Novel strategies to prevent the development of multidrug resistance (MDR) in cancer

Abstract

The development of multidrug resistance (MDR) is one of the major challenges to the success of traditional chemotherapy treatment in cancer patients. Most studies to date have focused on strategies to reverse MDR following its development. However, agents utilizing this approach have proven to be of limited clinical use, failing to demonstrate an improvement in therapeutic efficacy with almost no significant survival benefits observed in cancer clinical trials. An alternative approach that has been applied is to prevent or delay MDR prior or early in its development. Recent investigations have shown that preventing the emergence of MDR at the onset of chemotherapy treatment, rather than reversing MDR once it has developed, may assist in overcoming drug resistance. In this review, we focus on a number of novel strategies used by small-molecule inhibitors to prevent the development of MDR. These agents hold great promise for prolonging the efficacy of chemotherapy treatment and improving the clinical outcomes of patients with cancers that are susceptible to MDR development.

Keywords: MDR; Pgp; Pgp inhibitor; drug resistance; prevention.

Figure 1. Schematic of the mechanisms involved in the prevention of drug resistance

(1) Drug efflux is increased by the overexpression of ABC transporters during chemotherapy. Curcuminoids and NSC77037 can decrease NF-κB transcription [53, 97], while PSC833 and BVDU can suppress the ABCB1 gene amplification [29, 48]. VX710, XR9576, PSC833, NSC23925, Bexarotene, NS-398, Dexrazoxane, Curcuminoid, and P85 directly inhibit the protein expression of P-glycoprotein (Pgp) [19, 27, 33, 34]. (2) Anticancer drugs can become conjugated to glutathione (GSH), leading to their inactivation. This is catalyzed by Glutathione S-transferase (GST), through utilization of the energy derived from ATP hydrolysis. Ethacrynic acid (EA), P85 and selenium compounds can inhibit GST activity [28, 30, 42], and selenium compounds even can decrease the level of GSH [43]. (3) Apoptosis can be initiated through two signaling pathways, the intrinsic pathway (mitochondrial-mediated) and the extrinsic pathway (death receptor-mediated). NSC23925 can inhibit the expression of Bcl-xL, an anti-apoptotic protein, thereby promoting apoptosis [21].

Figure 2. Schematic summarizing how small-molecule inhibitors may prevent the development of drug resistance in vitro

(A) There are three main treatment schemes used to generate drug-resistant cell lines. In the first scheme, drug treatment is dose-dependent, whereas in the second and third the drug treatments are time-dependent. The first scheme is a progressive-concentration drug treatment, where sensitive parental cancer cells are exposed to gradually increasing concentrations of anticancer drugs [21]. The second scheme is continuous drug treatment, whereby sensitive parental cancer cells are exposed to a fixed concentration of drug for a continuous period of time [33]. In the third scheme, drug treatment is intermittent, with sensitive parental cancer cells exposed to repeated treatment cycles [34]. (B) In contrast to the anti-cancer agents alone causing chemotherapy resistance in these three schemes, in the presence of small-molecule inhibitors, resistance cannot develop during the drug exposure.

Figure 3. Small-molecule inhibitors prevent the development of drug resistance in vivo

(A) Chemotherapy drug treatment schedule in a drug-resistant xenograft tumor model. Tumor cells are implanted subcutaneously into the left and right axial regions of 3-to-4-week-old nude mice. When the tumor volumes can be measured, two different administration methods of anticancer drugs are applied. I. The mice are exposed to a single drug concentration for 3 weeks followed by a treatment-free interval of 2 weeks. A second round of the same treatment is then continued [21]. II. The mice are exposed to a single drug concentration for six weeks, without a treatment-free interval [35]. (B) Schematic demonstrating that compared with anticancer drug treatments alone, combining a small-molecule inhibitor can prevent the development of drug resistance and prevent tumor growth.