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

• Published in: Journal of inorganic biochemistry Vol. 150; pp. 48 - 62
• Main Authors: Tan, Yee Seng, Ooi, Kah Kooi, Ang, Kok Pian, Akim, Abdah Md, Cheah, Yoke-Kqueen, Halim, Siti Nadiah Abdul, Seng, Hoi-Ling, Tiekink, Edward R.T.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-09-2015
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antineoplastic Agents - toxicity; Apoptosis; Apoptosis - drug effects; Cell cycle; Cell Cycle Checkpoints - drug effects; Cell Line, Tumor; Cell selectivity; Coordination Complexes - chemical synthesis; Coordination Complexes - chemistry; Coordination Complexes - pharmacology; Coordination Complexes - toxicity; Dithiocarbamate; Genes, p53; Humans; Neoplasm Invasiveness; NF-kappa B - genetics; Rats; RNA, Messenger - genetics; Thiocarbamates - chemical synthesis; Thiocarbamates - chemistry; Thiocarbamates - pharmacology; Thiocarbamates - toxicity; Topoisomerase I; Topoisomerase I Inhibitors - chemical synthesis; Topoisomerase I Inhibitors - chemistry; Topoisomerase I Inhibitors - pharmacology; Topoisomerase I Inhibitors - toxicity; Zinc; Zinc - chemistry; CD40L; GADD45; CD40; CDKN1A; Annexin V–FITC; ICAM-1; Carboxy–H2DCFDA; P63; P21; CCND1; PBS; BNIP3L; DFFA; DAPK1; P73; AO; TNFRSF1A; CCNE1; BIRC5; SEM; Dithiocarbamate; PIKK; PCR; TNF-R1; COX-2; Chek1; APAF-1; XIAP; BCL-2; CCNB1; c-Src; Cell cycle; FADD; BID; tBID; EtBr; Cell selectivity; c-Abl; Topoisomerase I; Zinc; Cdc2; P53; FAK; MCM; BAX; FAS; PI; TAE; ATM; DPBS; ATR; Apoptosis
• ISSN: 0162-0134; 1873-3344
• DOI: 10.1016/j.jinorgbio.2015.06.009

In the solid state each of three binuclear zinc dithiocarbamates bearing hydroxyethyl groups, {Zn[S2CN(R)CH2CH2OH]2}2 for R=iPr (1), CH2CH2OH (2), and Me (3), and an all alkyl species, [Zn(S2CNEt2)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 G2/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-κB.
The {Zn[S2CN(R)CH2CH2OH]2}2 and Zn(S2CNEt2)2 compounds are cytotoxic and operate via intrinsic and extrinsic apoptotic mechanisms. [Display omitted]
•[Zn(S2CNRR′)2]2 (1–4) are more cytotoxic to human cancer cells than normal cells.•2 (R=R′=CH2CH2OH) is selectively cytotoxic against A2780.•1–4 cause apoptosis in HT-29 cells by both intrinsic and extrinsic pathways.•1–4 inhibit cell invasion by down-regulation of NF-ĸB.•All but 3 are topoisomerase I inhibitors.