Asian Pacifc Journal of Cancer Prevention, Vol 16, 2015 6831 DOI:http://dx.doi.org/10.7314/APJCP.2015.16.16.6831 Enhancing Anticancer Drug Activity in Multidrug Resistant Tumors by Modulating P-Glycoprotein with Dietary Nutraceuticals Asian Pac J Cancer Prev, 16 (16), 6831-6839 Introduction Cancer is one of the most virulent, devastating and deadliest disease in the world and it represents the second leading cause of death worldwide (Jemal et al., 2008; Siegel et al., 2012), with approximately 14 million new cases and 8.2 million cancer related deaths in 2012 (Ferlay et al., 2015). Chemotherapy is one of the most effective treatments for metastatic cancers (Chang, 2010). Multidrug resistance (MDR) is one of the major obstacles in the successful chemotherapy of various cancers (Baguley, 2010; Eid et al., 2012; Xu et al., 2012; Kibria et al., 2014; Liu et al., 2014). It is widely accepted now that MDR exists against every effective drug (Callaghan et al., 2014). Therefore, the modulation of cellular molecules involved in MDR and circumvent drug resistance is likely to improve chemotherapy (Gottesman et al., 2002; Gillet et al., 2010). P-glycoprotein, a 170 kDa transmembrane phosphorylated glycoprotein encoded by MDR1 (ABCB1), belongs to ATP-binding cassette (ABC) superfamily of membrane transporters (Eichhorn and Efferth, 2012; Eid et al., 2012). It is composed of 1280 amino acids and consists of two similar halves each containing six transmembrane domains and one ATP binding domain (Nabekura, 2010a; Zeino et al., 2015). P-gp was frst discovered in 1976 in Chinese hamster ovary (CHO) cells, where it was found to display resistance to anticancer drugs (Callaghan et al., 2014). By the 1980s antibodies had been developed to p-gp to detect the distribution and expression of this 1 College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning, P.R. China *For correspondence: khan2014@ dlmedu.edu.cn Abstract Multidrug resistance is a principal mechanism by which tumors become resistant to structurally and functionally unrelated anticancer drugs. Resistance to chemotherapy has been correlated with overexpression of p-glycoprotein (p-gp), a member of the ATP-binding cassette (ABC) superfamily of membrane transporters. P-gp mediates resistance to a broad-spectrum of anticancer drugs including doxorubicin, taxol, and vinca alkaloids by actively expelling the drugs from cells. Use of specifc inhibitors/blocker of p-gp in combination with clinically important anticancer drugs has emerged as a new paradigm for overcoming multidrug resistance. The aim of this paper is to review p-gp regulation by dietary nutraceuticals and to correlate this dietary nutraceutical induced-modulation of p-gp with activity of anticancer drugs. Keywords: Multidrug resistance - p-glycoprotein - dietary nutraceuticals - anticancer drugs MINI-REVIEW Enhancing Activity of Anticancer Drugs in Multidrug Resistant Tumors by Modulating P-Glycoprotein through Dietary Nutraceuticals Muhammad Khan*, Amara Maryam, Tahir Mehmood, Yaofang Zhang, Tonghui Ma protein in various cells. Soon, it became evident that p-gp expressed in various cancer as well as numerous normal cells (Callaghan et al., 2014). In 1987, it was frst detected in human KB carcinoma cells where its overexpression was found to be associated with cellular resistance to a wide range of anticancer drugs including colchincine, vinblastine, and doxorubicin (Ueda et al., 1987). Since then, researchers have compiled a myriad of research reports on the key role of p-gp in MDR (Bhardwaj et al., 2002; Eid et al., 2013; Molnar et al., 2010; Nabekura et al., 2008a; Nabekura et al., 2008b; Perestelo et al., 2011;Yang et al., 2014). It has become an established fact now that p-gp mediates MDR by actively transporting a wide range of anticancer drugs including paclitaxel, doxorubicin, daunorubicin, vinca alkaloids and eteposide (Zhang et al., 2003; Yoshida et al., 2005; Ferreira et al., 2006; Nabekura, 2010a; Yang et al., 2014). P-gp can interact and bind with a large number of structurally and functionally unrelated agents which suggests its multiple binding sites (Zhang et al., 2009; Chen et al., 2012). According to the interactions, these agents can be classifed into three main groups: substrate, inhibitors, and modulators. Agents that are actively transported by p-gp are categorized as substrates whereas those that inhibit the transporting activity of p-gp are termed as inhibitors. Modulators interact and bind with allosteric site of p-gp thereby reducing the substrate binding through conformational changes. Thus, inhibitors and modulators exert the same biological effect (Chen et al., 2012). Therefore, identifcation and characterization of p-gp inhibitors and modulators may provide a useful