G2/M cell cycle arrest on HT-29 cancer cells and toxicity assessment of triphenylphosphanegold(I) carbonimidothioates, Ph3PAu[SC(OR)=NPh], R=Me, Et, and iPr, during zebrafish development

• Published in: Journal of inorganic biochemistry Vol. 166; pp. 173 - 181
• Main Authors: Ooi, Kah Kooi, Yeo, Chien Ing, Mahandaran, Theventhiran, Ang, Kok Pian, Akim, Abdah Md, Cheah, Yoke-Kqueen, Seng, Hoi-Ling, Tiekink, Edward R.T.
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01-01-2017
• Subjects: Apoptosis; Carbonimidothioates; Gold(I) compounds; HT-29 cancer cell; Phosphanegold(I) thiolates; Zebrafish; Bcl-2; GADD45; CDKN1A; G2/M Phase; PS; Carbonimidothioates; JNK; APAF-1; XIAP; p73; p53; CHEK2/Chk2; NF-κB; CCNB1; c-Src; S Phase; FSC; G2 Phase; dpf; Phosphanegold(I) thiolates; hpf; cdc25C; PBS; Gold(I) compounds; SSC; CHEK1/Chk1; MMP2; Zebrafish; BIRC-5; MAPK; MMP9; p21; FAK; LC50; G1 Phase; CDK4; Tcf; CDK2; ROS; Bax; PI; M Phase; HT-29 cancer cell; PCR; Annexin V-FITC; ATR; Apoptosis
• ISSN: 0162-0134; 1873-3344
• DOI: 10.1016/j.jinorgbio.2016.11.008

Phosphanegold(I) thiolates, Ph3PAu[SC(OR)=NPh], R=Me (1), Et (2) and iPr (3), were previously shown to be significantly cytotoxic toward HT-29 cancer cells and to induce cell death by both intrinsic and extrinsic apoptotic pathways whereby 1 activated the p73 gene, and each of 2 and 3 activated p53; 2 also caused apoptotic cell death via the c-Jun N-terminal kinase/mitogen-activated protein kinase pathway. Apoptosis pathways have been further evaluated by mitochondrial cytochrome c measurements and annexin V screening, confirming apoptotic pathways of cell death. Cell cycle analysis showed the majority of treated HT-29 cells were arrested at the G2/M checkpoint after 24h; results of both assays were confirmed by changes in populations of relevant genes (PCR array analysis). Cell invasion studies showed inhibition of metastasis through Matrigel™ matrix to 17–22% cf. untreated cells. LC50 values were determined in zebrafish (8.36, 8.17, and 7.64μM for 1–3). Finally, the zebrafish tolerated doses of 1 and 2 up to 0.625μM, and 3 was tolerated at even higher doses of up to 1.25μM.
Ph3PAu[SC(OR)=NPh], R=Me, Et and iPr, kill HT-29 cells by apoptotic mechanisms, inhibit metastasis and are tolerated by zebrafish up to 1.25μM (R=iPr). [Display omitted]
•Phosphanegold(I) carbonimidothioates are potent to HT-29 cells.•They induce apoptotic pathways of cell death.•HT-29 cells were arrested at the G2/M checkpoint.•They inhibit metastasis through Madgrigal™ matrix.•Zebrafish tolerated doses up to 1.25μM.