One of the three well-characterized transporters associated with chemo-resistant mechanisms of a variety of drugs is
P-glycoprotein. It’s a transmembrane glycoprotein molecule with the size of 170-kDa that acts as an energy-dependent efflux transporter [
38]. It consists of 1280 amino acids constituted by two transmembrane domains (TMDs), each consisting of six transmembrane segments and two nucleotide binding domains linked with N- and C-termini (Fig.
2) [
9,
39,
40].
P-glycoprotein, an energy-dependent export transporter was the first human ABC transporter identified in 1976 [
41]. This protein is known to transport and efflux a different variety of hydrophobic compounds including cancer drugs [
31,
42].
P-gp is prominently expressed in the epithelial cells of mouse and human tissues at the physiological barriers such as the blood–brain barrier, gastrointestinal tract, kidney and liver [
43]. Its location at the apical membrane of endothelial cells enable its protective effect. The overexpression of this protein, associated with MDR has led to the identification of many important drugs that can serve as substrate that bind and enhance its transport function [
44].
P-gp have a high flexible drug binding sites that enable its interaction with hundreds of structurally diverse chemical compounds, including anticancer drugs, steroid hormones and hydrophobic toxic peptides [
45]. Another important feature of
P-gp is that it recognizes and transports hydrophobic drugs or substrates thus suggesting lipid membrane partitioning as an essential step for its transport [
39]. Despite understanding of the structure and cellular localization of
P-gp, its precise molecular mechanism of drug transport is still not fully understood. Nevertheless, several hypothetical models like hydrophobic vacuum cleaner and lipid flippase activity have tried to explain the mechanism of substrate efflux by
P-gp. According to the vacuum cleaner model of
P-gp function, the drug/substrate are partitioned into the membrane and are spontaneously translocated into the cytoplasmic leaflet where it gains access to the
P-gp substrate binding sites from within the bilayer interior and subsequently effluxes into the extracellular environment. In the lipid flippase activity model, drugs/substrates are flipped to the outer membrane leaflet after gaining access to the
P-gp substrate binding sites. Both activity models cause dimerization of the two nucleotide binding domains and thus ATP hydrolysis which returns the protein back to its inward facing drug binding conformation and reinitiates the transport cycle [
39,
46]. In tumour cells that express
P-gp, this would result in reduced intracellular concentrations, which decreases the cytotoxicity of several anticancer agents. However, there are possibilities that there might be other complementary mechanisms that are directly related to anticancer drug efflux which can confer resistance. Studies have demonstrated correlation between elevated
P-gp expression and patient response rate following chemotherapy. Trock and colleagues [
47] examined
P-gp expression in patients with breast cancer after administration of chemotherapy and the study showed a threefold likelihood of patients with over expression of
P-gp not to respond to chemotherapy than other patients. Other studies by Triller et al. [
48] and Leith et al. [
49] contradicted the report of Trock and his team by demonstrating that there is no relationship between patient’s response to therapy and
P-gp expression.