Molecular mechanisms of apoptosis and cell selectivity of zinc dithiocarbamates functionalized with hydroxyethyl substituents.

In the solid state each of three binuclear zinc dithiocarbamates bearing hydroxyethyl groups, {Zn[S 2 CN(R)CH 2 CH 2 OH] 2 } 2 for R = iPr ( 1 ), CH 2 CH 2 OH ( 2 ), and Me ( 3 ), and an all alkyl species, [Zn(S 2 CNEt 2 ) 2 ] 2 ( 4 ), features a centrosymmetric {ZnSCS} 2 core with a step topology; both 1 and 3 were isolated as monohydrates. All compounds were broadly cytotoxic, specifically against human cancer cell lines compared with normal cells, with greater potency than cisplatin. Notably, some selectivity were indicated with 2 being the most potent against human ovarian carcinoma cells (cisA2780), and 4 being more cytotoxic toward multidrug resistant human breast carcinoma cells (MCF-7R), human colon adenocarcinoma cells (HT-29), and human lung adenocarcinoma epithelial cells (A549). Based on human apoptosis PCR-array analysis, caspase activities, DNA fragmentation, cell apoptotic assays, intracellular reactive oxygen species (ROS) measurements and human topoisomerase I inhibition, induction of apoptosis in HT-29 cells is demonstrated via both extrinsic and intrinsic pathways. Compounds 2 – 4 activate the p53 gene while 1 activates both p53 and p73. Cell cycle arrest at the S and G 2 /M phases correlates with inhibition of HT-29 cell growth. Cell invasion is also inhibited by 1 – 4 which is correlated with down-regulation of NF -κ B. [ABSTRACT FROM AUTHOR]