Apoptosis and cell growth arrest in A375 human melanoma cells by diorganotin(IV) and triorganotin(IV) complexes of [meso-Tetra(4-sulfonatophenyl)porphine] manganese(III)chloride

Abstract

Abstract.In previous studies we have demonstrated that two derivatives of meso-Tetra(4-sulfonatophenyl)porphine (TPPS), (Bu 2 Sn) 2 TPPS and (Bu 3 Sn) 4 TPPS, cause apoptotic death of A375 melanoma cells and, at lower concentrations, arrest of cell proliferation. In the present study, we examined if the manganese metal inside the porphyrin cavity could improve the efficacy of this class of compounds. Thus, [mesoTetra(4-sulfonatophenyl)porphine]Mn(III)Cl (=MnTPPS) derivatives, namely (Me 2 Sn) 2 MnTPPS, (Bu 2 Sn) 2 MnTPPS, (Me 3 Sn) 4 MnTPPS and (Bu 3 Sn) 4 MnTPPS, were tested on the A375 human melanoma cell line. A cytotoxicity assay showed that (Bu 2 Sn) 2 MnTPPS and (Bu 3 Sn) 4 MnTPPS were highly cytotoxic by inducing apoptosis in melanoma cells, as shown by DNA fragmentation analysis and by apoptotic nuclei fluorescence, and when used at lower concentrations, they affected only cellular proliferation. An arrest of cell proliferation was also observed with (Me 3 Sn) 4 MnTPPS, but at the highest concentrations used. Moreover, the lower concentration of (Bu 3 Sn) 4 MnTPPS induced a change in cell morphology, from a polygonal to an elongated and spindleshaped phenotype, likewise to its cognate (Bu 3 Sn) 4 TPPS, previously tested. Western blotting analysis showed indeed that both tributyltin compounds, i.e. (Bu 3 Sn) 4 MnTPPS and (Bu 3 Sn) 4 TPPS, lowered levels of the major proteins involved in tumorigenesis: ß-catenin, c-myc and snail. We also demonstrated that all compounds entered the cells and localized in the nuclei. In conclusion, our results show that, in spite of the Mn(III) metal introduction, the butyl derivatives always have a higher efficacy than methyl derivatives, and the tributyltin compounds in particular have an interesting effect in vitro on A375 cell proliferation.

Dibutyltin(IV) and Tributyltin(IV) Derivatives of meso-Tetra(4-sulfonatophenyl)porphine Inhibit the Growth and the Migration of Human Melanoma Cells

“…We have previously reported the death due to apoptosis and in particular the activation of both the intrinsic and the extrinsic apoptotic pathways in human melanoma cells treated with micromolar concentrations of the (Bu 2 Sn) 2 TPPS and the (Bu 3 Sn) 4 TPPS [14,[23][24][25]. In this paper we improved upon and expanded this field of research by identifying that nanomolar concentrations of (Bu 2 Sn) 2 TPPS and (Bu 3 Sn) 4 TPPS that are sufficient to significantly induce the cell cycle arrest of some melanoma cell lines through the inhibition of cyclin D1 expression.…”