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Antioxid Redox Signal. 2017 Jan 10;26(2):70-83. doi: 10.1089/ars.2015.6457. Epub 2016 Aug 5.

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

Author information

1
1 Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University , Seoul, Republic of Korea.
2
2 Division of Cardiology, Department of Internal Medicine, School of Medicine, Kyung Hee University , Seoul, Republic of Korea.
3
3 Department of Pathology, School of Medicine, Kyung Hee University , Seoul, Republic of Korea.
4
4 Department of Cellular and Molecular Pharmacology, University of California , San Francisco, California.

Abstract

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. Antioxid. Redox Signal. 26, 70-83.

KEYWORDS:

breast cancer; carbonyl reductase 1; cardiotoxicity; chemotherapy; doxorubicin; doxorubicinol

PMID:
27357096
DOI:
10.1089/ars.2015.6457
[Indexed for MEDLINE]

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