PT  - JOURNAL ARTICLE
AU  - Trevor M. Penning
AU  - Sravan Jonnalagadda
AU  - Paul C. Trippier
AU  - Tea Lanišnik Rižner
ED  - Gottesman, Michael
TI  - Aldo-Keto Reductases and Cancer Drug Resistance
AID  - 10.1124/pharmrev.120.000122
DP  - 2021 Jul 01
TA  - Pharmacological Reviews
PG  - 1150--1171
VI  - 73
IP  - 3
4099  - http://pharmrev.aspetjournals.org/content/73/3/1150.short
4100  - http://pharmrev.aspetjournals.org/content/73/3/1150.full
SO  - Pharmacol Rev2021 Jul 01; 73
AB  - Human aldo-keto reductases (AKRs) catalyze the NADPH-dependent reduction of carbonyl groups to alcohols for conjugation reactions to proceed. They are implicated in resistance to cancer chemotherapeutic agents either because they are directly involved in their metabolism or help eradicate the cellular stress created by these agents (e.g., reactive oxygen species and lipid peroxides). Furthermore, this cellular stress activates the Nuclear factor-erythroid 2 p45-related factor 2 (NRF2)-Kelch-like ECH-associated protein 1 pathway. As many human AKR genes are upregulated by the NRF2 transcription factor, this leads to a feed-forward mechanism to enhance drug resistance. Resistance to major classes of chemotherapeutic agents (anthracyclines, mitomycin, cis-platin, antitubulin agents, vinca alkaloids, and cyclophosphamide) occurs by this mechanism. Human AKRs also catalyze the synthesis of androgens and estrogens and the elimination of progestogens and are involved in hormonal-dependent malignancies. They are upregulated by antihormonal therapy providing a second mechanism for cancer drug resistance. Inhibitors of the NRF2 system or pan-AKR1C inhibitors offer promise to surmount cancer drug resistance and/or synergize the effects of existing drugs.Significance Statement Aldo-keto  reductases (AKRs) are overexpressed in a large number of human tumors and mediate resistance to cancer chemotherapeutics and antihormonal therapies. Existing drugs and new agents in development may surmount this resistance by acting as specific AKR isoforms or AKR pan-inhibitors to improve clinical outcome.