Pharmacological Mechanisms of Kirenol against Ovarian Carcinoma: A Network Pharmacology and Experimental Validation Study In Vitro

Xiaoling Mao; Hong Zhu; Jun Gao; Shixin Lin; Yin Bao; Mingyue Zhang; Huan Yang

doi:10.2174/0113862073289977240216075724

Pharmacological Mechanisms of Kirenol against Ovarian Carcinoma: A Network Pharmacology and Experimental Validation Study In Vitro

Comb Chem High Throughput Screen. 2024 Feb 26. doi: 10.2174/0113862073289977240216075724. Online ahead of print.

Authors

Xiaoling Mao^{1

2}, Hong Zhu², Jun Gao², Shixin Lin³, Yin Bao^{1

2}, Mingyue Zhang², Huan Yang⁴

Affiliations

¹ Jiangxi University of Chinese Medicine, Nanchang, Jiangxi 330006, P.R. China.
² Department of Gynecologic Oncology, Jiangxi Cancer Hospital, Nanchang, Jiangxi 330029, P.R. China.
³ Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu 610041, P.R. China.
⁴ Department of Third Clinical Medical College of Nanchang University, Third Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330008, P.R. China.

PMID: 38415456
DOI: 10.2174/0113862073289977240216075724

Abstract

Background: Ovarian carcinoma is an aggressive gynecological malignancy. Kirenol, a diterpene compound, has recently gained attention for its potential anticancer properties. However, its exact anti-tumor mechanism remains largely unexplored.

Objective: In this study, we explored the inhibitory effects of Kirenol on ovarian cancer using network pharmacology and in vitro experiments and elucidated its underlying mechanisms.

Methods: Through the utilization of molecular docking, we established a network of proteinprotein interactions (PPI), which unveiled CDK4 as an essential target. Additionally, gene enrichment and pathway analysis highlighted the significance of the PI3K/AKT pathway. The viability of ovarian cancer cells and normal ovarian epithelial cells was evaluated using CCK8 assays to determine the effect of Kirenol. Following in vitro tests, cell colony formation, wound healing, flow cytometry, and Western blotting were conducted to assess its impact on cell proliferation, metastasis, apoptosis, and the cell cycle.

Results: Kirenol significantly reduced the viability of ovarian cancer cells (SKOV3 and A2780) compared to normal ovarian epithelial cells (IOSE-80). Moreover, Kirenol efficiently suppressed the growth and movement, caused a cell cycle halt, and stimulated programmed cell death in SKOV3 and A2780 cells. Through molecular analysis, it was observed that Kirenol increased the expression of Bax while decreasing the expression of MMP2, MMP9, and Bcl-2. It also attenuated the phosphorylation of PI3K, AKT, and RB and downregulated CDK4 and CCND1 expression. Notably, co-treatment with the PI3K pathway inhibitor LY294002 enhanced the inhibitory effect of Kirenol on ovarian cancer cells.

Conclusion: In summary, the combined results of our network pharmacology analysis and in vitro tests emphasized that Kirenol hinders the growth of ovarian cancer cells, causes cell cycle arrest, enhances apoptosis, and hampers migration, possibly by regulating the PI3K/AKT/CDK4 signaling pathway.

Keywords: Kiren; PI3K/AKT/CDK4; apoptosis; cell cycle; metastasis.; ovarian carcinoma.