Targeting of FLT3-ITD kinase contributes to high selectivity of imidazoacridinone C-1311 against FLT3-activated leukemia cells - Publikacja - MOST Wiedzy

Twoje konto

zaloguj

Wyszukiwarka

Targeting of FLT3-ITD kinase contributes to high selectivity of imidazoacridinone C-1311 against FLT3-activated leukemia cells

Abstrakt

Drugs targeting receptor tyrosine kinase FLT3 are of particular interest since activating FLT3-internal tandem duplication (ITD) mutations abundantly occur in fatal acute myeloid leukemias (AMLs). Imidazoacridinone C-1311, a DNA-reactive inhibitor of topoisomerase II, has been previously shown to be a potent and selective inhibitor of recombinant FLT3. Here, we expand those findings by studying its effect on leukemia cells with wild-type FLT3, FLT3-ITD mutant and no FLT3 receptor. While brief C-1311 exposure blocked wild-type and FLT3-ITD activity, profound and sustained inhibition was achieved only for FLT3-ITD mutants. C-1311 inhibited FLT3 downstream pathways (MAPK and AKT) independent of FLT3 status, yet translation to decreased viability was significant in FLT3-ITD cells. RNA interference against FLT3-ITD reduced cytotoxic effect and apoptosis induced by C-1311, indicating selective inhibition of FLT3-ITD crucial for high efficacy of drug against activated leukemia cells. Cellular responses in treated FLT3-ITD mutants included G1 and G2/M phase arrest, moderate inhibition of Bcl-2, caspase-3 activation, PARP cleavage, and depolarization of mitochondria. Consistent with selective decrease in FLT3-ITD activity, C-1311 remarkably reduced antiapoptotic survivin mRNA and protein expression, correlating well with enhanced apoptosis of FLT3-ITD cells. No survivin decrease and respectively lower level of apoptosis was found in wild-type and null-FLT3 cells. Combination of C-1311 with cytarabine or doxorubicin again showed distinct synergistic activity in FLT3-ITD-positive cells. The ability of C-1311 to selectively target constitutively active FLT3, suggests a favorable therapeutic index for AML carrying FLT3-ITD mutations. Thus further preclinical and clinical studies addressing its potency against FLT3-ITD kinase is well justified.

Cytowania

  • 1 0

    CrossRef

  • 0

    Web of Science

  • 1 1

    Scopus

Autorzy (7)

Cytuj jako

Pełna treść

pełna treść publikacji nie jest dostępna w portalu

Słowa kluczowe

Informacje szczegółowe

Kategoria:
Publikacja w czasopiśmie
Typ:
artykuł w czasopiśmie wyróżnionym w JCR
Opublikowano w:
BIOCHEMICAL PHARMACOLOGY nr 95, wydanie 4, strony 238 - 252,
ISSN: 0006-2952
Język:
angielski
Rok wydania:
2015
Opis bibliograficzny:
Skwarska A., Augustin E., Beffinger M., Wojtczyk A., Konicz S., Laskowska K., Polewska J.: Targeting of FLT3-ITD kinase contributes to high selectivity of imidazoacridinone C-1311 against FLT3-activated leukemia cells// BIOCHEMICAL PHARMACOLOGY. -Vol. 95, iss. 4 (2015), s.238-252
DOI:
Cyfrowy identyfikator dokumentu elektronicznego (otwiera się w nowej karcie) 10.1016/j.bcp.2015.04.006
Weryfikacja:
Politechnika Gdańska

wyświetlono 94 razy

Publikacje, które mogą cię zainteresować

The antitumor compound triazoloacridinone C-1305 inhibits FLT3 kinase activity and potentiates apoptosis in mutant FLT3-ITD leukemia cells.

2015

Anticancer imidazoacridinone C-1311 inhibits hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF) and angiogenesis

2011

DNA-reactive anticancer imidazoacridinone C-1311 is a new inhibitor of hypoxia-inducible factor 1 alpha, vascular endothelial growth factor and tumor angiogenesis

2011

Antitumor triazoloacridinone C-1305 as a potent FLT3 tyrosine kinase inhibitor in human acute myeloid leukemia (AML) cells.

2010
Meta Tagi