Sanja Vrbek (Author), Tijana Markovič (Author), Damjan Avsec (Author), Martina Gobec (Author), Helena Podgornik (Author), Žiga Jakopin (Author), Irena Mlinarič-Raščan (Author)

Abstract

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.

Keywords

chronic lymphocytic leukemia;L-902688;NF-{kappa]B inhibition;prostaglandin E4;receptor;synergistic cytotoxic activity;

Data

Language: English
Year of publishing:
Typology: 1.01 - Original Scientific Article
Organization: UL FFA - Faculty of Pharmacy
UDC: 616.155.392+577.27
COBISS: 43415299 Link will open in a new window
ISSN: 0006-2952
Views: 157
Downloads: 47
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Other data

Secondary language: Slovenian
Secondary keywords: prostaglandin E4;receptorji;sinergistična citotoksična aktivnost;celice kronične limfocitne levkemije;Kronična limfocitna levkemija;Citotoksičnost;
Type (COBISS): Article
Pages: str. 1-14
Issue: ǂVol. ǂ183
Chronology: 2021
DOI: 10.1016/j.bcp.2020.114352
ID: 15948760