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EP4 receptor agonist L-902688 augments cytotoxic activities of ibrutinib, idelalisib, and venetoclax against chronic lymphocytic leukemia cellsNabergoj, Sanja ...Treatment of patients with relapsed or refractory chronic lymphocytic leukemia (CLL) has significantly improved more recently with the approval of several new agents, including ibrutinib, idelalisib, ... and venetoclax. Despite the outstanding efficacies observed with these agents, these treatments are sometimes discontinued due to toxicity, unresponsiveness, transformation of the disease and/or resistance. Constitutive NF-[kappa]B activation that protects CLL cells from apoptotic stimuli represents one of molecular mechanisms that underlie the emergence of drug resistance. As prostaglandin E (EP)4 receptor agonists have been shown to successfully inhibit the NF-[kappa]B pathway in B-cell lymphoma cells, we investigated the potential of the highly specific EP4 receptor agonist L-902688 for the potential treatment of patients with CLL. We show here that low micromolar concentrations of L-902688 can indeed induce selective cytotoxicity towards several B-cell malignancies, including CLL. Moreover, L-902688-mediated activation of the EP4 receptor in patient derived CLL cells resulted in inhibition of the NF-[kappa]B pathway, cell proliferation, and induction of apoptosis. Most importantly, we show for the first time that in combination with ibrutinib, idelalisib, or venetoclax, L-902688 induces synergistic cytotoxic activity against patient derived CLL cells. To conclude, the modulation of NF-[kappa]B activity by EP4 receptor agonists represents an innovative approach to improve the treatment of patients with CLL. In particular, EP4 receptor agonists appear to represent promising adjuncts to the already existing therapies for patients with CLL due to these promising synergistic activities.Vir: Biochemical pharmacology. - ISSN 0006-2952 (Vol. 183, 2021, str. 1-14)Vrsta gradiva - članek, sestavni del ; neleposlovje za odrasleLeto - 2021Jezik - angleškiCOBISS.SI-ID - 43415299
Avtor
Nabergoj, Sanja |
Markovič, Tijana |
Avsec, Damjan, farmacevt, 1993- |
Gobec, Martina, 1983- |
Podgornik, Helena |
Jakopin, Žiga |
Mlinarič-Raščan, Irena
Teme
Kronična limfocitna levkemija |
Citotoksičnost |
chronic lymphocytic leukemia |
L-902688 |
NF-{kappa]B inhibition |
prostaglandin E4 |
receptor |
synergistic cytotoxic activity |
prostaglandin E4 |
receptorji |
sinergistična citotoksična aktivnost |
celice kronične limfocitne levkemije
Avtor | Nabergoj, Sanja ... |
Naslov | EP4 receptor agonist L-902688 augments cytotoxic activities of ibrutinib, idelalisib, and venetoclax against chronic lymphocytic leukemia cells |
Datum objave | 2021-01-29 |
COBISS.SI-ID | 43415299 |
Verzija objave v repozitoriju | Založnikova različica |
Licenca objave v repozitoriju | Creative Commons Priznanje avtorstva-Brez predelav 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 |
|
Farmacevtska kemija: načrtovanje, sinteza in vrednotenje učinkovin | P1-0208-2015 |
Javna agencija za znanstvenoraziskovalno in inovacijsko dejavnost Republike Slovenije |
Datoteke, ki spadajo k objavi
Povezava |
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https://www.sciencedirect.com/science/article/pii/S0006295220305888#! |
https://repozitorij.uni-lj.si/IzpisGradiva.php?id=138397 |
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Ime baze podatkov | Področje | Leto |
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Povezave do osebnih bibliografij avtorjev | Povezave do podatkov o raziskovalcih v sistemu SICRIS |
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Nabergoj, Sanja | 38165 |
Markovič, Tijana | 34223 |
Avsec, Damjan, farmacevt, 1993- | 52092 |
Gobec, Martina, 1983- | 32034 |
Podgornik, Helena | 12684 |
Jakopin, Žiga | 26496 |
Mlinarič-Raščan, Irena | 12443 |
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