20.500.12556/RUL-138397 EP4 receptor agonist L-902688 augments cytotoxic activities of ibrutinib, idelalisib, and venetoclax against chronic lymphocytic leukemia cells 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-κB 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-κB 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-κB 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-κB 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. chronic lymphocytic leukemia L-902688 NF-κB inhibition prostaglandin E4 receptor synergistic cytotoxic activity prostaglandin E4 receptor prostaglandin E4 receptorji sinergistična citotoksična aktivnost celice kronične limfocitne levkemije kronična limfocitna levkemija citotoksičnost true false true Angleški jezik Slovenski jezik Članek v reviji 2022-07-19 15:10:50 2022-07-19 15:10:57 2023-03-15 11:01:24 0000-00-00 00:00:00 2021 0 0 14 str. Vol. 183, art. 114352 2021 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 616.155.392+577.27 0006-2952 10.1016/j.bcp.2020.114352 43415299 1-s2.0-S0006295220305888-main.pdf 1-s2.0-S0006295220305888-main.pdf 1 911C26D2631695089BAF90E50D2B64E1 3cbe30a2a655e3d846d02498023c7c1ef960983edd48abf1c23c6ab78654d830 57eb0834-0764-11ed-8aca-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=158700 https://www.sciencedirect.com/science/article/pii/S0006295220305888 0 fb8c3db7-0763-11ed-8aca-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=158699 Fakulteta za farmacijo 0 0 0