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Antiproliferative activity exerted by tricyclohexylphosphanegold(I) n-mercaptobenzoate against MCF-7 and A2780 cell lines: the role of p53 signaling pathways

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Abstract

Based on the recent studies depicting the potential of heterometallic gold complexes as potent antiproliferative agents, herein we first reported the preliminary mechanistic data on the in-vitro antiproliferative activity of tricyclohexylphosphanegold(I) n-mercaptobenzoate, Cy3PAu(n-MBA) where n = 2 (1), 3 (2) and 4 (3), and MBA = mercaptobenzoic acid, treated using MCF-7 breast cancer and A2780 ovarian cancer cells, respectively. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay was used to assess the cytotoxicity of both cancer cells treated with 1–3, respectively. The IC50 of 1–3 were applied to the subsequent assays including cell invasion and thioredoxin reductase (TrxR) as well as ubiquitin activities specifically on Lys48 and Lys63-linked polyubiquitin chains via flowcytometric analysis. The mechanistic effect of 1–3 towards both cells were evaluated on human p53 signaling gene expressions via RT2 profiler Polymerase Chain Reductase (PCR) array. 1–3 were found to be highly cytotoxic towards both MCF-7 and A2780 cancer cell lines with the compounds were more sensitive towards the latter cells. 1–3 also suppressed TrxR and cell invasion activities by modulating p53 related genes related with proliferation, invasion and TrxR activities i.e. CCNB1, TP53, CDK4 etc. 1–3 also regulated Lys48 and Lys63-linked polyubiquitination by reactivation of p53, suggesting the ability of this gene in regulating inhibition of cytoskeletal reorganization via epithelial–mesenchymal transition (EMT), required for tumor progression. Taken together, the overall findings denoted that 1–3 exerted potent antiproliferative activity in MCF-7 and A2780 cells via activation of the p53 signaling pathway.

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Acknowledgements

This research was funded by Ministry of Higher Education, Malaysia, Grant Numbers UM.C/HIR-MOHE/SC/03 and UM.C/HIR-MOHE/SC/12. We thanked Universiti Malaya for providing the grants 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

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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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  1. Kok Pian Ang
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  2. Pit Foong Chan
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  3. Roslida Abd Hamid
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Conceptualization, RAH; methodology, RAH; validation, AKP, CPF and RAH; formal analysis, AKP and CPF; investigation, AKP and CPF; data curation, AKP; writing—original draft preparation, AKP; writing—review and editing, RAH; visualization, AKP and CPF; supervision, RAH; project administration, RAH. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Roslida Abd Hamid.

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Ang, K.P., Chan, P.F. & Hamid, R.A. Antiproliferative activity exerted by tricyclohexylphosphanegold(I) n-mercaptobenzoate against MCF-7 and A2780 cell lines: the role of p53 signaling pathways. Biometals 34, 141–160 (2021). https://doi.org/10.1007/s10534-020-00269-7

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