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

被引：27

作者：

Jo, Ara ^{[1
]}

Choi, Tae Gyu ^{[1
]}

Jo, Yong Hwa ^{[1
]}

Jyothi, K. R. ^{[1
]}

Minh Nam Nguyen ^{[1
]}

Kim, Jin-Hwan ^{[1
]}

Lim, Sangbin ^{[1
]}

Shahid, Muhammad ^{[1
]}

Akter, Salima ^{[1
]}

Lee, Seonmin ^{[1
]}

Lee, Kyung Hye ^{[2
]}

Kim, Weon ^{[2
]}

Cho, Hyuck ^{[3
]}

Lee, Juhie ^{[3
]}

Shokat, Kevan M. ^{[4
]}

Yoon, Kyung-Sik ^{[1
]}

Kang, Insug ^{[1
]}

Ha, Joohun ^{[1
]}

Kim, Sung Soo ^{[1
]}

机构：

[1] Kyung Hee Univ, Sch Med, Dept Biochem & Mol Biol, 26 Kyungheedae Ro, Seoul 02447, South Korea

[2] Kyung Hee Univ, Sch Med, Dept Internal Med, Div Cardiol, Seoul, South Korea

[3] Kyung Hee Univ, Sch Med, Dept Pathol, Seoul, South Korea

[4] Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94143 USA

来源：

ANTIOXIDANTS & REDOX SIGNALING | 2017年 / 26卷 / 02期

基金：

新加坡国家研究基金会;

关键词：

carbonyl reductase 1; doxorubicin; doxorubicinol; breast cancer; chemotherapy; cardiotoxicity; INDUCED CARDIOTOXICITY; CARDIAC TOXICITY; ADRIAMYCIN; ANTHRACYCLINES; CHEMOTHERAPY; HEART; METABOLITE; PACLITAXEL; CARCINOMA; ANTIBODY;

D O I：

10.1089/ars.2015.6457

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Aims: 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. Results: 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.

引用

页码：70 / +

页数：15

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