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Involvement of p53 in the cytotoxic activity of the NAMPT inhibitor FK866 in myeloid leukemic cells.

ABSTRACT: FK866 is a specific inhibitor of NAMPT and induces apoptosis of leukemic cells by depletion of intracellular NAD(+). Since up-regulation of NAMPT is associated with several cases of cancers, including leukemias, we asked whether in leukemic cells inhibition of NAMPT involves p53 pathway. We observed that FK866 induced apoptosis and reduced cell proliferation in NB-4, OCI-AML3 and MOLM-13 cell lines. In contrast, the leukemia cell lines, K-562 and Kasumi, containing nonfunctional p53 were relatively unaffected by FK866 treatment. Importantly, direct inhibition of sirtuins significantly reduced the viability of NB-4, OCI-AML3 and MOLM-13 cell lines. Activation of p53 by FK866 involved increased acetylation of p53 at lysine 382 with subsequent increase in the expression of p21 and BAX. Further, knockdown of p53 attenuated the effects of FK866 on apoptosis and cell cycle arrest, which was partly associated with decreased expression of p21 and BAX. Our results suggest the role of p53 acetylation pathway in the anti-leukemic effect of FK866.

SUBMITTER: Thakur BK

PROVIDER: S-EPMC3562481 | biostudies-other | 2013 Feb

REPOSITORIES: biostudies-other

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Involvement of p53 in the cytotoxic activity of the NAMPT inhibitor FK866 in myeloid leukemic cells.

Thakur Basant Kumar BK Dittrich Tino T Chandra Prakash P Becker Annette A Kuehnau Wolfgang W Klusmann Jan-Henning JH Reinhardt Dirk D Welte Karl K

International journal of cancer 20120812 4

FK866 is a specific inhibitor of NAMPT and induces apoptosis of leukemic cells by depletion of intracellular NAD(+). Since up-regulation of NAMPT is associated with several cases of cancers, including leukemias, we asked whether in leukemic cells inhibition of NAMPT involves p53 pathway. We observed that FK866 induced apoptosis and reduced cell proliferation in NB-4, OCI-AML3 and MOLM-13 cell lines. In contrast, the leukemia cell lines, K-562 and Kasumi, containing nonfunctional p53 were relativ ...[more]

PMID: 22815158

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Project description:Acute myeloid leukemia (AML) remains a difficult disease to treat and requires new therapies to improve treatment outcome. Wee1 inhibitors have been used to prevent activation of the G2 cell cycle checkpoint, thus enhancing the antitumor activity of DNA damaging agents. In this study, we investigated MK-1775 in AML cell lines and diagnostic blast samples to identify sensitive subtypes as well as possible mechanisms of resistance.In vitro MK-1775 cytotoxicities of AML cell lines and diagnostic blasts were measured using MTT assays. The effects of MK-1775 on cell cycle progression and related proteins were determined by propidium iodide (PI) staining and flow cytometry analysis and Western blotting. Drug-induced apoptosis was determined using annexin V/PI staining and flow cytometry analysis.We found that newly diagnosed and relapsed patient samples were equally sensitive to MK-1775. In addition, patient samples harboring t(15;17) translocation were significantly more sensitive to MK-1775 than non-t(15;17) samples. MK-1775 induced apoptosis in both AML cell lines and diagnostic blast samples, accompanied by decreased phosphorylation of CDK1 and CDK2 on Tyr-15 and increased DNA double-strand breaks (DSBs). Time-course experiments, using AML cell lines, revealed a time-dependent increase in DNA DSBs, activation of CHK1 and subsequent apoptosis following MK-1775 treatment, which could be attenuated by a CDK1/2 inhibitor, Roscovitine. Simultaneous inhibition of CHK1 and Wee1 resulted in synergistic anti-leukemic activity in both AML cell lines and primary patient samples ex vivo.Our study provides compelling evidence that CHK1 plays a critical role in the anti-leukemic activity of MK-1775 and highlights a possible mechanism of resistance to MK-1775. In addition, our study strongly supports the use of MK-1775 to treat both newly diagnosed and relapsed AML, especially cases with t(15;17) translocation, and supports the development of combination therapies with CHK1 inhibitors.

Dataset Information

Involvement of p53 in the cytotoxic activity of the NAMPT inhibitor FK866 in myeloid leukemic cells.

Publications

Involvement of p53 in the cytotoxic activity of the NAMPT inhibitor FK866 in myeloid leukemic cells.

Similar Datasets

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