Aldo-Keto Reductases as New Therapeutic Targets for Colon Cancer Chemoresistance

The aldo-keto reductase (AKR) superfamily comprises NAD(P)(H)-dependent enzymes that catalyze the oxidoreduction of a variety of substrates, including prostaglandins, steroids, toxic aldehydes and drugs. Among members of this superfamily, AKR1B10, AKR1C1, AKR1C2 and/or AKR1C3 are overexpressed in several types of cancers. Out of the four AKRs, AKR1B10, AKR1C1 and AKR1C3 are also significantly up-regulated with acquisition of resistance to several anticancer drugs in colon cancer, although the up-regulated enzyme species differ among themselves depending on the drug types. Studies with cell-based experiments have proposed multiple mechanisms leading to the drug resistance through regulation of cell proliferation and detoxification of lipid-derived toxicants by the up-regulated enzymes. Thus, the three enzymes have been recognized not only as potential diagnostic and/or prognostic markers, but also as potential therapeutic targets for the prevention and treatment of the colon cancer chemoresistance. Recently, potent and selective inhibitors of AKR1B10, AKR1C1 and AKR1C3 have been reported, and experimentally used for reversal of the colon cancer chemoresistance. In this chapter, we describe the current literature focusing mainly on the expression profiles of the three AKRs in chemoresistance of colon cancer cells and availability of the inhibitors for overcoming the anticancer drug resistance.