title: Molecular mechanisms of apoptosis and cell selectivity of zinc dithiocarbamates functionalized with hydroxyethyl substituents.
abstract: 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.
authors.affiliation: Department of Chemistry, University of Malaya, 50603 Kuala Lumpur, Malaysia.
authors.forename: Yee Seng
authors.initials: YS
authors.lastname: Tan
authors.affiliation: Department of Biomedical Science, Faculty of Medicine and Health Sciences, University Putra Malaysia, 43400 UPM Serdang, Selangor Darul Ehsan, Malaysia.
authors.forename: Kah Kooi
authors.initials: KK
authors.lastname: Ooi
authors.affiliation: Department of Biomedical Science, Faculty of Medicine and Health Sciences, University Putra Malaysia, 43400 UPM Serdang, Selangor Darul Ehsan, Malaysia.
authors.forename: Kok Pian
authors.initials: KP
authors.lastname: Ang
authors.affiliation: Department of Biomedical Science, Faculty of Medicine and Health Sciences, University Putra Malaysia, 43400 UPM Serdang, Selangor Darul Ehsan, Malaysia.
authors.forename: Abdah Md
authors.initials: AM
authors.lastname: Akim
authors.affiliation: Department of Biomedical Science, Faculty of Medicine and Health Sciences, University Putra Malaysia, 43400 UPM Serdang, Selangor Darul Ehsan, Malaysia. Electronic address: ykcheah@medic.upm.edu.my.
authors.forename: Yoke-Kqueen
authors.initials: YK
authors.lastname: Cheah
authors.affiliation: Department of Chemistry, University of Malaya, 50603 Kuala Lumpur, Malaysia.
authors.forename: Siti Nadiah Abdul
authors.initials: SN
authors.lastname: Halim
authors.affiliation: Department of Chemistry, University of Malaya, 50603 Kuala Lumpur, Malaysia; Department of Biological Sciences, Faculty of Science and Technology, Sunway University, 47500 Bandar Sunway, Selangor Darul Ehsan, Malaysia.
authors.forename: Hoi-Ling
authors.initials: HL
authors.lastname: Seng
authors.affiliation: Department of Chemistry, University of Malaya, 50603 Kuala Lumpur, Malaysia. Electronic address: Edward.Tiekink@um.edu.my.
authors.forename: Edward R T
authors.initials: ER
authors.lastname: Tiekink
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D016158:Genes, p53; D006801:Humans; D016328:NF-kappa B / Q000235:genetics; D009361:Neoplasm Invasiveness; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D013859:Thiocarbamates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D059004:Topoisomerase I Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D015032:Zinc / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D016328:NF-kappa B; D012333:RNA, Messenger; D013859:Thiocarbamates; D059004:Topoisomerase I Inhibitors; D015032:Zinc
keywords: Apoptosis; Cell cycle; Cell selectivity; Dithiocarbamate; Topoisomerase I; Zinc