EP4 receptor agonist L-902688 augments cytotoxic activities of ibrutinib, idelalisib, and venetoclax against chronic lymphocytic leukemia cells

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

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.

• Language: English
• Keywords: chronic lymphocytic leukemia, L-902688, NF-κB inhibition, prostaglandin E4, receptor, synergistic cytotoxic activity, prostaglandin E4 receptor
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2021
• Number of pages: 14 str.
• Numbering: Vol. 183, art. 114352
• PID: 20.500.12556/RUL-138397
• UDC: 616.155.392+577.27
• ISSN on article: 0006-2952
• DOI: 10.1016/j.bcp.2020.114352
• COBISS.SI-ID: 43415299
• Publication date in RUL: 19.07.2022

Record is a part of a journal

• Title: Biochemical pharmacology
• Shortened title: Biochem. pharmacol.
• Publisher: Elsevier
• ISSN: 0006-2952
• COBISS.SI-ID: 276759

Licences

• License: CC BY-NC-ND 4.0, Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
• Link: http://creativecommons.org/licenses/by-nc-nd/4.0/
• Description: The most restrictive Creative Commons license. This only allows people to download and share the work for no commercial gain and for no other purposes.

Secondary language

• Language: Slovenian
• Keywords: prostaglandin E4, receptorji, sinergistična citotoksična aktivnost, celice kronične limfocitne levkemije, kronična limfocitna levkemija, citotoksičnost