Antiproliferative activity and interactions with cell-cycle related proteins of the organotin compound triethyltin(IV)lupinylsulfide hydrochloride

Organotin compounds, particularly tri-organotin, have demonstrated cytotoxi c properties against a number of turner cell lines. On this basis, triethyl tin(IV)lupinylsulfide hydrochloride (IST-FS 29, a quinolizidine derivative, was synthesized and developed as a potential antitumor agent. This tin-der ived compound exhibited potent antiproliferative effects on three different human cancer cell lines: teratocarcinoma of the ovary (PA-I), colon carcin oma (HCT-8) and glioblastoma (A-172). Cytotoxic activity was assessed by MT T and cell count assays during time course experiments with cell recovery a fter compound withdrawal. Significant cell growth inhibition (up to 95% in HCT-S after 72 h of exposure), which also persisted after drug-free medium change, was reported in all the cell lines by both assays. In addition, the cytocidal effects exerted by IST-FS 29 appeared more consistent with necro sis or delayed cell death, rather than apoptosis as shown by morphologic ob servations under light microscope, DNA fragmentation analysis and flow cyto metry. In the attempt to elucidate whether this compound might affect genes playing a role in G1/S phase transition, the expressions of p53, p21(WAF1) , cyclin D1 and Rb, mainly involved in response to DNA-damaging stress, wer e analyzed by Western blot. Heterogeneous patterns of expression doting exp osure to IST-FS 29 were evidenced in the different cell lines suggesting th at these cell-cycle-related genes ale not likely: the primary targets of th is compound. Thus, the present data seem more indicative of a direct effect of IST-FS-29 on macromolecular synthesis :and cellular homeostasis. as pre viously hypothesized for other organotin complexes. (C) 2001 Elsevier Scien ce Ireland Ltd, All rights reserved.