title: A bismuth diethyldithiocarbamate compound promotes apoptosis in HepG2 carcinoma, cell cycle arrest and inhibits cell invasion through modulation of the NF-κB activation pathway.
abstract: The compound with R=CH2CH3 in Bi(S2CNR2)3 (1) is highly cytotoxic against a range of human carcinoma, whereas that with R=CH2CH2OH (2) is considerably less so. Both 1 and 2 induce apoptosis in HepG2 cells with some evidence for necrosis induced by 2. Based on DNA fragmentation, caspase activities and human apoptosis PCR-array analysis, both the extrinsic and intrinsic pathways of apoptosis have been shown to occur. While both compounds activate mitochondrial and FAS apoptotic pathways, compound 1 was also found to induce another death receptor-dependent pathway by induction of CD40, CD40L and TNF-R1 (p55). Further, 1 highly expressed DAPK1, a tumour suppressor, with concomitant down-regulation of XIAP and NF-κB. Cell cycle arrest at the S and G2/M phases correlates with the inhibition of the growth of HepG2 cells. The cell invasion rate of 2 is 10-fold higher than that of 1, a finding correlated with the down-regulation of survivin and XIAP expression by 1. Compounds 1 and 2 interact with DNA through different binding motifs with 1 interacting with AT- or TA-specific sites followed by inhibition of restriction enzyme digestion; 2 did not interfere with any of the studied restriction enzymes.
authors.affiliation: Department of Chemistry, University of Malaya, 50603 Kuala Lumpur, Malaysia.
authors.forename: Dayang Hazwani Abang
authors.initials: DH
authors.lastname: Ishak
authors.forename: Kah Kooi
authors.initials: KK
authors.lastname: Ooi
authors.forename: Kok-Pian
authors.initials: KP
authors.lastname: Ang
authors.forename: Abdah Md
authors.initials: AM
authors.lastname: Akim
authors.forename: Yoke-Kqueen
authors.initials: YK
authors.lastname: Cheah
authors.forename: Norshariza
authors.initials: N
authors.lastname: Nordin
authors.forename: Siti Nadiah Binti Abdul
authors.initials: SN
authors.lastname: Halim
authors.forename: Hoi-Ling
authors.initials: HL
authors.lastname: Seng
authors.forename: Edward R T
authors.initials: ER
authors.lastname: Tiekink
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001729:Bismuth / Q000737:chemistry*; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D002463:Cell Membrane Permeability / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D064550:Death-Associated Protein Kinases / Q000235:genetics; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects; D056945:Hep G2 Cells / Q000187:drug effects; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D009942:Organometallic Compounds / Q000737:chemistry* / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D016328:NF-kappa B; D009942:Organometallic Compounds; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C579096:DAPK1 protein, human; D064550:Death-Associated Protein Kinases; D001729:Bismuth
keywords: Apoptosis; Bismuth; Cell cycle; Metallopharmaceuticals; NF-κB