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Published on: August 2, 2024
Uncovering the Underlying Mechanism of Clotrimazole against Ovarian Cancer by Transcriptomics and Experimental
Xin Wang1, Ning Wang2, Jiaqian Liao3
1Department of Gynecology, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Peking University Cancer Hospital Yunnan, Kunming, 650118, China.
Introduction:
Ovarian cancer remains the most lethal gynecological malignancy globally. While Clotrimazole (CTZ) exhibits antitumor potential, its specific efficacy and mechanisms in ovarian cancer require elucidation.
Methods:
Proliferation and apoptosis were assessed in A2780 and SKOV3 cells using CCK-8, colony formation, and Annexin-V/PI assays. Mechanisms were explored via RNA sequencing, molecular docking, qRT-PCR, Western blotting, and immunofluorescence. In vivo efficacy and safety were validated using SKOV3 xenograft models.
Results:
CTZ inhibited cell viability with 48-h IC50 values of 19.36 µM (A2780) and 46.01 µM (SKOV3). Apoptotic rates increased significantly to 48.4% and 20.3%, respectively. RNA-seq analysis identified 4,066 differentially expressed genes primarily enriched in the HER2/PI3K/AKT pathway. Experimental validation confirmed that CTZ significantly downregulated this pathway in vitro and in vivo. In xenograft tumor models, intraperitoneal CTZ administration reduced tumor volume by 48.68% compared to the vehicle group, with slight systemic toxicity. However, oral administration showed limited efficacy.
Discussion:
It was found that CTZ inhibits ovarian cancer cell proliferation and induces apoptosis via the HER-2/PI3K/AKT signaling pathway. CTZ may bind to HER-2 and accelerate HER2 protein degradation. The Intraperitoneal administration of CTZ exerts potent in vivo antitumor effects, suggesting that future research should utilize novel drug delivery systems to improve oral bioavailability.
Conclusion:
CTZ is a promising therapeutic agent and may serve as a novel potent agent for ovarian cancer treatment. Its antitumor effects are at least partially mediated via the inhibition of the HER-2/PI3K/AKT signaling pathway.
