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Molecular Targets for Therapy

Inhibition of KSP by ARRY-520 induces cell cycle block and cell death via the mitochondrial pathway in AML cells

Leukemia volume 23, pages 1755–1762 (2009)Cite this article

Abstract

Kinesin spindle protein (KSP), a microtubule-associated motor protein essential for cell cycle progression, is overexpressed in many cancers and is a potential anti-tumor target. We found that inhibition of KSP by a selective inhibitor, ARRY-520, blocked cell cycle progression, leading to apoptosis in acute myeloid leukemia cell lines that express high levels of KSP. Knockdown of p53, overexpression of XIAP and mutation in caspase-8 did not significantly affect sensitivity to ARRY-520, suggesting that the response is independent of p53, XIAP and the extrinsic apoptotic pathway. Although ARRY-520 induced mitotic arrest in both HL-60 and Bcl-2-overexpressing HL-60Bcl-2 cells, cell death was blunted in HL-60Bcl-2 cells, suggesting that the apoptotic program is executed through the mitochondrial pathway. Accordingly, inhibition of Bcl-2 by ABT-737 was synergistic with ARRY-520 in HL-60Bcl-2 cells. Furthermore, ARRY-520 increased Bim protein levels prior to caspase activation in HL-60 cells. ARRY-520 significantly inhibited tumor growth of xenografts in SCID mice and inhibited AML blast but not normal colony formation, supporting a critical role for KSP in proliferation of leukemic progenitor cells. These results demonstrate that ARRY-520 potently induces cell cycle block and subsequent death in leukemic cells via the mitochondrial pathway and has the potential to eradicate AML progenitor cells.

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Acknowledgements

We thank Elena S Vess and Betty Notzon for helping with the preparation of the paper and Wenjing Chen for helping with collecting patient information. This work was supported in part by grants from the National Institutes of Health (P01 CA49639, P01 CA55164, and CA16672) to MA and Array BioPharma to BZC.

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Authors and Affiliations

  1. Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    B Z Carter, D H Mak, W D Schober & M Andreeff

  2. Array BioPharma, Inc., Boulder, CO, USA

    R Woessner & S Gross

  3. Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Z Estrov, H Kantarjian & M Andreeff

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  1. B Z Carter
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  2. D H Mak
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Correspondence to M Andreeff.

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

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Carter, B., Mak, D., Woessner, R. et al. Inhibition of KSP by ARRY-520 induces cell cycle block and cell death via the mitochondrial pathway in AML cells. Leukemia 23, 1755–1762 (2009). https://doi.org/10.1038/leu.2009.101

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