The controversial role of ABC transporters in clinical oncology

Abstract

The phenomenon of multidrug resistance in cancer is often associated with the overexpression of the ABC (ATP-binding cassette) transporters Pgp (P-glycoprotein) (ABCB1), MRP1 (multidrug resistance-associated protein 1) (ABCC1) and ABCG2 [BCRP (breast cancer resistance protein)]. Since the discovery of Pgp over 35 years ago, studies have convincingly linked ABC transporter expression to poor outcome in several cancer types, leading to the development of transporter inhibitors. Three generations of inhibitors later, we are still no closer to validating the 'Pgp hypothesis', the idea that increased chemotherapy efficacy can be achieved by inhibition of transporter-mediated efflux. In this chapter, we highlight the difficulties and past failures encountered in the development of clinical inhibitors of ABC transporters. We discuss the challenges that remain in our effort to exploit decades of work on ABC transporters in oncology. In learning from past mistakes, it is hoped that ABC transporters can be developed as targets for clinical intervention.

Figure 1.. Substrate transport by Pgp

(A) The substrate, shown in magenta, enters the membrane and diffuses through a portal in the transporter. (B) Once in the drug-binding pocket, coloured blue, ATP, shown in yellow, binds to the nucleotide-binding domains and causes a conformational change, leaving the drug-binding pocket facing the extracellular space. ATP then binds again to reset the transporter to its original conformation shown in (A). From [1]: Aller, S., Yu, J., Ward, A., Weng, Y., Chittaboina, S., Zhuo, R., Harrell, P., Trinh, Y., Zhang, Q., Urbatsch, I. and Chang, G. (2009) Structure of P-glycoprotein reveals a molecular basis for poly-specific drug binding. Science 323, 1718–1722. Reprinted with permission from AAAS.