Resveratrol Enhances Cytotoxic Effects of Cisplatin by Inducing Cell Cycle Arrest and Apoptosis in Ovarian Adenocarcinoma SKOV-3 Cells through Activating the p38 MAPK and Suppressing AKT

Abstract

In the current study, we identified a mechanism of resveratrol (RES) underlying its anti-cancer properties against human ovarian adenocarcinoma SKOV-3 cells. We investigated its anti-proliferative and apoptosis-inducing effects in combination with cisplatin, using cell viability assay, flow cytometry, immunofluorescence study and Western blot analysis. We discovered that RES suppressed cancer cell proliferation and stimulated apoptosis, especially when combined with cisplatin. This compound also inhibited SKOV-3 cell survival, which may partly be due to its potential to inhibit protein kinase B (AKT) phosphorylation and induce the S-phase cell cycle arrest. RES in combination with cisplatin strongly induced cancer cell apoptosis through activating the caspase-dependent cascade, which was associated with its ability to stimulate nuclear phosphorylation of p38 mitogen-activated protein kinase (MAPK), well recognized to be involved in transducing environmental stress signals. RES-induced p38 phosphorylation was very specific, and the activation status of extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK) was not mainly affected. Taken together, our study provides accumulated evidence that RES represses proliferation and promotes apoptosis in SKOV-3 ovarian cancer cells through activating the p38 MAPK pathway. It is interesting that this active compound may be used as an effective agent to sensitize ovarian cancer to apoptosis induced by standard chemotherapies.

Effectiveness of Sodium Thiosulfate and Resveratrol in Remodeling Lung Injury and Expression of BCL2 in Nicotine-Stressed Rats

“…In addition, the resveratrol group had higher Bcl-2 expression and lower Bax, caspase-3, and cytochrome c expression than the model group. Recently accumulated evidence confirm that Resveratrol stimulate P38-MAPK and suppress AKT activation in ovarian cancer cells may be via activation of signaling molecules suh as ERK1/2 and JNK these effect of resveratrol enhanced cisplatin inducing cell cycle arrest by downregulation the expression of responsible cycle proteins and activation caspase and has been an observed rise which occur in apoptotic cells [48]. RES alters the metabolic reprogramming of Staphylococcal enterotoxin-B (SEB) -activated immune cells, through suppression of mTOR activation and its downand upstream effects on energy metabolism.…”

An Update on Physiopathological Roles of Akt in the ReprodAKTive Mammalian Ovary

“…The inhibition of PI3K/Akt/mTOR pathway in vitro showed the effect on decreased chemoresistance of epithelial OC cells by the use of dactolisib in combination with cisplatin, increasing both ROS production and apoptosis mechanisms, and thus decreasing rates and outcomes of EMT [ 140 ]. Likewise, patient-derived OC spheroids cultured in vitro with LY-294002—a PI3K-Akt dual kinase inhibitor—showed a significant decrease in cancer stemness and chemoresistance to cisplatin [ 141 ], and resveratrol-treated OC cells SKOV-3 displayed increased apoptosis and induced cell cycle arrest through Akt suppression in vitro [ 142 ].…”

Advances in the role of resveratrol and its mechanism of action in common gynecological tumors

“…However, most patients develop inherent or acquired drug resistance to CDDP ( Rocha et al, 2018 ). RES treatment significantly enhances the sensitivity of SKOV-3 cells to CDDP ( Hankittichai et al, 2023 ). Specifically, the combination of RES and CDDP activates caspase-3, caspase-9, and poly (ADP-ribose) polymerase (PARP); inhibits cyclin A2 and cyclin B1 expression; and induces cell cycle arrest in the S phase, ultimately inhibiting cell proliferation and promoting apoptosis.…”

“…Specifically, the combination of RES and CDDP activates caspase-3, caspase-9, and poly (ADP-ribose) polymerase (PARP); inhibits cyclin A2 and cyclin B1 expression; and induces cell cycle arrest in the S phase, ultimately inhibiting cell proliferation and promoting apoptosis. Further experiments revealed that RES strongly activates p38 phosphorylation and inhibits AKT activation ( Hankittichai et al, 2023 ). Yue et al (2019) showed that RES enhances the sensitivity of HeLa cells to CDDP by inducing G1 phase blockage and apoptosis.…”