*Correspondence: linge@cuhk.edu.hk

School of Biomedical Sciences, Faculty of Medicine, The Chinese University

of Hong Kong, Shatin, Hong Kong SAR, China

Multi-drug resistance (MDR) in cancer chemotherapy refers to the ability of cancer cells to survive from treatment of a wide range of drugs [1]. In addition to the MDR induced by drugs in early exposure, the MDR cancer cells may subsequently develop cross-resistance to several unexposed and structurally unrelated chemotherapeutic agents [2]. Mechanisms of MDR include decreased uptake of drugs, alterations in cellular pathways and increased active efflux of drugs [3-5] (Figure 1). Overexpression of ATP-binding cassette (ABC) transporters is one of the most common mechanisms. ABC transporters are large membrane-bound proteins consisting of two nucleotide-binding domains (NBDs) and two transmembrane domains (TMDs) which mediate the active transport of substrate drugs out of the cell (Figure 2). Overexpression of the three major ABC transporters, i.e. P-glycoprotein (Pgp), multidrug-resistance-associated protein 1 (MRP1) and breast cancer resistance protein (BCRP/ABCG2) is frequently observed in cancer cell lines selected with chemotherapeutic drugs [6] and critical to clinical drug resistance [7]. P-glycoprotein (Pgp) P-glycoprotein (Pgp) [8], which is also referred to as ABCB1 and MDR1, is the most studied ABC transporter. Pgp transports a wide range of chemotherapeutic agents including the anthracyclines, vincas, taxanes, etoposide and mitoxantrone [6]. Pgp is expressed in various tissues in the body. Remarkably high expression can be found in endothelial cells of capillary blood vessels in the brain as well as other organs including intestines, testes and skin [9,10]. Pgp expression is often detected in renal carcinoma, colon carcinoma, adrenal carcinoma and teratocarcinoma [9]. Substrate drugs can bind to Pgp through multiple binding sites, thereby allowing flexibility in the mechanism of transport [11,12]. Multidrug-resistance-associated protein 1 (MRP1) The second major MDR transporter, multidrug-resistance- associated protein (MRP), was first discovered in a doxorubicin-selected lung cancer cell line [13]. A member of the ABCC subfamily, MRP1 is encoded by the ABCC1 gene [14]. Physiologically, MRP1 tends to pump drugs into the body, rather than excreting them into the bile, urine or gut [15,16]. MRP1 was highly expressed in skeletal muscles [17]. Overexpression of MRP1 is in cancer types such as lung, colon and various forms of leukaemia [18]. 

 

• Chinese medicine and MDR 

How to tackle the MDR cells in chemotherapy is a pressing issue in cancer treatments. Verapamil was the first known Pgp inhibitor to increase the intracellular concentration of anticancer agents in MDR cells by binding to Pgp and inhibiting the Pgp-mediated efflux [26]. It was believed that anticancer drug resistance could be reversed by drug efflux inhibition. Researchers developed and tested a range of Pgp inhibitors to improve the pharmacological effects of chemotherapy in cancer patients [27-29]. However, none of these Pgp inhibitors was further developed for clinical use. Many researchers are looking into Chinese medicine (CM) for potential MDR reversing agents. This article reviews some of the recent findings on the circumvention of ABC transporters-mediated MDR by various ingredients and extracts of CM and their formulae based on whether the MDR reversal involved Pgp alteration. 

• MDR reversal involving Pgp inhibition 

• Active ingredients - saponins 

Quercetin is one of the most widely distributed flavonoids in natural products including Chinese medicinal herbs such as Sophora japonica (Huai). Quercetin inhibited the binding of heat shock factor at the MDR1 promoter, thereby decreasing MDR1 transcription and reducing Pgp expression [61]. Quercetin also inhibited the overexpression of Pgp mediated by arsenite [62]. In HL-60/DOX and K562/DOX cell lines, quercetin enhanced the anticancer sensitivity to daunorubicin and decreased Pgp expression [63,64]. MDR reversal effect of quercetin was probably mediated by its action on mitochondrial membrane potential and the induction of apoptosis. Furthermore, quercetin derivatives rather than quercetin itself reversed MDR [65]. Quercetin increased the sensitivity of Pgp-overexpressing KBV1 cell line towards vinblastine and paclitaxel in a dosedependent manner. Among many active flavonoids, quercetin was less potent than kaempferol but more effective than genistein and daidzein in reversing MDR. Genistein and daidzein had no effect on Pgp expression [66]. Although quercetin may be a potential MDR reversing agent, lethal drug-drug interaction between quercetin and digoxin has been reported. Quercetin (40 mg/ kg) elevated the peak blood concentration of digoxin and caused sudden death of tested animals [67]. Curcumin, the major component in Curcuma longa (Jianghuang), inhibited the transport activity of all three major ABC transporters, i.e. Pgp, MRP1 and ABCG2 [68]. Curcumin reversed MDR of doxorubicin or daunorubicin in K562/DOX cell line and decreased Pgp expression in a time-dependent manner [69]. Curcumin enhanced the sensitivity to vincristine by the inhibition of Pgp in SGC7901/VCR cell line [70]. Moreover, curcumin was useful in reversing MDR associated with a decrease in bcl-2 and survivin expression but an increase in caspase-3 expression in COC1/DDP cell line [71]. The cytotoxicity of vincristine and paclitaxel were also partially restored by curcumin in resistant KBV20C cell line [72]. Curcumin derivatives reversed MDR by inhibiting Pgp efflux [72]. A chlorine substituent at the meta-or para-position on benzamide improved MDR reversal [72]. Bisdemethoxycurcumin modified from curcumin resulted in greater inhibition of Pgp expression [73]. Tetrahydrocurcumin, the major metabolite of curcumin, inhibited all three major ABC transporters [74]. Curcumin induced atypical and caspase-independent cell death in MDR cells [75]. In leukaemic cells collected from 78 childhood leukaemia patients, curcumin reduced Pgp expression [76]. A specialized nanoemulsion of curcumin is better than conventional solution form drugs in enhancing the efficiency of drug delivery into the cells, down-regulating Pgp expression, inhibiting the NF_B pathway and promoting apoptotic response [68,77].