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

  • Toshiyuki Matsunaga
  • Ossama El-Kabbani
  • Akira Hara
Part of the Resistance to Targeted Anti-Cancer Therapeutics book series (RTACT, volume 1)


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.


Aldo-keto reductase AKR1B10 AKR1C1 AKR1C3 Colon cancers Chemotherapy Chemoresistance Proliferation 



Aldo-keto reductase


Antioxidant response element


3-Bromo-5-phenylsalicylic acid




3-Chloro-5-phenyl salicylic acid




Epidermal growth factor










3-(4-Hydroxy-2-methoxyphenyl)acrylic acid 3-(3-hydroxyphenyl)propyl ester




Hydroxysteroid dehydrogenase


HT29 phenotype resistant to cisplatin


Kelch-like ECH-associated protein 1




Mitogen-activated protein kinase


Mitomycin C


Non-steroidal anti-inflammatory agent


Nuclear factor-κB


Nuclear factor-erythroid 2-related factor 2








Peroxisome proliferator-activated receptor


Reactive oxygen species


Vascular endothelial growth factor


No Conflict Statement

No potential conflicts of interest were disclosed.


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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Toshiyuki Matsunaga
    • 1
  • Ossama El-Kabbani
    • 2
  • Akira Hara
    • 1
  1. 1.Laboratory of BiochemistryGifu Pharmaceutical UniversityGifuJapan
  2. 2.Monash Institute of Pharmaceutical SciencesMonash UniversityParkvilleAustralia

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