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Sensitivity and Resistance to Therapy

Combination therapy of an anticancer drug with the FNIII14 peptide of fibronectin effectively overcomes cell adhesion-mediated drug resistance of acute myelogenous leukemia

Leukemia volume 22, pages 353–360 (2008)Cite this article

Abstract

We investigated whether FNIII14, a 22-mer peptide derived from fibronectin (FN) that potently impairs interaction of FN with β1-integrin, could overcome cell adhesion-mediated drug resistance (CAM-DR) induced by very late antigen (VLA)-4-to-FN interaction in acute myelogenous leukemia (AML). Two AML cell lines, U937 cells and HL-60 cells, and fresh leukemic cells from six AML patients with high α4-integrin expression exhibited CAM-DR to cytosine arabinoside (Ara C) through VLA-4-to-FN interaction, while fresh leukemic cells from two AML patients with low α4-integrin expression did not display CAM-DR to Ara C. FNIII14 impaired VLA-4-to-FN interaction and restored sensitivity to Ara C in the CAM-DR leukemic cells. In these CAM-DR leukemic cells, upregulation of Bcl-2, which was induced through the focal adhesion kinase/Akt signal pathway upon VLA-4-to-FN interaction, was inhibited by FNIII14 treatment. In a mouse model of minimal residual disease (MRD) in bone marrow, 100% survival was achieved by combining FNIII14 with Ara C, whereas Ara C alone prolonged survival only slightly. The myelosuppression induced by Ara C was not augmented by the combination of FNIII14 in mouse experiments. Thus, the combination of anticancer drugs and FNIII14 holds promise to eradicate MRD in bone marrow after chemotherapy.

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Acknowledgements

We thank Mr Kevin Litton (BA in English) for editorial assistance.

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Author notes

  1. T Matsunaga and F Fukai: These authors contributed equally to this work.

Authors and Affiliations

  1. Fourth Department of Internal Medicine, Sapporo Medical University, School of Medicine, Sapporo, Japan

    T Matsunaga, M Tanaka, T Nagaya, R Takimoto, T Takayama & Y Niitsu

  2. Department of Molecular Pathophysiology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Tokyo, Japan

    F Fukai, S Miura, Y Nakane & T Owaki

  3. Department of Biochemistry, Faculty of Science and Engineering, Saga University, Saga, Japan

    H Kodama

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Correspondence to Y Niitsu.

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Matsunaga, T., Fukai, F., Miura, S. et al. Combination therapy of an anticancer drug with the FNIII14 peptide of fibronectin effectively overcomes cell adhesion-mediated drug resistance of acute myelogenous leukemia. Leukemia 22, 353–360 (2008). https://doi.org/10.1038/sj.leu.2405017

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