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

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

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.

• Jezik: Angleški jezik
• Ključne besede: chronic lymphocytic leukemia, L-902688, NF-κB inhibition, prostaglandin E4, receptor, synergistic cytotoxic activity, prostaglandin E4 receptor
• Vrsta gradiva: Članek v reviji
• Tipologija: 1.01 - Izvirni znanstveni članek
• Organizacija: FFA - Fakulteta za farmacijo
• Status publikacije: Objavljeno
• Različica publikacije: Objavljena publikacija
• Leto izida: 2021
• Št. strani: 14 str.
• Številčenje: Vol. 183, art. 114352
• PID: 20.500.12556/RUL-138397
• UDK: 616.155.392+577.27
• ISSN pri članku: 0006-2952
• DOI: 10.1016/j.bcp.2020.114352
• COBISS.SI-ID: 43415299
• Datum objave v RUL: 19.07.2022

Gradivo je del revije

• Naslov: Biochemical pharmacology
• Skrajšan naslov: Biochem. pharmacol.
• Založnik: Elsevier
• ISSN: 0006-2952
• COBISS.SI-ID: 276759

Licence

• Licenca: CC BY-NC-ND 4.0, Creative Commons Priznanje avtorstva-Nekomercialno-Brez predelav 4.0 Mednarodna
• Povezava: http://creativecommons.org/licenses/by-nc-nd/4.0/deed.sl
• Opis: Najbolj omejujoča licenca Creative Commons. Uporabniki lahko prenesejo in delijo delo v nekomercialne namene in ga ne smejo uporabiti za nobene druge namene.

Sekundarni jezik

• Jezik: Slovenski jezik
• Ključne besede: prostaglandin E4, receptorji, sinergistična citotoksična aktivnost, celice kronične limfocitne levkemije, kronična limfocitna levkemija, citotoksičnost