期刊
JOURNAL OF BIOLOGICAL INORGANIC CHEMISTRY
卷 20, 期 5, 页码 855-873出版社
SPRINGER
DOI: 10.1007/s00775-015-1271-5
关键词
Gold(I) compounds; Carbonimidothioates; Phosphanegold thiolates; Apoptosis; Nuclear factor-kappa B activation pathway
资金
- Ministry of Higher Education (Malaysia)
- University of Malaya [UM.C/HIR-MOHE/SC/12]
- University of Malaya Research Grants scheme [RG125/10AFR]
The phosphanegold(I) carbonimidothioates, Ph3PAu{SC(OR)=NC6H4Me-4} for R = Me (1), Et (2) and iPr (3), feature linear P-Au-S coordination geometries and exhibit potent in vitro cytotoxicity against HT-29 colon cancer cells in both monolayer and multi-cellular spheroid models (e.g., IC50 = 11.9 +/- A 0.4 and 20.3 +/- A 0.3 mu M for 2, respectively). Both intrinsic and extrinsic pathways of apoptosis are demonstrated by human apoptosis PCR array analysis, caspase activities, DNA fragmentation and cell apoptotic assays. Compounds 1-3 induce an extrinsic pathway that leads to down-regulation of NF kappa B. Compound 2 also exhibits an extrinsic apoptotic pathway involving the activation of both p53 and p73, whereas 3 activates p53 only. Lys48- and Lys63-linked polyubiquitination are also promoted by 1-3. Each of cytotoxic Ph3PAu{SC(OR)=NC6H4Me-4}, for R = Me (1), Et (2) and iPr (3), induce an intrinsic apoptotic pathway as well as an extrinsic pathway leading to down-regulation of NF kappa B. Lys48- and Lys63-linked polyubiquitination are promoted by 1-3 and these are able to inhibit cell invasion and to suppress the activity of TrxR. [GRAPHICS] .
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