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Aldo-Keto Reductase

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Trevor M. Penning – 1st expert on this subject based on the ideXlab platform

  • The Aldo-Keto Reductase Superfamily
    Comprehensive Toxicology, 2020
    Co-Authors: Trevor M. Penning

    Abstract:

    Aldo-Keto Reductases (AKRs) are a gene superfamily whose members catalyze the nicotinamide adenine dinucleotide (phosphate) reduced dependent interconversion of aldehydes and ketones with primary and secondary alcohols. AKRs by functionalizing carbonyl groups for subsequent conjugation reactions are considered Phase I enzymes. There are 15 human AKR isoforms which are pluripotent. Endogenous substrates include sugar aldehydes, lipid aldehydes, prostaglandins, and steroid hormones. Xenobiotic substrates include carbonyl containing drugs and carcinogen metabolites (polycyclic aromatic trans -dihydrodiols, nicotine derived nitrosamino-ketones, and aflatoxin dialdehyde); and they have been implicated in cancer chemotherapeutic drug resistance. Human isoforms are regulated by primordial signals (osmotic, electrophilic, and oxidative stress) so that a counterresponse to the stressor may ensue. Many contain an Anti-oxidant Response Element in their gene promoters suggesting that cancer chemopreventive strategies that target this element could also affect endogenous and exogenous substrate utilization.

  • Aldo-Keto Reductase 1C3-Assessment as a new target for the treatment of endometriosis.
    Pharmacological Research, 2019
    Co-Authors: Tea Lanišnik Rižner, Trevor M. Penning

    Abstract:

    Abstract Endometriosis is a common gynecological disorder, which is treated surgically and/ or pharmacologically with an unmet clinical need for new therapeutics. A completed phase I trial and a recent phase II trial that investigated the steroidal Aldo-Keto Reductase 1C3 (AKR1C3) inhibitor BAY1128688 in endometriosis patients prompted this critical assessment on the role of AKR1C3 in endometriosis. This review includes an introduction to endometriosis with emphasis on the roles of prostaglandins and progesterone in its pathophysiology. This is followed by an overview of the major enzymatic activities and physiological functions of AKR1C3 and of the data published to date on the expression of AKR1C3 in endometriosis at the mRNA and protein levels. The review concludes with the rationale for using AKR1C3 inhibitors, a discussion of the effects of AKR1C3 inhibition on the pathophysiology of endometriosis and a brief overview of other drugs under clinical investigation for this indication.

  • potent and highly selective aldo keto Reductase 1c3 akr1c3 inhibitors act as chemotherapeutic potentiators in acute myeloid leukemia and t cell acute lymphoblastic leukemia
    Journal of Medicinal Chemistry, 2019
    Co-Authors: Kshitij Verma, Trevor M. Penning, Tianzhu Zang, Paul C Trippier

    Abstract:

    Aldo–keto Reductase 1C3 (AKR1C3) catalyzes the synthesis of 9α,11β-prostaglandin (PG) F2α and PGF2α prostanoids that sustain the growth of myeloid precursors in the bone marrow. The enzyme is overexpressed in acute myeloid leukemia (AML) and T-cell acute lymphoblastic leukemia (T-ALL). Moreover, AKR1C3 confers chemotherapeutic resistance to the anthracyclines: first-line agents for the treatment of leukemias. The highly homologous isoforms AKR1C1 and AKR1C2 inactivate 5α-dihydrotestosterone, and their inhibition would be undesirable. We report herein the identification of AKR1C3 inhibitors that demonstrate exquisite isoform selectivity for AKR1C3 over the other closely related isoforms to the order of >2800-fold. Biological evaluation of our isoform-selective inhibitors revealed a high degree of synergistic drug action in combination with the clinical leukemia therapeutics daunorubicin and cytarabine in in vitro cellular models of AML and primary patient-derived T-ALL cells. Our developed compounds exhibi…

Kar Ming Fung – 2nd expert on this subject based on the ideXlab platform

  • Original Article Expression of Aldo-Keto Reductase family 1 member C3 (AKR1C3) in neuroendocrine tumors & adenocarcinomas of pancreas, gastrointestinal tract, and lung
    , 2020
    Co-Authors: Theodore S Chang, Qing Yang, Lacy S Brame, Kyle A Rogers, Kar Ming Fung

    Abstract:

    Human Aldo-Keto Reductase family 1 member C3 (AKR1C3) was initially identified as an enzyme in reduc – ing 5α-dihydrotestosterone (5α-DHT) to 5α-androstane-3α, 17β-diol (3α-diol) and oxidizing 3α-diol to androsterone. It was subsequently demonstrated to possess ketosteroid Reductase activity in metabolizing other steroids including estrogen and progesterone, 11-ketoprostaglandin Reductase activity in metabolizing prostaglandins, and dihydrodiol dehydrogenase x (DDx) activity in metabolizing xenobiotics. AKR1C3 was demonstrated in sex hormone-dependent tissues including testis, breast, endometrium, and prostate; in sex hormone-independent tissues including kidney and urothelium. Our previous study described the expression of AKR1C3 in squamous cell carcinoma and ad- enocarcinoma but not in small cell carcinoma. In this report, we studied the expression of AKR1C3 in normal tis- sue, adenocarcinomas (43 cases) and neuroendocrine (NE) tumors (40 cases) arising from the aerodigestive tract and pancreas. We demonstrated wide expression of AKR1C3 in superficially located mucosal cells, but not in NE cells. AKR1C3-positive immunoreactivity was detected in 38 cases (88.4%) of adenocarcinoma, but only in 7 cases (17.5%) of NE tumors in all cases. All NE tumors arising from the pancreas and appendix and most tumors from the colon and lung were negative. The highest ratio of positive AKR1C3 in NE tumors was found in tumors arising from the small intestine (50%). These results raise the question of AKR1C3’s role in the biology of normal mucosal epithelia and tumors. In addition, AKR1C3 may be a useful adjunct marker for the exclusion of the NE phenotype in diagnostic pathology.

