Tackling multidrug resistance mediated by efflux transporters in tumor-initiating cells

ABSTRACT

Introduction: Expression of the multifunctional ATP-binding cassette (ABC) efflux transporter gene family is a well-established mechanism for protecting cancer stem cells (CSCs) from damage or death due to toxins. The outcome of such protection makes CSCs innately multidrug resistant (MDR) to conventional chemotherapy.

Areas covered: While research has focused on gaining better insight into the role of ABC transporters in CSC drug resistance, various strategies to circumvent the function of these transporters have been proposed, including inhibition of transporter function through targeted tyrosine kinase inhibitors, competitive and allosteric modulators, shRNA-mediated inhibition, nanoparticle-mediated delivery of inhibitors, and modulating the regulation of transcriptional and signaling pathways involving ABC transporters. This review highlights the role of MDR mediated by ABC transporters, particularly in CSCs, and the current progress and pitfalls of strategies to circumvent MDR in CSCs.

Expert opinion: Cancer stem cells are now a subject of intense research, as it is hypothesized that these progenitors predominantly beget tumorigenesis, chemoresistance, and metastasis. Consequently, the design and synthesis of more effective ABC transporter inhibitors, to increase cytotoxic drug concentrations in CSCs (thus increasing their eradication), is a promising approach for the field of oncology.

KEYWORDS:

• ABC transporters
• cancer stem cells
• chemosensitization
• multidrug resistance
• nanotechnology

Article highlights

• Overexpression of ATP-binding cassette in cancer stem cells (CSCs) has been implicated in the development of innate multidrug resistance (MDR).

• Previous strategies proposed to overcome MDR through targeting ABC-transporters (as outlined in this article) have shown limited clinical efficacy.

• Fundamental understanding of regulatory pathways of ABC transporters in stem cell biology will be imperative to understand MDRX-genesis mechanisms.

• Synergistic inhibition of multiple regulatory targets of ABC transporters, combined with targeting other MDR mechanisms, is a promising approach to cancer therapy.

This box summarizes key points contained in the article.

Acknowledgments

We thank Ms. Charisse Montgomery, University of Toledo for critical reading of this manuscript.

Declaration of interest

This work was supported by start-up funds provided to AK Tiwari through the Department of Pharmacology and Experimental Therapeutics at College of Pharmacy, University of Toledo. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.