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Reversal of ATP-binding cassette drug transporter activity to modulate chemoresistance: why has it failed to provide clinical benefit?

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Abstract

Enhanced drug extrusion from cells due to the overexpression of the ATP-binding cassette (ABC) drug transporters inhibits the cytotoxic effects of structurally diverse and mechanistically unrelated anticancer agents and is a major cause of multidrug resistance (MDR) of human malignancies. Multiple compounds can suppress the activity of these efflux transporters and sensitize resistant tumor cells, but despite promising preclinical and early clinical data, they have yet to find a role in oncologic practice. Based on the knowledge of the structure, function, and distribution of MDR-related ABC transporters and the results of their preclinical and clinical evaluation, we discuss probable reasons why these inhibitors have not improved the outcome of therapy for cancer patients. We also outline new MDR-reversing strategies that directly target ABC transporters or circumvent relevant signaling pathways.

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Acknowledgments

We would like to thank Dr. Krupa Patel and Carol M. Lee for insightful discussion. We are grateful to several past trainees in our laboratory for contributing to the development of some ideas presented in this review. Work in our laboratory was supported by grants from the Canadian Institutes of Health Research (209710 to I.F.T.) and the Susan G. Komen Foundation. A.O. and I.F.T. receive research funding from Sanofi Aventis. We apologize to all colleagues whose work could not be properly cited due to space restrictions.

Conflict of interest

The authors claim that there are no conflicts of interest in relation with this review.

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Authors and Affiliations

  1. Ontario Cancer Institute/Princess Margaret Hospital, University of Toronto, Suite 5-208, 610 University Avenue, Toronto, ON, Canada, M5G 2M9

    Man Yu & Ian F. Tannock

  2. Medical Oncology Department and AECC Unit, Albacete University Hospital, Albacete, Spain

    Alberto Ocana

  3. Division of Medical Oncology and Hematology, Princess Margaret Hospital, University of Toronto, Toronto, ON, Canada

    Alberto Ocana & Ian F. Tannock

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  1. Man Yu
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Correspondence to Ian F. Tannock.

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Summary

• ATP-binding cassette (ABC) transporters, including P-glycoprotein, multidrug resistance-associated protein 1, and breast cancer resistance protein, cause active efflux of anticancer agents out of tumor cells and confer multidrug resistance (MDR).

• ABC transporters are expressed in a broad range of human solid tumors and hematologic malignancies. Expression of these drug transporters is associated with resistance to chemotherapy in preclinical models, as well as poor response and prognosis in patients treated with chemotherapy.

• Three generations of inhibitors of ABC transporters have been developed to sensitize multidrug-resistant tumor cells. Several problems, including unacceptable cytotoxic effects, altered pharmacokinetics of anticancer drugs, lack of preselection of patients, and adversely modified drug distribution, have prevented their successful translation to the clinic.

• There has been inadequate preclinical evaluation of most MDR inhibitors, with testing most often undertaken in animals using tumors that were either not established or large enough to be representative of human cancer.

• Alternative strategies to direct the inhibition of the activity of ABC efflux pumps have been developed, such as RNA interference and nanoparticles to avert or overcome ABC transporter-mediated MDR; they have demonstrated encouraging results in preclinical studies.

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Yu, M., Ocana, A. & Tannock, I.F. Reversal of ATP-binding cassette drug transporter activity to modulate chemoresistance: why has it failed to provide clinical benefit?. Cancer Metastasis Rev 32, 211–227 (2013). https://doi.org/10.1007/s10555-012-9402-8

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