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However, treatment with cisplatin may cause serious side effects, such as myelosuppression, nausea, ototoxicity, nephrotoxicity, and cell resistance processes. In addition, cardiotonic steroids, particularly digoxin, have recently been suggested to exert potent anticancer effects. Therefore, it is possible that the combined treatment of HeLa cells with cisplatin and digoxin can ameliorate the cytotoxic effects and decrease the side effects of cisplatin. In this study, we demonstrated that the interaction between cisplatin and digoxin had a synergistic effect on cervical cancer cells and a significantly positive cytotoxic and antiproliferative effect on this cell line compared to the control and single cisplatin treatments. Although a decrease in the Na,K\u2010ATPase \u03b11 subunit expression was observed in total extracts, its expression remains unchanged in the membrane, as does the Na,K\u2010ATPase activity. The antiproliferative effect of the synergistic treatment appears to depend on Src kinase activation, indicating the possible involvement of the Scr\u2010EGFR\u2010ERK1\/2 pathway in the antitumor effect. The inhibition of ERK1\/2 provoked the same synergism with 1\u2009\u03bcM cisplatin as that observed with 1\u2009nM digoxin plus 1\u2009\u03bcM cisplatin but not with 1 nM digoxin. Pretreatment with PP2 during combined treatment abolished the synergistic effect on the antiproliferative activity. Cisplatin and digoxin are already used in the clinical setting; therefore, this study opens possibilities for future clinical trials of combined treatments to improve treatment outcomes with a lower incidence of toxicity and side effects.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/jcb.26499","type":"journal-article","created":{"date-parts":[[2017,11,11]],"date-time":"2017-11-11T10:22:36Z","timestamp":1510395756000},"page":"3352-3362","source":"Crossref","is-referenced-by-count":16,"title":["Involvement of Src signaling in the synergistic effect between cisplatin and digoxin on cancer cell viability"],"prefix":"10.1002","volume":"119","author":[{"given":"Duane G.","family":"Pereira","sequence":"first","affiliation":[{"name":"Faculdade de Bioquimica, Laboratorio de Bioquimica Celular, Universidade Federal de S\u00e3o Jo\u00e3o Del Rei Campus Centro\u2010Oeste Dona Lindu Divinopolis, MG Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariana 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