Cytarabine-induced differentiation of AML cells depends on Chk1 activation and shares the mechanism with inhibitors of DHODH and pyrimidine synthesis

Tomic, Barbara; Smoljo, Tomislav; Lalić, Hrvoje; Dembitz, Vilma; Batinić, Josip; Batinic, Drago; Bedalov, Antonio; Visnjic, Dora

doi:10.1038/s41598-022-15520-z

Pregled bibliografske jedinice broj: 1211738

Cytarabine-induced differentiation of AML cells depends on Chk1 activation and shares the mechanism with inhibitors of DHODH and pyrimidine synthesis

Tomic, Barbara; Smoljo, Tomislav; Lalić, Hrvoje; Dembitz, Vilma; Batinić, Josip; Batinic, Drago; Bedalov, Antonio; Visnjic, Dora

Cytarabine-induced differentiation of AML cells depends on Chk1 activation and shares the mechanism with inhibitors of DHODH and pyrimidine synthesis // Scientific reports, 12 (2022), 1; 11344, 16 doi:10.1038/s41598-022-15520-z (međunarodna recenzija, članak, znanstveni)

CROSBI ID: 1211738 Za ispravke kontaktirajte CROSBI podršku putem web obrasca

Naslov
Cytarabine-induced differentiation of AML cells depends on Chk1 activation and shares the mechanism with inhibitors of DHODH and pyrimidine synthesis

Autori
Tomic, Barbara ; Smoljo, Tomislav ; Lalić, Hrvoje ; Dembitz, Vilma ; Batinić, Josip ; Batinic, Drago ; Bedalov, Antonio ; Visnjic, Dora

Izvornik
Scientific reports (2045-2322) 12 (2022), 1; 11344, 16

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
cytarabine ; acute myeloid leukemia ; differentiation ; Chk1 ; brequinar ; AICAr ; DHODH ; pyrimidine synthesis

Sažetak
Acute myeloid leukemia (AML) is characterized by arrested differentiation making differentiation therapy a promising treatment strategy. Recent success of inhibitors of mutated isocitrate dehydrogenase (IDH) invigorated interest in differentiation therapy of AML so that several new drugs have been proposed, including inhibitors of dihydroorotate dehydrogenase (DHODH), an enzyme in pyrimidine synthesis. Cytarabine, a backbone of standard AML therapy, is known to induce differentiation at low doses, but the mechanism is not completely elucidated. We have previously reported that 5-aminoimidazole-4-carboxamide ribonucleoside (AICAr) and brequinar, a DHODH inhibitor, induced differentiation of myeloid leukemia by activating the ataxia telangiectasia and Rad3-related (ATR)/checkpoint kinase 1 (Chk1) via pyrimidine depletion. In this study, using immunoblotting, flow cytometry analyses, pharmacologic inhibitors and genetic inactivation of Chk1 in myeloid leukemia cell lines, we show that low dose cytarabine induces differentiation by activating Chk1. In addition, cytarabine induces differentiation ex vivo in a subset of primary AML samples that are sensitive to AICAr and DHODH inhibitor. The results of our study suggest that leukemic cell differentiation stimulated by low doses of cytarabine depends on the activation of Chk1 and thus shares the same pathway as pyrimidine synthesis inhibitors.

Izvorni jezik
Engleski

Znanstvena područja
Temeljne medicinske znanosti

POVEZANOST RADA

Projekti:
--IP-2016-06-4581 - Signalni mehanizmi i metaboličke promjene u diferencijaciji stanica akutne mijeloične leukemije (SignalmetabAML) (Višnjić, Dora) ( CroRIS)
--KK.01.1.1.01.0007 - Znanstveni centar izvrnosti - Eksperimentalna i klinička istraživanja hipoksijsko-ishemijskog oštećenja mozga u perinatalnoj i odrasloj dobi (ZCI - NEURO) (Judaš, Miloš) ( CroRIS)

Ustanove:
Medicinski fakultet, Zagreb,
Klinički bolnički centar Zagreb

Profili:

Hrvoje Lalić (autor)