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EM012, a microtubule-interfering agent, inhibits the progression of multidrug-resistant human ovarian cancer both in cultured cells and in athymic nude mice

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Abstract

Drug resistance, in particular multidrug resistance, is a serious problem that impedes the effectiveness of chemotherapy. Multidrug resistance results mainly from an enhanced efflux of drugs by drug pumps located on the cell membrane such as P-glycoprotein. In the study reported here we showed that EM012, a microtubule-interfering agent, is a weak substrate for P-glycoprotein and inhibited the proliferation of A2780/ADR human ovarian cancer cells, which possess multidrug resistance due to P-glycoprotein overexpression. A2780/ADR cells treated with EM012 exhibited pronounced mitotic arrest, developed large multilobed nuclei, and eventually died through the initiation of apoptosis. Intraperitoneal treatment of A2780/ADR xenograft tumors in athymic nude mice with EM012 significantly inhibited tumor progression through triggering apoptosis and conferred an apparent survival advantage. Furthermore, EM012 treatment did not cause detectable toxicity to normal tissues. These findings suggest that EM012 may serve as a novel chemotherapeutic agent for the treatment of multidrug-resistant human ovarian cancer.

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Acknowledgements

This work was supported by grants from the National Institutes of Health to H.C.J. and R.R.T.

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Authors and Affiliations

  1. Department of Cell Biology, Emory University School of Medicine, 615 Michael Street, Atlanta, GA, 30322, USA

    Jun Zhou, Min Liu & Harish C. Joshi

  2. Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, GA, 30322, USA

    Roopa Luthra, Jeremy Jones & Rajeshwar R. Tekmal

  3. Department of Obstetrics and Gynecology, University of Texas Health Science Center, San Antonio, TX, 78229, USA

    Jeremy Jones & Rajeshwar R. Tekmal

  4. Department of Chemistry, University of Delhi, Delhi, 110007, India

    Ritu Aneja

  5. Dr. B. R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi, 110007, India

    Ritu Aneja & Ramesh Chandra

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  1. Jun Zhou
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  2. Min Liu
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  3. Roopa Luthra
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  4. Jeremy Jones
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  5. Ritu Aneja
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  7. Rajeshwar R. Tekmal
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  8. Harish C. Joshi
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Correspondence to Harish C. Joshi.

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Zhou, J., Liu, M., Luthra, R. et al. EM012, a microtubule-interfering agent, inhibits the progression of multidrug-resistant human ovarian cancer both in cultured cells and in athymic nude mice. Cancer Chemother Pharmacol 55, 461–465 (2005). https://doi.org/10.1007/s00280-004-0903-1

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  • DOI: https://doi.org/10.1007/s00280-004-0903-1

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