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

• Published in: Journal of biological inorganic chemistry Vol. 26; no. 7; pp. 833 - 853
• Main Authors: Ang, Kok Pian, Chan, Pit Foong, Hamid, Roslida Abd
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01-10-2021; Springer Nature B.V
• Subjects: Adenocarcinoma; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis; Biochemistry; Biomedical and Life Sciences; Caspase; Cell Line, Tumor; Chemotherapy; Cisplatin; Cisplatin - pharmacology; Cyclin-dependent kinase 4; Cytochrome c; FADD protein; FasL protein; Female; Humans; Inorganic chemistry; Life Sciences; Microbiology; Original Paper; Ovarian cancer; Ovarian Neoplasms - drug therapy; p53 Protein; S phase; Thioredoxin; Tumor necrosis factor receptors; p53-induced apoptosis; A2780; Phosphanegold(I) thiolates; Cell cycle; Ovarian cancer
• ISSN: 0949-8257; 1432-1327
• DOI: 10.1007/s00775-021-01892-6

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 IC
50
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.
Graphic abstract