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Induction of apoptosis on ovarian adenocarcinoma cells, A2780 by tricyclohexylphosphanegold (I) mercaptobenzoate derivatives via intrinsic and extrinsic pathways

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Abstract

Tricyclohexylphosphanegold(I) n-mercaptobenzoate (n = 2, 3, 4) labelled as 1–3 were previously reported to significantly suppress thioredoxin reductase (TrxR) activities towards ovarian cancer cells, A2780, in vitro. Herein, we explored the role of 1–3 for their apoptosis inducing ability against A2780 cells. 1–3 exhibited IC50 values at 1.19 ± 0.03 µM, 2.28 ± 0.04 μM and 0.78 ± 0.01 μM, respectively, compared to cisplatin at 26.8 ± 0.15 µM. The compounds induced A2780 apoptosis via a caspase-dependent mitochondrion pathway as evidenced by ROS production, cytochrome c release, caspases-3/7, -8, -9 and -10 activation, APAF1 and BAX upregulation as well as BCL2A1 and BCL2 genes’ downregulation. In addition, the death mode of 1–3 was also mediated via death receptor extrinsic pathway manifested by FAS, FASL, FADD, and TNFR1 genes’ upregulation via Human Rt PCR analysis. In addition, 1–3 significantly caused A2780 arrest at S phase, which was associated with the upregulation of TP53, E2F1, RB1 and CDKN1A upregulation and downregulation of CDK1, CDK4, CDC25A and CDC25C genes. Based on these promising results, these phosphanegold(I) thiolate derivatives could act as feasible candidates for further advanced in vivo ovarian cancer studies to develop novel chemotherapeutic agents derived from metal-based agents.

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Abbreviations

BRCA1:

Breast cancer 1

BRCA2:

Breast cancer 2

FBS:

Fetal bovine serum

DMSO:

Dimethylsulfoxide

MTT:

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide

PBS:

Phosphate buffer saline

FACS:

Fluorescence-activated cell sorting

DCFH-DA:

Dichloro-dihydro-fluorescein diacetate

PI:

Propidium iodide

FSC:

Forward scatter

SSC:

Side scatter

DNA:

Deoxyribonucleic acid

ROS:

Reactive oxygen species

FLICA:

Fluorochrome inhibitor of caspases

CDK:

Cyclin-dependent kinase

PCR:

Polymerase chain reaction

ELISA:

Enzyme-linked immunosorbent assay

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Acknowledgements

This research was funded by Ministry of Higher Education, Malaysia, grant number UM.C/HIR-MOHE/SC/03 and UM.C/HIR-MOHE/SC/12. We thanked Prof Edward R.T. Tiekink for providing the compounds and Universiti Malaya for providing the funding under High Impact Research Schemes and collaborated with us by providing the compounds and the funding. We also thanked Prof Dr Noor Saadah Abd Rahman, the Deputy Vice Chancellor (Research and Innovation) at the University of Malaya for giving us the consent to publish the data.

Funding

This research was funded by Ministry of Higher Education, Malaysia, grant number UM.C/HIR-MOHE/SC/03 and UM.C/HIR-MOHE/SC/12.

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  1. Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia

    Kok Pian Ang, Pit Foong Chan & Roslida Abd Hamid

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AKP performed the experiments and wrote the original draft. CPF contributed to experimental studies and data collection. RAH supervised the project, validated the data analysis, edited, revised and submitted the manuscript.

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Correspondence to Roslida Abd Hamid.

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Ang, K.P., Chan, P.F. & Hamid, R.A. Induction of apoptosis on ovarian adenocarcinoma cells, A2780 by tricyclohexylphosphanegold (I) mercaptobenzoate derivatives via intrinsic and extrinsic pathways. J Biol Inorg Chem 26, 833–853 (2021). https://doi.org/10.1007/s00775-021-01892-6

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