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

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

doi:10.3389/fphar.2020.00186

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 1/2IC50DIG:IC50ADR and IC50DIG:IC50ADR 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.

Highlights

Digoxin, as a member of cardiac glycosides, has been in clinical use for the treatment of heart failure and atrial arrhythmias for many years
We first examined the antiproliferative effects of digoxin on A549 and H1299 cells after treatment for 24 h by using MTT assay
We reported digoxin exhibited antitumor activities on NSCLC A549 and H1299 cells

Summary

Introduction

As a member of cardiac glycosides, has been in clinical use for the treatment of heart failure and atrial arrhythmias for many years. Inhibition of Na+/K+-ATPase and topoisomerase (Beheshti Zavareh et al, 2008), alterations of Ca2+ signaling (Raynal et al, 2016), as well as inhibition of HIF-1a synthesis (Zhang et al, 2008; Gayed et al, 2012) were reported to play roles in the anticancer effects of digoxin. Signaling pathways such as Src/ MAPK (Wang et al, 2009), Akt/mTOR (Zhang et al, 2017), NFkB (Wang et al, 2017) and Nrf (Zhou et al, 2019) were known to be involved. Digoxin was recently reported to inhibit DNA double strand break repair as a novel anticancer mechanism (Surovtseva et al, 2016)

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Conclusion