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Ketotifen reverses MDR1-mediated multidrug resistance in human breast cancer cells in vitro and alleviates cardiotoxicity induced by doxorubicin in vivo

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Abstract

Purpose

To investigate the effect of the antihistamine ketotifen on multidrug resistance in human breast cancer cells and doxorubicin toxicity in mice.

Methods

Clonogenicity assays were used to test the effect of ketotifen on human multidrug resistant breast cancer cell lines exposed to chemotherapeutic agents. Flow cytometry was used to measure accumulation of doxorubicin in cells. Fluorimetry was used to measure accumulation of doxorubicin in cardiac tissues. Histological analysis and toxicity studies in mice were used to test the effect of ketotifen on doxorubicin-induced toxicity.

Results

Ketotifen was found to restore the sensitivity of P-glycoprotein-overexpressing multidrug-resistant MCF-7/adr cells to doxorubicin, mitoxantrone, VP-16 and vinblastine, but not to methotrexate or camptothecin. Ketotifen, however, was unable to restore sensitivity of BCRP-overexpressing MCF-7/mx cells or MRP-overexpressing MCF-7/vp cells to mitoxantrone or VP-16, respectively. In vivo, pretreatment of mice with ketotifen caused an increased accumulation of doxorubicin in cardiac tissue, consistent with a block in drug clearance. However, unlike verapamil, ketotifen pretreatment did not enhance doxorubicin toxicity but in fact provided protection, both at the level of cardiac tissue damage and in terms of survival.

Conclusions

Taken together, these observations show that ketotifen is unique in its ability both to reverse multidrug resistance due to P-glycoprotein overexpression and to provide cardioprotection to doxorubicin.

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Acknowledgements

We thank Dr. Ian Tannock for providing the MCF-7/adr cell line and Dr. Erasmus Schneider for providing the MCF-7/mx and MCF-7/vp cell lines. We also thank Dr. Jagdish Butany (Toronto) for assisting with the histological review of the slides.

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Authors and Affiliations

  1. Arthritis and Immune Disorder Research Centre, University Health Network, 620 University Avenue, Toronto, Ontario, M5G 2M9, Canada

    Yicheng Zhang & Stuart A. Berger

  2. Department of Immunology, University of Toronto, Toronto, Ontario, M5G 2M9, Canada

    Stuart A. Berger

Authors
  1. Yicheng Zhang
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  2. Stuart A. Berger
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Corresponding author

Correspondence to Stuart A. Berger.

Additional information

This work was supported by grants from the National Cancer Institute of Canada and the Leukemia Research Fund of Canada to S.A.B.

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Zhang, Y., Berger, S.A. Ketotifen reverses MDR1-mediated multidrug resistance in human breast cancer cells in vitro and alleviates cardiotoxicity induced by doxorubicin in vivo. Cancer Chemother Pharmacol 51, 407–414 (2003). https://doi.org/10.1007/s00280-003-0600-5

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  • DOI: https://doi.org/10.1007/s00280-003-0600-5

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