Overcoming multidrug-resistance in cancer: statins offer a logical candidate

About seven million people die of cancer every year. This is largely due to development of drug resistance, particularly multidrug resistance, in the tumor cells. Multidrug resistance (MDR) arises due to over-expression of MDR proteins in the cancer cells, which cause efflux of anticancer drugs from the cells using ATP. MDR proteins are members of the family of ABC transporters that occur universally, and are structurally and functionally conserved during evolution. In Drosophila, the germ cell attractant peptide is secreted by an ABC transport protein, mdr49. Recently, the peptide has been shown to undergo conjugation with the lipid geranylgeranyl before secretion. If conjugation with the lipid is inhibited, mdr49 protein is unable to transport the peptide. Similarly, in the case of yeast mating factor pheromone, farnesylation is required to occur before the export of the pheromone by ste6 protein, an ABC transporter. In view of the homology of mdr49 and ste6 proteins with mammalian MDR proteins, we postulate that the drug transporters also require their ligands to be conjugated to a lipid. This view finds support from the studies with synthetic inhibitors of geranylgeranyl-/farnesyl-diphosphate synthetase or transferase: The inhibitors are reported to overcome multidrug resistance in cancer cell lines or xenografts in animals. Thus, the MDR transporters also appear to require their substrates to be conjugated with a lipid. Statins are the widely used inhibitors of HMG-CoA reductase. By depleting precursors of the mevalonate pathway, statins can prevent the formation of lipids like geranylgeranyl and farnesyl. Accordingly, they should also be able to overcome multidrug resistance in cancer. A few reports in the literature indicate that they appear to do so. Statins are in wide clinical use, and their pharmacology is well known. Besides, statins per se have mild beneficial effect on the outcome of the disease. We propose that statins should be seriously investigated for their ability to overcome multidrug resistance in cancer. This should be done after careful standardization of the protocol of simultaneous treatment with anticancer drugs and a statin.