{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T06:03:09Z","timestamp":1790402589358,"version":"4.1.0"},"reference-count":54,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2023,11,9]],"date-time":"2023-11-09T00:00:00Z","timestamp":1699488000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University of Pisa, MIUR, Italy","award":["PRIN 2017XP72RF"],"award-info":[{"award-number":["PRIN 2017XP72RF"]}]},{"name":"Italian Ministry of University and Research (MIUR)","award":["PRIN 2017XP72RF"],"award-info":[{"award-number":["PRIN 2017XP72RF"]}]},{"name":"international consortium \u201cSPARK PISA\u201d University of Pisa\/University of Stanford","award":["PRIN 2017XP72RF"],"award-info":[{"award-number":["PRIN 2017XP72RF"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Metformin (Met) is the first-line therapy in type 2 diabetes mellitus but, in last few years, it has also been evaluated as anti-cancer agent. Several pathways, such as AMPK or PI3K\/Akt\/mTOR, are likely to be involved in the anti-cancer Met activity. In addition, hydrogen sulfide (H2S) and H2S donors have been described as anti-cancer agents affecting cell-cycle and inducing apoptosis. Among H2S donors, isothiocyanates are endowed with a further anti-cancer mechanism: the inhibition of the histone deacetylase enzymes. On this basis, a hybrid molecule (Met-ITC) obtained through the addition of an isothiocyanate moiety to the Met molecule was designed and its ability to release Met has been demonstrated. Met-ITC exhibited more efficacy and potency than Met in inhibiting cancer cells (AsPC-1, MIA PaCa-2, MCF-7) viability and it was less effective on non-tumorigenic cells (MCF 10-A). The ability of Met-ITC to release H2S has been recorded both in cell-free and in cancer cells assays. Finally, its ability to affect the cell cycle and to induce both early and late apoptosis has been demonstrated on the most sensitive cell line (MCF-7). These results confirmed that Met-ITC is a new hybrid molecule endowed with potential anti-cancer properties derived both from Met and H2S.<\/jats:p>","DOI":"10.3390\/ijms242216131","type":"journal-article","created":{"date-parts":[[2023,11,9]],"date-time":"2023-11-09T08:08:58Z","timestamp":1699517338000},"page":"16131","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Anti-Proliferative Properties of the Novel Hybrid Drug Met-ITC, Composed of the Native Drug Metformin with the Addition of an Isothiocyanate H2S Donor Moiety, in Different Cancer Cell Lines"],"prefix":"10.3390","volume":"24","author":[{"given":"Valentina","family":"Citi","sequence":"first","affiliation":[{"name":"Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9814-7195","authenticated-orcid":false,"given":"Elisabetta","family":"Barresi","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy"},{"name":"Center for Instrument Sharing of the University of Pisa (CISUP), University of Pisa, Lungarno Pacinotti 43\/44, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6558-3065","authenticated-orcid":false,"given":"Eugenia","family":"Piragine","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7308-372X","authenticated-orcid":false,"given":"Jacopo","family":"Spezzini","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2431-6248","authenticated-orcid":false,"given":"Lara","family":"Testai","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy"},{"name":"Center for Instrument Sharing of the University of Pisa (CISUP), University of Pisa, Lungarno Pacinotti 43\/44, 56126 Pisa, Italy"},{"name":"Interdepartmental Research Center \u201cBiology and Pathology of Ageing\u201d, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7897-7917","authenticated-orcid":false,"given":"Federico","family":"Da Settimo","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy"},{"name":"Center for Instrument Sharing of the University of Pisa (CISUP), University of Pisa, Lungarno Pacinotti 43\/44, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2090-7107","authenticated-orcid":false,"given":"Alma","family":"Martelli","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy"},{"name":"Center for Instrument Sharing of the University of Pisa (CISUP), University of Pisa, Lungarno Pacinotti 43\/44, 56126 Pisa, Italy"},{"name":"Interdepartmental Research Center \u201cBiology and Pathology of Ageing\u201d, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8675-939X","authenticated-orcid":false,"given":"Sabrina","family":"Taliani","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy"},{"name":"Center for Instrument Sharing of the University of Pisa (CISUP), University of Pisa, Lungarno Pacinotti 43\/44, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincenzo","family":"Calderone","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy"},{"name":"Center for Instrument Sharing of the University of Pisa (CISUP), University of Pisa, Lungarno Pacinotti 43\/44, 56126 Pisa, Italy"},{"name":"Interdepartmental Research Center \u201cBiology and Pathology of Ageing\u201d, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1586","DOI":"10.1007\/s00125-017-4336-x","article-title":"Metformin: Clinical use in type 2 diabetes","volume":"60","author":"Inzucchi","year":"2017","journal-title":"Diabetologia"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1210\/endrev\/bnaa023","article-title":"Cellular and molecular mechanisms of metformin action","volume":"42","author":"LaMoia","year":"2021","journal-title":"Endocr. 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