Esomeprazole Alleviates Cisplatin Resistance by Inhibiting the AKT/mTOR Pathway in Ovarian Cancer Cells

Abstract

Purpose

Ovarian cancer is the most lethal malignancy in gynecology. Due to limited treatment strategies and platinum resistance, newer drugs and therapeutic options are needed. Esomeprazole (ESO) has been reported to have multiple anticancer activities in preclinical and clinical research. Therefore, this study aimed to explore the anticancer effects of esomeprazole on ovarian cancer and its underlying molecular mechanisms.

Methods

CCK-8 and 5-ethynyl-2′-deoxyuridine (EdU) assays were used to detect cell viability and proliferation. The Transwell assay was used to evaluate cell migration and invasion capacity. Flow cytometry was used to detect cell apoptosis. Western blotting and immunofluorescence were used to detect protein expression.

Results

ESO effectively inhibited the cell viability, proliferation, invasion, migration, and induced apoptosis of ovarian cancer cells in a concentration-dependent manner. Treatment with ESO decreased the expression of c-MYC, SKP2, E2F1, N-cadherin, vimentin, and matrix metalloproteinase 2 (MMP2), while it increased E-cadherin, caspase3, p53, BAX, and cleaved poly (ADP-ribose) polymerase (PARP) expression, and downregulated the PI3K/AKT/mTOR signaling pathway. Furthermore, ESO combined with cisplatin showed synergistic effects in inhibiting proliferation, invasion, and migration of cisplatin-resistant ovarian cancer cells. The mechanism may be related to the increased inhibition of c-MYC, epithelial-mesenchymal transition (EMT), and the AKT/mTOR signaling pathway and enhanced the upregulation of the pro-apoptotic protein BAX and cleaved PARP levels. Moreover, ESO combined with cisplatin synergistically upregulated the expression of the DNA damage marker γH2A.X.

Conclusion

ESO exerts multiple anticancer activities and has a synergistic effect in combination with cisplatin on cisplatin-resistant ovarian cancer cells. This study provides a promising strategy to improve chemosensitivity and overcome resistance to cisplatin in ovarian cancer.

Keywords:

• esomeprazole
• ovarian cancer
• cisplatin resistance
• synergistic effect
• AKT/mTOR pathway

Disclosure

Dr Zisen Zhang reports grants from Department of Education of Henan Province, during the conduct of the study. The authors report no other conflicts of interest in this work.

Additional information

Funding

This work was supported by the Science and Technology Project of Henan Province (grant number 212102310618) and the Key Scientific Research Project Plan of Henan Province (grant number 22A320005).