A bismuth diethyldithiocarbamate compound promotes apoptosis in HepG2 carcinoma, cell cycle arrest and inhibits cell invasion through modulation of the NF-κB activation pathway

• Published in: Journal of inorganic biochemistry Vol. 130; pp. 38 - 51
• Main Authors: Ishak, Dayang Hazwani Abang, Ooi, Kah Kooi, Ang, Kok-Pian, Akim, Abdah Md, Cheah, Yoke-Kqueen, Nordin, Norshariza, Halim, Siti Nadiah Binti Abdul, Seng, Hoi-Ling, Tiekink, Edward R.T.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-01-2014
• Subjects: Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Apoptosis - genetics; Bismuth; Bismuth - chemistry; Cell cycle; Cell Cycle Checkpoints - drug effects; Cell Membrane Permeability - drug effects; Cell Movement - drug effects; Death-Associated Protein Kinases - genetics; Drug Screening Assays, Antitumor - methods; Gene Expression Regulation - drug effects; Hep G2 Cells - drug effects; Humans; Metallopharmaceuticals; NF-kappa B - metabolism; NF-κB; Organometallic Compounds - chemistry; Organometallic Compounds - pharmacology; Signal Transduction - drug effects; X-Linked Inhibitor of Apoptosis Protein - genetics; X-Linked Inhibitor of Apoptosis Protein - metabolism; Metallopharmaceuticals; Bismuth; NF-κB; Cell cycle; Apoptosis
• ISSN: 0162-0134; 1873-3344
• DOI: 10.1016/j.jinorgbio.2013.09.018

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.
The Bi(S2CNEt2)3 and Bi[S2CN(CH2CH2OH)2]3 compounds are cytotoxic towards HepG2 carcinoma and induce apoptosis by both extrinsic and intrinsic pathways. [Display omitted]
•Bi(S2CNEt2)3 is cytotoxic against several human carcinoma.•Bi(S2CNEt2)3 causes apoptosis in HepG2 cells by both extrinsic and intrinsic pathways.•Cell cycle arrest occurs at the S and G2/M phases.•Bi(S2CNEt2)3 interacts with DNA at AT- or TA-specific sites.