{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T09:05:07Z","timestamp":1779786307258,"version":"3.53.1"},"reference-count":43,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T00:00:00Z","timestamp":1779753600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Pancreatic adenocarcinoma remains a highly lethal malignancy with limited effective treatment options, largely due to late-stage detection and rapid progression to metastatic disease. Therapeutic strategies capable of targeting both pre-metastatic and metastatic tumors are critically needed. In this study, we evaluated a combination therapy consisting of non-thermal plasma (NTP), a generator of reactive oxygen and nitrogen species, and the hypoxia-activated prodrug tirapazamine (TPZ). We further investigated whether sulforaphane (SF), a bioactive phytochemical, could further enhance therapeutic efficacy. NTP and TPZ produced strong cytotoxic effects as single agents and demonstrated additive to synergistic activity when combined, reducing viability by 87% in pre-metastatic BxPC-3 cells and achieving near-complete elimination of metastatic AsPC-1 cells. The addition of sulforaphane (10 \u00b5M) further enhanced cytotoxicity across all treatment conditions, with Bliss independence analysis indicating additive to synergistic interactions depending on cell line and treatment combination. Sulforaphane-mediated enhancement occurred without restoration of connexin 43 expression or coordinated reversal of epithelial-to-mesenchymal transition markers, and treatments did not induce N-cadherin upregulation or suggest acquisition of invasive characteristics. Together, these findings support NTP + TPZ as a potent combinatorial strategy for pancreatic adenocarcinoma and identify sulforaphane as an effective adjunct that enhances cytotoxic efficacy through mechanisms that remain to be fully elucidated.<\/jats:p>","DOI":"10.3390\/cells15110975","type":"journal-article","created":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T08:16:08Z","timestamp":1779783368000},"page":"975","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Sulforaphane Enhances Cytotoxic Effects of Non-Thermal Plasma and Tirapazamine Combination Therapy in Pancreatic Adenocarcinoma Cells"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-5919-8716","authenticated-orcid":false,"given":"Ishfar","family":"Shaan","sequence":"first","affiliation":[{"name":"Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY 14203, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brandon","family":"Gulledge","sequence":"additional","affiliation":[{"name":"School of Pharmacy, D\u2019Youville University, Buffalo, NY 14201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maksym","family":"Poplavskyi","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, D\u2019Youville University, Buffalo, NY 14201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Eubank","sequence":"additional","affiliation":[{"name":"Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY 14203, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anastasiia","family":"Domukhovska","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, D\u2019Youville University, Buffalo, NY 14201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anya","family":"Weinrieb","sequence":"additional","affiliation":[{"name":"Department of Biology, Ithaca College, Ithaca, NY 14850, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dilbar","family":"Alseid","sequence":"additional","affiliation":[{"name":"School of Pharmacy, D\u2019Youville University, Buffalo, NY 14201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"Prentice","sequence":"additional","affiliation":[{"name":"Department of Biology, D\u2019Youville University, Buffalo, NY 14201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel","family":"Rosen","sequence":"additional","affiliation":[{"name":"Department of Biology, Colorado College, Colorado Springs, CO 80903, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0611-9646","authenticated-orcid":false,"given":"Gamal","family":"Rayan","sequence":"additional","affiliation":[{"name":"Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, Medical University of South Carolina, Charleston, SC 29425, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-5356-1616","authenticated-orcid":false,"given":"Shoshanna N.","family":"Zucker","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical, Social and Administrative Sciences, School of Pharmacy, D\u2019Youville University, Buffalo, NY 14201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1007\/s12029-025-01183-2","article-title":"Trends in the Global Incidence of Pancreatic Cancer and a Brief Review of its Histologic and Molecular Subtypes","volume":"56","author":"Leiphrakpam","year":"2025","journal-title":"J. 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