  • expression of aldo keto Reductase family 1 member c3 akr1c3 in neuroendocrine tumors adenocarcinomas of pancreas gastrointestinal tract and lung
    International Journal of Clinical and Experimental Pathology, 2013
    Co-Authors: Theodore S Chang, Qing Yang, Lacy S Brame, Kyle A Rogers, Kar Ming Fung

    Abstract:

    Human Aldo-Keto Reductase family 1 member C3 (AKR1C3) was initially identified as an enzyme in reducing 5α-dihydrotestosterone (5α-DHT) to 5α-androstane-3α, 17β-diol (3α-diol) and oxidizing 3α-diol to androsterone. It was subsequently demonstrated to possess ketosteroid Reductase activity in metabolizing other steroids including estrogen and progesterone, 11-ketoprostaglandin Reductase activity in metabolizing prostaglandins, and dihydrodiol dehydrogenase x (DDx) activity in metabolizing xenobiotics. AKR1C3 was demonstrated in sex hormone-dependent tissues including testis, breast, endometrium, and prostate; in sex hormone-independent tissues including kidney and urothelium. Our previous study described the expression of AKR1C3 in squamous cell carcinoma and adenocarcinoma but not in small cell carcinoma. In this report, we studied the expression of AKR1C3 in normal tissue, adenocarcinomas (43 cases) and neuroendocrine (NE) tumors (40 cases) arising from the aerodigestive tract and pancreas. We demonstrated wide expression of AKR1C3 in superficially located mucosal cells, but not in NE cells. AKR1C3-positive immunoreactivity was detected in 38 cases (88.4%) of adenocarcinoma, but only in 7 cases (17.5%) of NE tumors in all cases. All NE tumors arising from the pancreas and appendix and most tumors from the colon and lung were negative. The highest ratio of positive AKR1C3 in NE tumors was found in tumors arising from the small intestine (50%). These results raise the question of AKR1C3’s role in the biology of normal mucosal epithelia and tumors. In addition, AKR1C3 may be a useful adjunct marker for the exclusion of the NE phenotype in diagnostic pathology.

  • Expression of Aldo-Keto Reductase family 1 member C3 (AKR1C3) in neuroendocrine tumors & adenocarcinomas of pancreas, gastrointestinal tract, and lung.
    International Journal of Clinical and Experimental Pathology, 2013
    Co-Authors: Theodore S Chang, Qing Yang, Lacy S Brame, Kyle A Rogers, Kar Ming Fung

    Abstract:

    Human Aldo-Keto Reductase family 1 member C3 (AKR1C3) was initially identified as an enzyme in reducing 5α-dihydrotestosterone (5α-DHT) to 5α-androstane-3α, 17β-diol (3α-diol) and oxidizing 3α-diol to androsterone. It was subsequently demonstrated to possess ketosteroid Reductase activity in metabolizing other steroids including estrogen and progesterone, 11-ketoprostaglandin Reductase activity in metabolizing prostaglandins, and dihydrodiol dehydrogenase x (DDx) activity in metabolizing xenobiotics. AKR1C3 was demonstrated in sex hormone-dependent tissues including testis, breast, endometrium, and prostate; in sex hormone-independent tissues including kidney and urothelium. Our previous study described the expression of AKR1C3 in squamous cell carcinoma and adenocarcinoma but not in small cell carcinoma. In this report, we studied the expression of AKR1C3 in normal tissue, adenocarcinomas (43 cases) and neuroendocrine (NE) tumors (40 cases) arising from the aerodigestive tract and pancreas. We demonstrated wide expression of AKR1C3 in superficially located mucosal cells, but not in NE cells. AKR1C3-positive immunoreactivity was detected in 38 cases (88.4%) of adenocarcinoma, but only in 7 cases (17.5%) of NE tumors in all cases. All NE tumors arising from the pancreas and appendix and most tumors from the colon and lung were negative. The highest ratio of positive AKR1C3 in NE tumors was found in tumors arising from the small intestine (50%). These results raise the question of AKR1C3’s role in the biology of normal mucosal epithelia and tumors. In addition, AKR1C3 may be a useful adjunct marker for the exclusion of the NE phenotype in diagnostic pathology.

Yoshiteru Kamiyma – 3rd expert on this subject based on the ideXlab platform

  • asp9521 a novel selective orally bioavailable akr1c3 type 5 17s hydroxysteroid dehydrogenase inhibitor in vitro and in vivo characterization
    Journal of Clinical Oncology, 2013
    Co-Authors: Aya Kikuchi, Kentaro Enjo, Takashi Furutani, Hidenori Azami, Tatsuya Nimi, Sadao Kuromitsu, Yoshiteru Kamiyma

    Abstract:

    5046 Background: Aldo–keto Reductase 1C3 (AKR1C3), also known as type 5, 17β-hydroxysteroid dehydrogenase, is reported to be highly expressed in human normal prostate and prostate cancer (PC) and t…