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

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 zebra?sh 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.

SUBMITTER: Wang Y

PROVIDER: S-EPMC7059749 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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

Wang Yingying Y Ma Qian Q Zhang Shaolu S Liu Hongyan H Zhao Baoquan B Du Bo B Wang Wei W Lin Peng P Zhang Zhe Z Zhong Yuxu Y Kong Dexin D

Frontiers in pharmacology 20200228

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, ...[more]

PMID: 32180730

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Project description:Everolimus is a kind of mammalian target of rapamycin (mTOR) inhibitors. Activated mitogen-activated protein kinase interacting kinases/eukaryotic translation initiation factor 4E (MNK/eIF4E) axis plays a crucial role in resistance to Everolimus in non-small cell lung cancer (NSCLC). The eIF4E phosphorylation increased by mTOR inhibitors is mainly mediated by MNKs. However, the mechanisms are poorly understood. Recently, extensive reprogramming of miRNA profiles has also been found after long-term mTOR inhibitor exposure. Our previous studies have confirmed that tumor suppressor miR-7-5p is decreased in A549 cells after treatment with Everolimus. Exactly, MNK1 is the target of miR-7-5p. In this study, we investigated the biological functions and potential molecular mechanisms of miR-7-5p in the NSCLC undergoing treatment with Everolimus. We confirmed that Everolimus targeted mTORC1 inducing NSCLC cells to secrete miR-7-5p-loaded exosomes in Rab27A and Rab27B-dependent manners. Loss of intracellular miR-7-5p induced phosphorylation of MNK/eIF4E axis, but a supplement of extra exosomal miR-7-5p could reverse it. Of note, both low expression of miR-7-5p and elevated MNK1 protein were associated with a poor prognosis of NSCLC. Both endogenous miR-7-5p and exo-miR-7-5p enhanced the therapeutic efficacy of Everolimus by inhibiting the proliferation, migration, and metastasis of NSCLC in vitro and in vivo. The combination of miR-7-5p with Everolimus induced apoptosis to exhibit a synergistic anticancer therapeutic efficacy through dual abrogation of MNK/eIF4E and mTOR in NSCLC. In conclusion, Everolimus decreases the intracellular miR-7-5p by releasing of miR-7-5p loaded exosomes from NSCLC cells in Rab27A and Rab27B dependent manners. Either endogenous miR-7-5p or exo-miR-7-5p combined with Everolimus can enhance the anticancer efficacy by targeting MNK/eIF4E axis and mTOR. Besides, both low levels of miR-7-5p and positive expression of MNK1 act as independent poor prognostic biomarkers for NSCLC. Therefore, restoring miR-7-5p carried by exosome may be a promising novel combined therapeutic strategy with Everolimus for NSCLC.

Project description:Introduction: In the last few decades, there has been a rapid development in cancer therapies and improved detection strategies, hence the death rates caused by cancer have decreased. However, it has been reported that cardiovascular disease has become the second leading cause of long-term morbidity and fatality among cancer survivors. Cardiotoxicity from anticancer drugs affects the heart's function and structure and can occur during any stage of the cancer treatments, which leads to the development of cardiovascular disease. Objectives: To investigate the association between anticancer drugs for non-small cell lung cancer (NSCLC) and cardiotoxicity as to whether: different classes of anticancer drugs demonstrate different cardiotoxicity potentials; different dosages of the same drug in initial treatment affect the degree of cardiotoxicity; and accumulated dosage and/or duration of treatments affect the degree of cardiotoxicity. Methods: This systematic review included studies involving patients over 18 years old with NSCLC and excluded studies in which patients' treatments involve radiotherapy only. Electronic databases and registers including Cochrane Library, National Cancer Institute (NCI) Database, PubMed, Scopus, Web of Science, ClinicalTrials.gov and the European Union Clinical Trials Register were systematically searched from the earliest available date up until November 2020. A full version protocol of this systematic review (CRD42020191760) had been published on PROSPERO. Results: A total of 1785 records were identified using specific search terms through the databases and registers; 74 eligible studies were included for data extraction. Based on data extracted from the included studies, anticancer drugs for NSCLC that are associated with cardiovascular events include bevacizumab, carboplatin, cisplatin, crizotinib, docetaxel, erlotinib, gemcitabine and paclitaxel. Hypertension was the most reported cardiotoxicity as 30 studies documented this cardiovascular adverse event. Other reported treatment-related cardiotoxicities include arrhythmias, atrial fibrillation, bradycardia, cardiac arrest, cardiac failure, coronary artery disease, heart failure, ischemia, left ventricular dysfunction, myocardial infarction, palpitations, and tachycardia. Conclusion: The findings of this systematic review have provided a better understanding of the possible association between cardiotoxicities and anticancer drugs for NSCLC. Whilst variation is observed across different drug classes, the lack of information available on cardiac monitoring can result in underestimation of this association. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020191760, identifier PROSPERO CRD42020191760.

Dataset Information

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

Publications

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

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