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Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms
Published on: December 9, 2015
Aldo-Keto Reductases and Cancer Drug Resistance
Trevor M Penning1, Sravan Jonnalagadda2, Paul C Trippier2
1Center of Excellence in Environmental Toxicology, Department of Systems Pharmacology & Translational Therapeutics, Philadelphia, Pennsylvania (T.M.P.); Department of Pharmaceutical Science (S.J., P.C.T.) and Fred and Pamela Buffett Cancer Center (P.C.T.), University of Nebraska Medical Center and UNMC Center for Drug Discovery, Omaha, Nebraska; and Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia (T.L.R.) penning@upenn.edu.
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 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.
Insights
Human aldo-keto reductases (AKRs) are overexpressed in tumors, driving resistance to chemotherapy and antihormonal therapies. Inhibiting AKR or the NRF2 pathway may overcome this resistance, improving cancer treatment outcomes.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Human aldo-keto reductases (AKRs) are enzymes crucial for reducing carbonyl groups, playing roles in cellular detoxification and hormone metabolism.
- AKRs are implicated in cancer drug resistance through direct metabolism of chemotherapeutics and by mitigating cellular stress.
- The Nuclear factor-erythroid 2 p45-related factor 2 (NRF2) pathway, often activated by cellular stress, upregulates many AKR genes, creating a feedback loop for enhanced drug resistance.
Purpose of the Study:
- To elucidate the mechanisms by which human AKRs contribute to cancer drug resistance.
- To explore the role of the NRF2 pathway in AKR-mediated chemoresistance and hormonal therapy resistance.
- To identify potential therapeutic strategies targeting AKRs or the NRF2 pathway to overcome cancer drug resistance.
Main Methods:
- Analysis of AKR gene expression in relation to NRF2 activation and response to various chemotherapeutic agents.
- Investigation of AKR involvement in the metabolism of anticancer drugs and hormonal therapies.
- Evaluation of the efficacy of NRF2 inhibitors and pan-AKR1C inhibitors in preclinical models of cancer.
Main Results:
- Human AKRs confer resistance to major classes of chemotherapeutic agents, including anthracyclines, mitomycin, cisplatin, and cyclophosphamide.
- AKRs are upregulated by antihormonal therapy, contributing to resistance in hormone-dependent malignancies.
- Inhibitors targeting the NRF2 system or AKR1C isoforms show promise in overcoming established drug resistance and potentiating existing therapies.
Conclusions:
- Overexpression of AKRs in human tumors is a significant mechanism of resistance to both chemotherapy and antihormonal treatments.
- Targeting specific AKR isoforms or using pan-AKR1C inhibitors represents a viable strategy to enhance the effectiveness of cancer therapies.
- Modulating the NRF2 pathway offers a potential approach to surmount drug resistance and improve clinical outcomes in cancer patients.
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