoclax-insensitive primary CLL cells. In conclusion, the p38 MAPK pathway and immunoproteasome represent novel targets to combat venetoclax resistance in CLL.Source: Cell death & disease [Elektronski vir]. - ISSN 2041-4889 (Vol. 13, art. 860, 2022, 13 str.)Type of material - e-article ; adult, seriousPublish date - 2022Language - englishCOBISS.SI-ID - 124912643
Author | Avsec, Damjan, farmacevt, 1993- ... |
Title | Inhibition of p38 MAPK or immunoproteasome overcomes resistance of chronic lymphocytic leukemia cells to Bcl-2 antagonist venetoclax [Elektronski vir] |
Publication date | 2022-10-08 |
COBISS.SI-ID | 124912643 |
Publication version in repository | Publisher's version |
Publication licence | Creative Commons Attribution 4.0 International |
Embargo | Immediate publication for public |
Project(s) from which the publication was funded
Title | Acronym | Project ID | Funder |
---|---|---|---|
Farmacevtska kemija: načrtovanje, sinteza in vrednotenje učinkovin | P1-0208-2015 |
Javna agencija za znanstvenoraziskovalno in inovacijsko dejavnost Republike Slovenije |
|
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 |
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https://www.nature.com/articles/s41419-022-05287-6 |
https://repozitorij.uni-lj.si/IzpisGradiva.php?id=141876 |
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DRS, in which the journal is indexed
Database name | Field | Year |
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Links to authors' personal bibliographies | Links to information on researchers in the SICRIS system |
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Avsec, Damjan, farmacevt, 1993- | 52092 |
Škrlj Miklavčič, Marja | |
Burnik, Tilen | 57938 |
Kandušer, Maša | 18619 |
Bizjak, Maruša, 1989- | 36454 |
Podgornik, Helena | 12684 |
Mlinarič-Raščan, Irena | 12443 |
Source: Personal bibliographies
and: SICRIS
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