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EP4 receptor agonist L-902688 augments cytotoxic activities of ibrutinib, idelalisib, and venetoclax against chronic lymphocytic leukemia cells
ID Nabergoj, Sanja (Avtor), ID Markovič, Tijana (Avtor), ID Avsec, Damjan (Avtor), ID Gobec, Martina (Avtor), ID Podgornik, Helena (Avtor), ID Jakopin, Žiga (Avtor), ID Mlinarič-Raščan, Irena (Avtor)

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URLURL - Izvorni URL, za dostop obiščite https://www.sciencedirect.com/science/article/pii/S0006295220305888 Povezava se odpre v novem oknu

Izvleček
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 Povezava se odpre v novem oknu
UDK:616.155.392+577.27
ISSN pri članku:0006-2952
DOI:10.1016/j.bcp.2020.114352 Povezava se odpre v novem oknu
COBISS.SI-ID:43415299 Povezava se odpre v novem oknu
Datum objave v RUL:19.07.2022
Število ogledov:1010
Število prenosov:81
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Gradivo je del revije

Naslov:Biochemical pharmacology
Skrajšan naslov:Biochem. pharmacol.
Založnik:Elsevier
ISSN:0006-2952
COBISS.SI-ID:276759 Povezava se odpre v novem oknu

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

Projekti

Financer:ARRS - Agencija za raziskovalno dejavnost Republike Slovenije
Številka projekta:P1-0208
Naslov:Farmacevtska kemija: načrtovanje, sinteza in vrednotenje učinkovin

Financer:ARRS - Agencija za raziskovalno dejavnost Republike Slovenije
Številka projekta:NC-0004
Naslov:NOBIL - Novi biološki označevalci v levkemiji

Financer:EC - European Commission
Program financ.:European Regional Development Fund
Akronim:EATRIS-TRI.SI

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