International Journal of Molecular Sciences (Nov 2023)

Anti-Proliferative Properties of the Novel Hybrid Drug Met-ITC, Composed of the Native Drug Metformin with the Addition of an Isothiocyanate H<sub>2</sub>S Donor Moiety, in Different Cancer Cell Lines

  • Valentina Citi,
  • Elisabetta Barresi,
  • Eugenia Piragine,
  • Jacopo Spezzini,
  • Lara Testai,
  • Federico Da Settimo,
  • Alma Martelli,
  • Sabrina Taliani,
  • Vincenzo Calderone

DOI
https://doi.org/10.3390/ijms242216131
Journal volume & issue
Vol. 24, no. 22
p. 16131

Abstract

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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.

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