TY - JOUR
T1 - Aldo-keto reductases and cancer drug resistance
AU - Penning, Trevor M.
AU - Jonnalagadda, Sravan
AU - Trippier, Paul C.
AU - Rižner, Tea Lanišnik
N1 - Funding Information:
Thee tudie were upported in part by National Intitute of Health [Grant P30-ES013508 and R01-ES029294] (to T.M.P.) and [Grant R01-CA226436] (to P.C.T.) and by the Slovenian Reearch Agency [Grant J3-8212 and J3-2535] (to T.L.R.).
Funding Information:
Address correspondence to: Dr. Trevor M. Penning, Department of Systems Pharmacology & Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, 1315 BRBII/IIII, 421 Curie Blvd. Philadelphia, PA 19104. E-mail: penning@upenn.edu These studies were supported in part by National Institutes of Health [Grants P30-ES013508 and R01-ES029294] (to T.M.P.) and [Grant R01-CA226436] (to P.C.T.) and by the Slovenian Research Agency [Grants J3-8212 and J3-2535] (to T.L.R.). https://doi.org/10.1124/pharmrev.120.000122
Funding Information:
XI. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1168 Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1169 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1169 Abstract——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 Address correspondence to: Dr. Trevor M. Penning, Department of Systems Pharmacology & Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, 1315 BRBII/IIII, 421 Curie Blvd. Philadelphia, PA 19104. E-mail: penning@upenn.edu These studies were supported in part by National Institutes of Health [Grants P30-ES013508 and R01-ES029294] (to T.M.P.) and [Grant R01-CA226436] (to P.C.T.) and by the Slovenian Research Agency [Grants J3-8212 and J3-2535] (to T.L.R.). https://doi.org/10.1124/pharmrev.120.000122 1150
Publisher Copyright:
© 2021 by The American Society for Pharmacology and Experimental Therapeutics.
PY - 2021/7/1
Y1 - 2021/7/1
N2 - Human aldo-keto reductases (AKRs) catalyze the NADPH-dependent reduction of carbon-yl groups to alcohols for conjugation reactions to proceed. They are implicated in resistance to cancer chemotherapeutic agents either because they are di-rectly involved in their metabolism or help eradicate the cellular stress created by these agents (e.g., reactive oxygen species and lipid peroxides). Further-more, 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, mitomy-cin, cis-platin, antitubulin agents, vinca alkaloids, and cyclophosphamide) occurs by this mechanism. Human AKRs also catalyze the synthesis of andro-gens and estrogens and the elimination of progesto-gens 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 chemothera-peutics 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.
AB - Human aldo-keto reductases (AKRs) catalyze the NADPH-dependent reduction of carbon-yl groups to alcohols for conjugation reactions to proceed. They are implicated in resistance to cancer chemotherapeutic agents either because they are di-rectly involved in their metabolism or help eradicate the cellular stress created by these agents (e.g., reactive oxygen species and lipid peroxides). Further-more, 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, mitomy-cin, cis-platin, antitubulin agents, vinca alkaloids, and cyclophosphamide) occurs by this mechanism. Human AKRs also catalyze the synthesis of andro-gens and estrogens and the elimination of progesto-gens 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 chemothera-peutics 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.
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U2 - 10.1124/pharmrev.120.000122
DO - 10.1124/pharmrev.120.000122
M3 - Article
C2 - 34312303
AN - SCOPUS:85111735986
SN - 0031-6997
VL - 73
SP - 1150
EP - 1171
JO - Pharmacological Reviews
JF - Pharmacological Reviews
IS - 3
ER -