{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:03:22Z","timestamp":1760144602742,"version":"build-2065373602"},"reference-count":43,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2024,5,6]],"date-time":"2024-05-06T00:00:00Z","timestamp":1714953600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Fondazione CARIPLO-Regione Lombardia","award":["#2016-1019"],"award-info":[{"award-number":["#2016-1019"]}]},{"name":"AIRC","award":["#2016-1019"],"award-info":[{"award-number":["#2016-1019"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Epigenetic alterations my play a role in the aggressive behavior of Non-Small Cell Lung Cancer (NSCLC). Treatment with the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA, vorinostat) has been reported to interfere with the proliferative and invasive potential of NSCLC cells. In addition, the DNA methyltransferase inhibitor azacytidine (AZA, vidaza) can modulate the levels of the metastasis suppressor KiSS-1. Thus, since cisplatin is still clinically available for NSCLC therapy, the aim of this study was to evaluate drug combinations between cisplatin and SAHA as well as AZA using cisplatin-sensitive H460 and -resistant H460\/Pt NSCLC cells in relation to KiSS-1 modulation. An analysis of drug interaction according to the Combination-Index values indicated a more marked synergistic effect when the exposure to SAHA or AZA preceded cisplatin treatment with respect to a simultaneous schedule. A modulation of proteins involved in apoptosis (p53, Bax) was found in both sensitive and resistant cells, and compared to the treatment with epigenetic agents alone, the combination of cisplatin and SAHA or AZA increased apoptosis induction. The epigenetic treatments, both as single agents and in combination, increased the release of KiSS-1. Finally, the exposure of cisplatin-sensitive and -resistant cells to the kisspeptin KP10 enhanced cisplatin induced cell death. The efficacy of the combination of SAHA and cisplatin was tested in vivo after subcutaneous inoculum of parental and resistant cells in immunodeficient mice. A significant tumor volume inhibition was found when mice bearing advanced tumors were treated with the combination of SAHA and cisplatin according to the best schedule identified in cellular studies. These results, together with the available literature, support that epigenetic drugs are amenable for the combination treatment of NSCLC, including patients bearing cisplatin-resistant tumors.<\/jats:p>","DOI":"10.3390\/ijms25095048","type":"journal-article","created":{"date-parts":[[2024,5,6]],"date-time":"2024-05-06T15:05:01Z","timestamp":1715007901000},"page":"5048","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["KiSS-1 Modulation by Epigenetic Agents Improves the Cisplatin Sensitivity of Lung Cancer Cells"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5961-4109","authenticated-orcid":false,"given":"Giovanni Luca","family":"Beretta","sequence":"first","affiliation":[{"name":"Molecular Pharmacology Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Desir\u00e8","family":"Alampi","sequence":"additional","affiliation":[{"name":"Molecular Pharmacology Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cristina","family":"Corno","sequence":"additional","affiliation":[{"name":"Molecular Pharmacology Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nives","family":"Carenini","sequence":"additional","affiliation":[{"name":"Molecular Pharmacology Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elisabetta","family":"Corna","sequence":"additional","affiliation":[{"name":"Molecular Pharmacology Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2806-7269","authenticated-orcid":false,"given":"Paola","family":"Perego","sequence":"additional","affiliation":[{"name":"Molecular Pharmacology Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,5,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"17","DOI":"10.3322\/caac.21763","article-title":"Cancer statistics, 2023","volume":"73","author":"Siegel","year":"2023","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1016\/j.cllc.2011.09.004","article-title":"Oncogenic pathways, molecularly targeted therapies, and highlighted clinical trials in non-small-cell lung cancer (NSCLC)","volume":"13","author":"Reungwetwattana","year":"2012","journal-title":"Clin. Lung Cancer"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.1056\/NEJMra0802714","article-title":"Lung cancer","volume":"359","author":"Herbst","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"63","DOI":"10.5732\/cjc.012.10098","article-title":"The genetics and biology of KRAS in lung cancer","volume":"32","author":"Westcott","year":"2013","journal-title":"Chin. J. Cancer"},{"key":"ref_5","first-page":"S479","article-title":"Molecular biology of lung cancer","volume":"5","author":"Cooper","year":"2013","journal-title":"J. Thorac. Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.lungcan.2013.03.019","article-title":"Prognostic value of K-RAS mutations in patients with non-small cell lung cancer: A systematic review with meta-analysis","volume":"81","author":"Meng","year":"2013","journal-title":"Lung Cancer"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.drup.2007.02.002","article-title":"Multiple paths to a drug resistance phenotype: Mutations, translocations, deletions and amplification of coding genes or promoter regions, epigenetic changes and microRNAs","volume":"10","author":"Fojo","year":"2007","journal-title":"Drug Resist. Updates"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1186\/s12967-022-03415-6","article-title":"RNA adenosine modifications related to prognosis and immune infiltration in osteosarcoma","volume":"20","author":"Chen","year":"2022","journal-title":"J. Transl. Med."},{"key":"ref_9","first-page":"501","article-title":"In vitro neutralization of autocrine IL-10 affects Op18\/stathmin signaling in non-small cell lung cancer cells","volume":"41","author":"Zhao","year":"2019","journal-title":"Oncol. Rep."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2244","DOI":"10.1158\/1078-0432.CCR-13-2088","article-title":"New strategies in lung cancer: Epigenetic therapy for non-small-cell lung cancer","volume":"20","author":"Forde","year":"2014","journal-title":"Clin. Cancer Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1284","DOI":"10.1016\/j.cell.2017.10.022","article-title":"Epigenetic Therapy Ties MYC Depletion to Reversing Immune Evasion and Treating Lung Cancer","volume":"171","author":"Topper","year":"2017","journal-title":"Cell"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Bajbouj, K., Al-Ali, A., Ramakrishnan, R.K., Saber-Ayad, M., and Hamid, Q. (2021). Histone Modification in NSCLC: Molecular Mechanisms and Therapeutic Targets. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222111701"},{"key":"ref_13","first-page":"863","article-title":"Activation of p53\/p21Waf1\/Cip1 pathway by 5-aza-2\u2032-deoxycytidine inhibits cell proliferation, induces pro-apoptotic genes and mitogen-activated protein kinases in human prostate cancer cells","volume":"26","author":"Pulukuri","year":"2005","journal-title":"Int. J. Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1008","DOI":"10.1038\/nsmb1337","article-title":"Covalent modifications of histones during development and disease pathogenesis","volume":"14","author":"Bhaumik","year":"2007","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1074","DOI":"10.1126\/science.1063127","article-title":"Translating the histone code","volume":"293","author":"Jenuwein","year":"2001","journal-title":"Science"},{"key":"ref_16","first-page":"37","article-title":"Histone Deacetylase Inhibitors as a Novel Targeted Therapy Against Non-small Cell Lung Cancer: Where Are We Now and What Should We Expect?","volume":"38","author":"Damaskos","year":"2018","journal-title":"Anticancer Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1038\/onc.2011.267","article-title":"Endogenous modulators and pharmacological inhibitors of histone deacetylases in cancer therapy","volume":"31","author":"Spiegel","year":"2012","journal-title":"Oncogene"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"106270","DOI":"10.1016\/j.phrs.2022.106270","article-title":"Demethylzeylasteral targets lactate by inhibiting histone lactylation to suppress the tumorigenicity of liver cancer stem cells","volume":"181","author":"Pan","year":"2022","journal-title":"Pharmacol. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1016\/j.bcp.2011.11.010","article-title":"Sensitization of tumor cells by targeting histone deacetylases","volume":"83","author":"Perego","year":"2012","journal-title":"Biochem. Pharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1129","DOI":"10.1016\/j.ejca.2009.01.003","article-title":"The promises and pitfalls of epigenetic therapies in solid tumours","volume":"45","author":"Graham","year":"2009","journal-title":"Eur. J. Cancer"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.bcp.2015.01.002","article-title":"Targeting the invasive phenotype of cisplatin-resistant non-small cell lung cancer cells by a novel histone deacetylase inhibitor","volume":"94","author":"Zuco","year":"2015","journal-title":"Biochem. Pharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1007\/978-3-642-21631-2_3","article-title":"Deacetylation of nonhistone proteins by HDACs and the implications in cancer","volume":"206","author":"Peng","year":"2011","journal-title":"Handb. Exp. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1441","DOI":"10.1093\/jnci\/djm135","article-title":"Drug resistance and the solid tumor microenvironment","volume":"99","author":"Tredan","year":"2007","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_24","first-page":"2989","article-title":"DNA methyltransferase inhibitors and their emerging role in epigenetic therapy of cancer","volume":"33","author":"Gnyszka","year":"2013","journal-title":"Anticancer Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.bcp.2016.12.004","article-title":"DNA methyltransferase inhibitors in cancer: From pharmacology to translational studies","volume":"129","author":"Pechalrieu","year":"2017","journal-title":"Biochem. Pharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"814","DOI":"10.1158\/1078-0432.CCR-13-1483","article-title":"DNA methyltransferase inhibition reverses epigenetically embedded phenotypes in lung cancer preferentially affecting polycomb target