Digoxin Enhances the Anticancer Effect on Non-Small Cell Lung Cancer While Reducing the Cardiotoxicity of Adriamycin

Yingying Wang; Qian Ma; Shaolu Zhang; Hongyan Liu; Baoquan Zhao; Bo Du; Wei Wang; Peng Lin; Zhe Zhang; Yuxu Zhong; Dexin Kong

doi:10.3389/fphar.2020.00186

Digoxin Enhances the Anticancer Effect on Non-Small Cell Lung Cancer While Reducing the Cardiotoxicity of Adriamycin

Front Pharmacol. 2020 Feb 28:11:186. doi: 10.3389/fphar.2020.00186. eCollection 2020.

Authors

Yingying Wang¹, Qian Ma^{1

2}, Shaolu Zhang^{1

2}, Hongyan Liu², Baoquan Zhao², Bo Du³, Wei Wang⁴, Peng Lin⁴, Zhe Zhang¹, Yuxu Zhong², Dexin Kong¹

Affiliations

¹ Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmaceutical Sciences, Tianjin Medical University, Tianjin, China.
² State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, China.
³ Tianjin Key Laboratory of Biomedical Materials, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
⁴ Department of Otorhinolaryngology Head and Neck, Institute of Otorhinolaryngology, Tianjin First Central Hospital, Tianjin, China.

Abstract

Digoxin is widely used to treat heart failure. Epidemiological studies suggested it might be used as an anticancer drug or sensitizing agent for cancer therapy. Adriamycin is a well-known anticancer drug, but often causes cardiotoxicity which limits its use. We recently investigated the anticancer effects of digoxin alone or in combination with adriamycin on human non-small cell lung cancer in vitro and in vivo. Digoxin reduced the viability of A549 and H1299 cells in vitro, increased DNA damage by promoting ROS generation and inhibiting both DNA double strand break (DSB) and single strand break (SSB) repair. Combination with adriamycin showed synergistic antiproliferative effects at the ratios of 1/2IC50_DIG:IC50_ADR and IC50_DIG:IC50_ADR on A549 and H1299 cells, respectively. In vivo, digoxin potently inhibited A549 growth in both zebraﬁsh and nude mouse xenograft model. Co-treatment with adriamycin not only enhanced the antitumor efficacy, but also reduced the cardiotoxicity. Our findings suggest that digoxin has the potential to be applied as an antitumor drug via inhibiting both DNA DSB and SSB repair, and combination with adriamycin for therapy of human non-small cell lung cancer is reasonable.

Keywords: DNA damage repair; adriamycin; decreased cardiotoxicity; digoxin; non-small cell lung cancer.