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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 Kok Pian Ang . Pit Foong Chan . Roslida Abd Hamid

Received: 9 August 2020 / Accepted: 4 November 2020 Ó Springer Nature B.V. 2020

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) nmercaptobenzoate, 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-2yl)-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 Lys63linked 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

Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10534-020-00269-7) contains supplementary material, which is available to authorized users. K. P. Ang  P. F. Chan  R. A. Hamid (&) Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia e-mail: [email protected]

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 Lys63linked 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. Keywords p53  Gold (1) complexes  Thioredoxin reductase  Cell invasion  Antiproliferative  MCF-7

Introduction Concurrent global modernization leads to changes in several habits such as dietary intake, sedentary lifestyles and occupational exposure to heavy metals caused several health problems. Amongst them, cancer is one of the most major public health issues and ranked the top three leading causes of death after infectious diseases and cardiovascular diseases. Up to date, there was a total of 14.1 million new cancer cases have been reported and the mortality rate of cancer is

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