Abstract
Multidrug resistance (MDR) is a major hurdle which must be overcome to effectively treat cancer. ATP-binding cassette transporters (ABC transporters) play pivotal roles in drug absorption and disposition, and overexpression of ABC transporters has been shown to attenuate cellular/tissue drug accumulation and thus increase MDR across a variety of cancers. Overcoming MDR is one desired approach to improving the survival rate of patients. To date, a number of modulators have been identified which block the function and/or decrease the expression of ABC transporters, thereby restoring the efficacy of a range of anticancer drugs. However, clinical MDR reversal agents have thus far proven ineffective and/or toxic. The need for new, effective, well-tolerated and nontoxic compounds has led to the development of natural compounds and their derivatives to ameliorate MDR. This review evaluates whether synthetically modifying natural compounds is a viable strategy to generate potent, nontoxic, ABC transporter inhibitors which may potentially reverse MDR.
Highlights
Multidrug resistance (MDR) is the process by which cells become resistant to multiple unrelated drugs [1,2]
One of the main mechanisms by which cancer cells become resistant is up-regulation of various ABC transporters such as P-glycoprotein (P-gp), Breast Cancer Resistant Protein (BCRP) and Multidrug Resistant Protein 1 (MRP1) which efficiently remove the drug from the cell, causing the drug to lose its effect [3]
ABC transporters are made up of two components—the transmembrane domain (TMD) which creates the passageway for substrates to pass through membranes and the nucleotide-binding domain (NBD), where ATP is hydrolyzed [5]
Summary
Multidrug resistance (MDR) is the process by which cells become resistant to multiple unrelated drugs [1,2]. Genistein much like resveratrol exhibits low bioavailability in clinic which could be related to its broad interactions with BCRP, P-gp and MRP2 [22,23,24] All of these natural, highly bioactive, poorly bioavailable compounds may rely on ABC transporter inhibitors or synthetic modification to improve their activity in clinic. In vitro results showed higher potency and specificity in clinic the second generation modulators showed little MDR reversal effects and various side effects such as neutropenia and high toxicity [25], because they inhibit CYP450-mediated anti-cancer drug metabolism which lead togreatly increased systemic exposure of cytotoxics and enhanced toxicity [25] Third generation inhibitors such as tariquidar and zosuquidar were developed with improved potency and minimized CYP450 inhibitory activity [25]. It suggests that much of the research and designs for MDR modulators has not been wasted
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