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

Jingya Duan; Zisen Zhang; Jinfeng Du; Jihua Zhang; Minmin Li; Canyu Li

doi:10.2147/OTT.S406009

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

Onco Targets Ther. 2023 Jun 20:16:425-440. doi: 10.2147/OTT.S406009. eCollection 2023.

Authors

Jingya Duan^#¹, Zisen Zhang^#², Jinfeng Du², Jihua Zhang¹, Minmin Li¹, Canyu Li¹

Affiliations

¹ Department of Gynecology, the Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, People's Republic of China.
² Department of Oncology, the Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, People's Republic of China.

^# Contributed equally.

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: AKT/mTOR pathway; cisplatin resistance; esomeprazole; ovarian cancer; synergistic effect.

Grants and 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).