title: Phosphanegold(I) thiolates, Ph3PAu[SC(OR)=NC 6H 4Me-4] for R = Me, Et and iPr, induce apoptosis, cell cycle arrest and inhibit cell invasion of HT-29 colon cancer cells through modulation of the nuclear factor-κB activation pathway and ubiquitination.
abstract: 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 ± 0.4 and 20.3 ± 0.3 μM 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 NFκB. 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 NFκB. 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.
authors.affiliation: Department of Biomedical Science, Faculty of Medicine and Health Sciences, University Putra Malaysia, UPM, 43400, Serdang, Selangor Darul Ehsan, Malaysia.
authors.forename: Kah Kooi
authors.initials: KK
authors.lastname: Ooi
authors.forename: Chien Ing
authors.initials: CI
authors.lastname: Yeo
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: Siti Nadiah 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 / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019073:HT29 Cells; D006801:Humans; D015394:Molecular Structure; D016328:NF-kappa B / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000473:pathology / Q000517:prevention & control; D050607:Organogold Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010720:Phosphines / Q000737:chemistry / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000737:chemistry / Q000494:pharmacology*; D054875:Ubiquitination / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D016328:NF-kappa B; D050607:Organogold Compounds; D010720:Phosphines; D013438:Sulfhydryl Compounds; C044646:phosphine