Selenotriapine – An isostere of the most studied thiosemicarbazone with pronounced pro-apoptotic activity, low toxicity and ability to challenge phenotype reprogramming of 3-D mammary adenocarcinoma tumors

Nenad R. Filipović (1) , Snežana Bjelogrlić (2) , Sveva Pelliccia (3) , Vesna Jovanović (1) , Milan Kojić (1) , Milan Senćanski (1) , Giuseppe La Regina (4, 5) , Romano Silvestri (4, 5) , Christian D. Muller (6) , Tamara Todorović (1)

1 University of Belgrade [Belgrade]
2 National Cancer Research Center of Serbia
3 University of Naples Federico II = Università degli studi di Napoli Federico II
4 Institut Pasteur, Fondation Cenci Bolognetti - Istituto Pasteur Italia, Fondazione Cenci Bolognetti
5 UNIROMA - Università degli Studi di Roma "La Sapienza" = Sapienza University [Rome]
6 DSA-IPHC - Département Sciences Analytiques et Interactions Ioniques et Biomoléculaires

Triapine, the most studied α-N-heterocyclic thiosemicarbazone, revealed potent activity against advanced leukemia, but was ineffective against a variety of solid tumors. Moreover, methemoglobinemia, which is a side effect of triapine administration, may limits all clinical application. To enhance anticancer activity and reduce side effects, we applied an isosteric replacement of sulfur to selenium atom was performed by synthesis and characterization of selenium triapine analog, 3-aminopyridine-2-carboxaldehyde selenosemicarbazone (selenotriapine). Compared to triapine, selenotriapine revealed superior pro-apoptotic activity with activation of intrinsic apoptotic pathway in both human monocytic leukemia (THP-1) and mammary adenocarcinoma (MCF-7) cell lines. For MCF-7 2-D cultures, selenotriapine induced notable increase in mitochondrial superoxide radical generation and dissipation of mitochondrial transmembrane potential. A significant delay in growth of MCF-7 spheroids (3-D culture) was accompanied by phenotypic stem cell reprogramming (Oct-4 expression). Additionally, selenotriapine demonstrated a very low toxicity profile as compared to triapine, confirmed over alleviated extent of methemoglobin formation and higher IC50 value in brine shrimp cytotoxicity assay.

Mots clés: Selenosemicarbazone; 3-D culture; Apoptosis; Mitochondrial superoxide production; Oct-4

Domaines: Cancer; Pharmacologie; Hépatologie et Gastroentérologie

Nenad R. Filipović, Snežana Bjelogrlić, Sveva Pelliccia, Vesna Jovanović, Milan Kojić, et al.. Selenotriapine – An isostere of the most studied thiosemicarbazone with pronounced pro-apoptotic activity, low toxicity and ability to challenge phenotype reprogramming of 3-D mammary adenocarcinoma tumors. Arabian Journal of Chemistry, 2020, 13 (1), pp.1466 - 1489. ⟨10.1016/j.arabjc.2017.11.017⟩. ⟨hal-02106906⟩