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

Kah Kooi Ooi; Chien Ing Yeo; Theventhiran Mahandaran; Kok Pian Ang; Abdah Md Akim; Yoke-Kqueen Cheah; Hoi-Ling Seng; Edward R T Tiekink

doi:10.1016/j.jinorgbio.2016.11.008

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

J Inorg Biochem. 2017 Jan:166:173-181. doi: 10.1016/j.jinorgbio.2016.11.008. Epub 2016 Nov 4.

Authors

Kah Kooi Ooi¹, Chien Ing Yeo², Theventhiran Mahandaran³, Kok Pian Ang⁴, Abdah Md Akim⁴, Yoke-Kqueen Cheah⁴, Hoi-Ling Seng⁵, Edward R T Tiekink⁶

Affiliations

¹ Department of Biomedical Science, Faculty of Medicine and Health Sciences, University Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia; Research Centre for Crystalline Materials, Faculty of Science and Technology, Sunway University, 47500 Bandar Sunway, Selangor Darul Ehsan, Malaysia.
² Research Centre for Crystalline Materials, Faculty of Science and Technology, Sunway University, 47500 Bandar Sunway, Selangor Darul Ehsan, Malaysia.
³ Department of Biotechnology, Faculty of Engineering and Science, Malaysia University of Science and Technology, 47301 Petaling Jaya, Selangor, Malaysia.
⁴ Department of Biomedical Science, Faculty of Medicine and Health Sciences, University Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia.
⁵ Department of Biological Sciences, Faculty of Science and Technology, Sunway University, 47500 Bandar Sunway, Selangor Darul Ehsan, Malaysia. Electronic address: hoilings@sunway.edu.my.
⁶ Research Centre for Crystalline Materials, Faculty of Science and Technology, Sunway University, 47500 Bandar Sunway, Selangor Darul Ehsan, Malaysia. Electronic address: edwardt@sunway.edu.my.

PMID: 27865929
DOI: 10.1016/j.jinorgbio.2016.11.008

Abstract

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.

Keywords: Apoptosis; Carbonimidothioates; Gold(I) compounds; HT-29 cancer cell; Phosphanegold(I) thiolates; Zebrafish.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line, Tumor
Cytotoxins* / chemical synthesis
Cytotoxins* / chemistry
Cytotoxins* / pharmacology
Drug Screening Assays, Antitumor
G2 Phase Cell Cycle Checkpoints / drug effects*
Humans
M Phase Cell Cycle Checkpoints / drug effects*
Neoplasm Invasiveness
Neoplasms / drug therapy*
Neoplasms / metabolism
Neoplasms / pathology
Organogold Compounds* / chemical synthesis
Organogold Compounds* / chemistry
Organogold Compounds* / pharmacology
Zebrafish / embryology*

Substances

Cytotoxins
Organogold Compounds