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Induction of apoptosis on ovarian adenocarcinoma cells, A2780 by tricyclohexylphosphanegold (I) mercaptobenzoate derivatives via intrinsic and extrinsic pathways
JBIC Journal of Biological Inorganic Chemistry  (IF3.358),  Pub Date : 2021-09-03, DOI: 10.1007/s00775-021-01892-6
Ang, Kok Pian, Chan, Pit Foong, Hamid, Roslida Abd

Tricyclohexylphosphanegold(I) n-mercaptobenzoate (n = 2, 3, 4) labelled as 13 were previously reported to significantly suppress thioredoxin reductase (TrxR) activities towards ovarian cancer cells, A2780, in vitro. Herein, we explored the role of 13 for their apoptosis inducing ability against A2780 cells. 13 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 13 was also mediated via death receptor extrinsic pathway manifested by FAS, FASL, FADD, and TNFR1 genes’ upregulation via Human Rt PCR analysis. In addition, 13 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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