Multidrug Resistance of Cancer Cells and the Vital Role of P-Glycoprotein

Abstract

P-glycoprotein (P-gp) is a major factor in the multidrug resistance phenotype in cancer cells. P-gp is a protein that regulates the ATP-dependent efflux of a wide range of anticancer medicines and confers resistance. Due to its wide specificity, several attempts have been made to block the action of P-gp to restore the efficacy of anticancer drugs. The major goal has been to create molecules that either compete with anticancer medicines for transport or function as a direct P-gp inhibitor. Despite significant in vitro success, there are presently no drugs available in the clinic that can "block" P-gp-mediated resistance. Toxicity, unfavourable pharmacological interactions, and a variety of pharmacokinetic difficulties might all be the reason for the failure. On the other hand, P-gp has a significant effect in the body. It protects the vital organs from the entry of foreign bodies and other toxic chemicals. Hence, the inhibitors of P-gp should not hinder its action in the normal cells. To develop an effective inhibitor of P-gp, thorough background knowledge is needed in this field. The main aim of this review article was to set forth the merits and demerits of the action of P-gp on cancer cells as well as on normal cells. The influence of P-gp on cancer drug delivery and the contribution of P-gp to activating drug resistance were also mentioned.

Keywords: P-gp; cancer; clinical trials; inhibitors; multidrug resistance.

Figure 1

The structure of P-gp and its binding capacity. Abbreviations: TM–transmembrane, NBD–Nucleotide binding site, ATP–Adenosine triphosphatase.

Figure 2

P-gp expression upregulation and its mechanism. Abbreviations: IL–interleukin, P-gp–P-glycoprotein, HIF–Hypoxia-inducible factor, SIK–Salt-inducible kinase, TNF–tumour necrosis factor.