Inhibition of Carbonyl Reductase 1 Safely Improves the Efficacy of Doxorubicin in Breast Cancer Treatment

• DOI: 10.1089/ars.2015.6457
• Publication Date: 2016-06-30T02:27:51Z
• Authors: Ara Jo; Tae Gyu Choi; Yong Hwa Jo; K.R. Jyothi; Minh Nam Nguyen; Jin-Hwan Kim; Sangbin Lim; Muhammad Shahid; Salima Akter; Seonmin Lee; Kyung Hye Lee; Weon Kim; Hyuck Cho; Juhie Lee; Kevan M. Shokat; Kyung-Sik Yoon; Insug Kang; Joohun Ha; Sung Soo Kim
• Keywords: 0303 health sciences; Cell Death; Gene Expression; Antineoplastic Agents; Apoptosis; Breast Neoplasms; Drug Synergism; Cardiotoxicity; 3. Good health; Alcohol Oxidoreductases; Disease Models, Animal; Mice; 03 medical and health sciences; Doxorubicin; Cell Line, Tumor; Gene Knockdown Techniques; Animals; Creatine Kinase, MB Form; Humans; Female; Myocytes, Cardiac; Enzyme Inhibitors; Biomarkers

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.