genes","volume":"20","author":"Hascher","year":"2014","journal-title":"Clin. Cancer Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1192","DOI":"10.3892\/ijo.2014.2792","article-title":"5-azacytidine enhances efficacy of multiple chemotherapy drugs in AML and lung cancer with modulation of CpG methylation","volume":"46","author":"Klein","year":"2015","journal-title":"Int. J. Oncol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1016\/j.ijdevneu.2013.03.006","article-title":"Emerging concepts on the epigenetic and transcriptional regulation of the Kiss1 gene","volume":"31","author":"Semaan","year":"2013","journal-title":"Int. J. Dev. Neurosci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1731","DOI":"10.1093\/jnci\/88.23.1731","article-title":"KiSS-1, a novel human malignant melanoma metastasis-suppressor gene","volume":"88","author":"Lee","year":"1996","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"437","DOI":"10.3389\/fendo.2018.00437","article-title":"KISS1\/KISS1R in Cancer: Friend or Foe?","volume":"9","author":"Guzman","year":"2018","journal-title":"Front. Endocrinol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1093\/jnci\/djk053","article-title":"Requirement of KISS1 secretion for multiple organ metastasis suppression and maintenance of tumor dormancy","volume":"99","author":"Nash","year":"2007","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1016\/j.eururo.2008.02.048","article-title":"Metastin inhibits migration and invasion of renal cell carcinoma with overexpression of metastin receptor","volume":"55","author":"Shoji","year":"2009","journal-title":"Eur. Urol."},{"key":"ref_33","first-page":"583","article-title":"\u03b1-Bisabolol Inhibits Invasiveness and Motility in Pancreatic Cancer Through KISS1R Activation","volume":"36","author":"Uno","year":"2016","journal-title":"Anticancer Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"5791","DOI":"10.21873\/anticanres.12918","article-title":"Kisspeptin Inhibits Colorectal Cancer Cell Invasiveness by Activating PKR and PP2A","volume":"38","author":"Kim","year":"2018","journal-title":"Anticancer Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"115","DOI":"10.3389\/fendo.2018.00115","article-title":"Kisspeptin and Cancer: Molecular Interaction, Biological Functions, and Future Perspectives","volume":"9","author":"Ciaramella","year":"2018","journal-title":"Front. Endocrinol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"192","DOI":"10.3389\/fendo.2018.00192","article-title":"Controversial Role of Kisspeptins\/KiSS-1R Signaling System in Tumor Development","volume":"9","author":"Fratangelo","year":"2018","journal-title":"Front. Endocrinol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"883","DOI":"10.2174\/138161213804547187","article-title":"Modulation of sensitivity to antitumor agents by targeting the MAPK survival pathway","volume":"19","author":"Cossa","year":"2013","journal-title":"Curr. Pharm. Des."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1182853","DOI":"10.3389\/fonc.2023.1182853","article-title":"Kisspeptin-mediated improvement of sensitivity to BRAF inhibitors in vemurafenib-resistant melanoma cells","volume":"13","author":"Guzzetti","year":"2023","journal-title":"Front. Oncol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1315","DOI":"10.21037\/tlcr-22-52","article-title":"Increased serum levels of KiSS1-derived peptides in non-small cell lung cancer patient liquid biopsies and biological relevance","volume":"11","author":"Gatti","year":"2022","journal-title":"Transl. Lung Cancer Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3163","DOI":"10.1038\/onc.2011.39","article-title":"KiSS1 mediates platinum sensitivity and metastasis suppression in head and neck squamous cell carcinoma","volume":"30","author":"Jiffar","year":"2011","journal-title":"Oncogene"},{"key":"ref_41","first-page":"2051","article-title":"Introduction of exogenous wild-type p53 mediates the regulation of oncoprotein 18\/stathmin signaling via nuclear factor-kappaB in non-small cell lung cancer NCI-H1299 cells","volume":"41","author":"Chen","year":"2019","journal-title":"Oncol. Rep."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1016\/j.ajpath.2011.05.009","article-title":"KISS1 methylation and expression as tumor stratification biomarkers and clinical outcome prognosticators for bladder cancer patients","volume":"179","author":"Cebrian","year":"2011","journal-title":"Am. J. Pathol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1124\/jpet.113.210054","article-title":"Improved apoptotic cell death in drug-resistant non-small-cell lung cancer cells by tumor necrosis factor-related apoptosis-inducing ligand-based treatment","volume":"348","author":"Gatti","year":"2014","journal-title":"J. Pharmacol. Exp. Ther."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/9\/5048\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:40:22Z","timestamp":1760107222000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/9\/5048"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,6]]},"references-count":43,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2024,5]]}},"alternative-id":["ijms25095048"],"URL":"https:\/\/doi.org\/10.3390\/ijms25095048","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2024,5,6]]}}}