Targeting Aldose Reductase for the Treatment of Cancer

R.      Tammali; S.      K. Srivastava; K.      V. Ramana

doi:10.2174/156800911795655958

Abstract

It is strongly established by numerous studies that oxidative stress-induced inflammation is one of the major causative agents in a variety of cancers. Various factors such as bacterial, viral, parasitic infections, chemical irritants, carcinogens are involved in the initiation of oxidative stress-mediated inflammation. Chronic and persistent inflammation promotes the formation of cancerous tumors. Recent investigations strongly suggest that aldose reductase [AR; AKR1B1], a member of aldo-keto reductase superfamily of proteins, is the mediator of inflammatory signals induced by growth factors, cytokines, chemokines, carcinogens etc. Further, AR reduced product(s) of lipid derived aldehydes and their metabolites such as glutathionyl 1,4-dihydroxynonanol (GS-DHN) have been shown to be involved in the activation of transcription factors such as NF-κB and AP-1 which transcribe the genes of inflammatory cytokines. The increased inflammatory cytokines and growth factors promote cell proliferation, a main feature involved in the tumorigenesis process. Inhibition of AR has been shown to prevent cancer cell growth in vitro and in vivo models. In this review, we have described the possible association between AR with oxidative stress- and inflammation- initiated carcinogenesis. A thorough understanding of the role of AR in the inflammation – associated cancers could lead to the use of AR inhibitors as novel chemotherapeutic agents against cancer.

Keywords: Aldose reductase, oxidative stress, inflammation, cancer, NF-κB, Activator protein, Azoxymethane, 1,4-dihydroxynonene, Basic fibroblast growth factor, Glutathionyl-4-hydroxynonenal, Small interfering RNA, Insulin growth factor, Hepatocyte growth factor