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Oncogenes, Fusion Genes and Tumor Suppressor Genes

Divergent cytotoxic effects of PKC412 in combination with conventional antileukemic agents in FLT3 mutation-positive versus -negative leukemia cell lines

Leukemia volume 21, pages 1005–1014 (2007)Cite this article

Abstract

FMS-like tyrosine kinase-3 (FLT3) is a new therapeutic target for acute myelocytic leukemia (AML), because FLT3 mutations are the most common genetic alterations in AML and are directly related to leukemogenesis. We studied cytotoxic interactions of a FLT3 inhibitor, PKC412, with eight conventional antileukemic agents (cytarabine, doxorubicin, idarubicin, mitoxantrone, etoposide, 4-hydroperoxy-cyclophosphamide, methotrexate and vincristine) using three leukemia cell lines carrying FLT3 mutations (MOLM13, MOLM14 and MV4-11) and five leukemia cell lines without FLT3 mutations (KOPB-26, THP-1, BALL-1, KG-1 and U937). PKC412 showed synergistic effects with all agents studied except methotrexate for FLT3-mutated cell lines in isobologram analysis. In contrast, PKC412 was rather antagonistic to most drugs, except for 4-hydroperoxy-cyclophosphamide and vincristine, in leukemia cell lines without FLT3 mutations. Cell-cycle analysis revealed that PKC412 induced G1 arrest in leukemia cell lines carrying FLT3 mutations, whereas it arrested cells in G2/M phase in the absence of FLT3 mutations, which may underlie the divergent cytotoxic interactions. These results suggest that the simultaneous administration of PKC412 and other agents except methotrexate is clinically effective against FLT3 mutation-positive leukemias, whereas it would be of little benefit for FLT3 mutation-negative leukemias. Our findings may be of help for the design of PKC412-based combination chemotherapy.

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Acknowledgements

Supported in part by High-Tech Research Center Project for Private Universities: Matching Fund Subsidy from MEXT 2002-2006, and grants from Mitsubishi Pharma Research Foundation and Vehicle Racing Commemorative Foundation.

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Authors and Affiliations

  1. Department of Stem Cell Regulation, Center for Molecular Medicine, Jichi Medical School, Tochigi, Japan

    Y Furukawa & T Odgerel

  2. Division of Ultrafine Structure, Department of Clinical Pathology, Research Institute, International Medical Center of Japan, Tokyo, Japan

    H A Vu & Y Sato

  3. Division of Hematology, Department of Internal Medicine, Tochigi Cancer Center, Tochigi, Japan

    M Akutsu, T Izumi, S Tsunoda & Y Kano

  4. Department of Cell Biology, Grandsoul Research Institute for Immunology, Nara, Japan

    Y Matsuo

  5. Department of Hematology, University of Yamanashi, Yamanashi, Japan

    K Kirito

  6. Department of Functional Genomics, Center for Molecular Medicine, Jichi Medical School, Tochigi, Japan

    H Mano

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  1. Y Furukawa
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Correspondence to Y Furukawa.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Furukawa, Y., Vu, H., Akutsu, M. et al. Divergent cytotoxic effects of PKC412 in combination with conventional antileukemic agents in FLT3 mutation-positive versus -negative leukemia cell lines. Leukemia 21, 1005–1014 (2007). https://doi.org/10.1038/sj.leu.2404593

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