title: Inhibition of Carbonyl Reductase 1 Safely Improves the Efficacy of Doxorubicin in Breast Cancer Treatment.
abstract: Doxorubicin (DOX) is a chemotherapeutic drug that is used to treat many cancers, but its use is limited by cardiotoxic side effect. Carbonyl reductase 1 (CBR1) is an NADPH-dependent oxidoreductase that reduces DOX to doxorubicinol (DOXOL), a less potent derivative that is responsible for DOX cardiotoxicity. Thus, we aimed to demonstrate that inhibition of CBR1 enhances the chemotherapeutic efficacy of DOX and attenuates cardiotoxicity.
  
  
  
  Pharmacological or genetic inhibition of CBR1 improved the anticancer effects of DOX in preclinical models of breast cancer. RNA interference or chemical inhibition of CBR1 improved the anticancer effect of DOX in breast cancer. Moreover, CBR1 overexpression enabled breast cancer cells to obtain chemotherapeutic resistance to DOX treatment. Intriguingly, inhibition of CBR1 decreased DOX-induced cardiotoxicity in animal model. Innovation and Conclusions: Inhibition of CBR1 increases chemotherapeutic efficacy of DOX and reduces cardiotoxicity by blocking DOX reduction to DOXOL. Therefore, we offer preclinical proof-of-concept for a combination strategy to safely leverage the efficacy of doxorubicin by blunting its cardiotoxic effects that limit use of this cytotoxic agent used widely in the oncology clinic. Antioxid. Redox Signal. 26, 70-83.
authors.affiliation: 1 Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University , Seoul, Republic of Korea.
authors.forename: Ara
authors.initials: A
authors.lastname: Jo
authors.affiliation: 1 Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University , Seoul, Republic of Korea.
authors.forename: Tae Gyu
authors.initials: TG
authors.lastname: Choi
authors.affiliation: 1 Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University , Seoul, Republic of Korea.
authors.forename: Yong Hwa
authors.initials: YH
authors.lastname: Jo
authors.affiliation: 1 Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University , Seoul, Republic of Korea.
authors.forename: K R
authors.initials: KR
authors.lastname: Jyothi
authors.affiliation: 1 Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University , Seoul, Republic of Korea.
authors.forename: Minh Nam
authors.initials: MN
authors.lastname: Nguyen
authors.affiliation: 1 Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University , Seoul, Republic of Korea.
authors.forename: Jin-Hwan
authors.initials: JH
authors.lastname: Kim
authors.affiliation: 1 Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University , Seoul, Republic of Korea.
authors.forename: Sangbin
authors.initials: S
authors.lastname: Lim
authors.affiliation: 1 Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University , Seoul, Republic of Korea.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Shahid
authors.affiliation: 1 Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University , Seoul, Republic of Korea.
authors.forename: Salima
authors.initials: S
authors.lastname: Akter
authors.affiliation: 1 Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University , Seoul, Republic of Korea.
authors.forename: Seonmin
authors.initials: S
authors.lastname: Lee
authors.affiliation: 2 Division of Cardiology, Department of Internal Medicine, School of Medicine, Kyung Hee University , Seoul, Republic of Korea.
authors.forename: Kyung Hye
authors.initials: KH
authors.lastname: Lee
authors.affiliation: 2 Division of Cardiology, Department of Internal Medicine, School of Medicine, Kyung Hee University , Seoul, Republic of Korea.
authors.forename: Weon
authors.initials: W
authors.lastname: Kim
authors.affiliation: 3 Department of Pathology, School of Medicine, Kyung Hee University , Seoul, Republic of Korea.
authors.forename: Hyuck
authors.initials: H
authors.lastname: Cho
authors.affiliation: 3 Department of Pathology, School of Medicine, Kyung Hee University , Seoul, Republic of Korea.
authors.forename: Juhie
authors.initials: J
authors.lastname: Lee
authors.affiliation: 4 Department of Cellular and Molecular Pharmacology, University of California , San Francisco, California.
authors.forename: Kevan M
authors.initials: KM
authors.lastname: Shokat
authors.affiliation: 1 Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University , Seoul, Republic of Korea.
authors.forename: Kyung-Sik
authors.initials: KS
authors.lastname: Yoon
authors.affiliation: 1 Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University , Seoul, Republic of Korea.
authors.forename: Insug
authors.initials: I
authors.lastname: Kang
authors.affiliation: 1 Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University , Seoul, Republic of Korea.
authors.forename: Joohun
authors.initials: J
authors.lastname: Ha
authors.affiliation: 1 Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University , Seoul, Republic of Korea.
authors.forename: Sung Soo
authors.initials: SS
authors.lastname: Kim
mesh_terms: D000429:Alcohol Oxidoreductases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015415:Biomarkers; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D066126:Cardiotoxicity; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D052279:Creatine Kinase, MB Form / Q000378:metabolism; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000494:pharmacology*; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D004791:Enzyme Inhibitors; D004317:Doxorubicin; D000429:Alcohol Oxidoreductases; C531129:CBR1 protein, human; D052279:Creatine Kinase, MB Form
keywords: breast cancer; carbonyl reductase 1; cardiotoxicity; chemotherapy; doxorubicin; doxorubicinol