APG-115 synergizes with bortezomib to induce apoptosis in cervical cancer cells.

Abstract

Despite significant advancements in vaccination, screening, and therapeutic strategies have substantially reduced cervical cancer incidence, effective treatment for this disease remains a major clinical challenge. This study reveals that APG-115, a murine double minute 2 (MDM2) inhibitor, upregulates the transcription and expression of MDM2, p53, and p21, effectively inhibiting cell proliferation and inducing apoptosis in cervical cancer cells. Mechanistically, APG-115 suppresses the activation of the AKT and ERK signaling pathways and reduces the expression of antiapoptotic proteins BCL-2, BCL-xL, and MCL-1, while promoting the expression of pro-apoptotic proteins BAK, BAX, and BIM. Notably, the combination of APG-115 with bortezomib enhances p53 and p21 expression, synergistically induces cell apoptosis. In the cervical cancer xenograft models, APG-115 and bortezomib significantly downregulated the expression of Ki67 and BCL-2 while markedly increasing p21 protein levels, effectively suppressing tumor growth and inducing apoptosis. The combination further amplified the effects on Ki67, BCL-2, and p21 expression, leading to enhanced tumor growth inhibition. In summary, this study demonstrates that APG-115 exerts antitumor effects in cervical cancer, and its combination with bortezomib further enhances this inhibitory effect, probably through maximal activation of p53 and inhibition of BCL-2, suggesting a potential application of APG-115 in the treatment of cervical cancer.