{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T15:09:04Z","timestamp":1783436944254,"version":"3.54.6"},"reference-count":48,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2019,6,10]],"date-time":"2019-06-10T00:00:00Z","timestamp":1560124800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Medicine"],"published-print":{"date-parts":[[2019,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Modulated electro\u2010hyperthermia (mEHT), a noninvasive complementary treatment of human chemo\u2010 and radiotherapy, can generate selective ~42\u00b0C heat in cancer due to elevated glycolysis (Warburg\u2010effect) and electric conductivity in malignant tissues. Here we tested the molecular background of mEHT and its combination with doxorubicin chemotherapy using an in vitro model.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>C26 mouse colorectal adenocarcinoma cultures were mEHT treated at 42\u00b0C for 2\u00a0\u00d7\u00a060\u00a0minutes (with 120\u00a0minutes interruption) either alone or in combination with 1\u00a0\u00b5mol\/L doxorubicin (mEHT\u00a0+\u00a0Dox). Cell stress response, apoptosis, and cell cycle regulation related markers were detected using qPCR and immunocytochemistry supported with resazurin cell viability assay, cell death analysis using flow\u2010cytometry and clonogenic assay.<\/jats:p><\/jats:sec><jats:sec><jats:title>Result<\/jats:title><jats:p>Cell\u2010stress by mEHT alone was indicated by the significant upregulation and release of hsp70 and calreticulin proteins 3\u00a0hours posttreatment. Between 3 and 9\u00a0hours after treatment significantly reduced anti\u2010apoptotic XIAP, BCL\u20102, and BCL\u2010XL and elevated pro\u2010apoptotic BAX and PUMA, as well as the cyclin dependent kinase inhibitor p21<jats:sup>waf1<\/jats:sup> mRNA levels were detected. After 24\u00a0hours, major elevation and nuclear translocation of phospho\u2010p53(Ser15) protein levels and reduced phospho\u2010Akt(Ser473) levels were accompanied by a significant caspase\u20103\u2010mediated programmed cell death response. While mEHT dominantly induced apoptosis, Dox administration primarily led to tumor cell necrosis, and both significantly reduced the number of tumor progenitor colonies 10 days post\u2010treatment. Furthermore, mEHT promoted the uptake of Dox by tumor cells and the combined treatment additively reduced tumor cell viability and augmented cell death near to synergy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>In C26 colorectal adenocarcinoma mEHT\u2010induced irreversible cell stress can activate both caspase\u2010dependent apoptosis and p21<jats:sup>waf1<\/jats:sup> mediated growth arrest pathways, likely to be driven by the upregulated nuclear p53 protein. Elevated phospho\u2010p53(Ser15) might contribute to p53 escape from mdm2 control, which was further supported by reduced phospho\u2010Akt(Ser473) protein levels. In combinations, mEHT could promote the uptake and significantly potentiate the cytotoxic effect of doxorubicin.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cam4.2330","type":"journal-article","created":{"date-parts":[[2019,6,11]],"date-time":"2019-06-11T05:38:43Z","timestamp":1560231523000},"page":"4292-4303","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["Modulated electro\u2010hyperthermia induced p53 driven apoptosis and cell cycle arrest additively support doxorubicin chemotherapy of colorectal cancer in vitro"],"prefix":"10.1002","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5892-3682","authenticated-orcid":false,"given":"Tamas","family":"Vancsik","sequence":"first","affiliation":[{"name":"1st Department of Pathology and Experimental Cancer Research Semmelweis University Budapest 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