Ailanthone as a novel AKT1 inhibitor that induces mitochondrial apoptosis and exerts anti-tumor activity in cervical cancer

Background: As a significant global burden on women’s health, cervical cancer necessitates the exploration of novel therapeutic strategies driven by the limitations inherent in the current treatment options. Ailanthone (AIL), a natural compound derived from Ailanthus altissima, has significant inhibitory effects against various tumor types. However, its function in cervical cancer and associated molecular mechanisms are yet to be elucidated.

Methods: We evaluated the antitumor activity of AIL in cervical cancer through a series of in vitro cellular experiments using the human cervical cancer cell line HeLa and in vivo animal models using female BALB/c mice. We also investigated the mechanism of action by using network pharmacology and molecular docking techniques. Cellular Thermal Shift Assay (CETSA) was then performed to validate the findings.

Results: The in vitro experiments conducted in HeLa cells have shown that AIL effectively suppressed the proliferative, migratory, and invasive capacities of HeLa cells. Furthermore, it triggered cell cycle arrest in the G0/G1 phase and promoted apoptosis. Xenograft models in nude mice further confirmed the potent inhibitory effects of AIL on tumor growth. Network pharmacology and molecular docking techniques predicted the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT) signaling pathway as a potential key pathway and identified AKT1 as a core target protein. The CETSA demonstrated that, under gradually increasing temperature, the thermal stability of AKT1 in the AIL-treated group was stronger than that in the dimethyl sulfoxide-treated control group, verifying the previous prediction.

Conclusions: Our findings from the cervical cancer cell model indicate that the anti-tumor effect of AIL against cervical cancer may be dependent on AKT1 protein regulation and intracellular apoptotic pathway activation.