Onvansertib介导的PLK1抑制降低神经母细胞瘤细胞的活力

Background: Neuroblastoma is the most common extracranial solid tumor of childhood and accounts for a significant proportion of pediatric cancer-related mortality. Despite advances in multimodal therapy including intensive chemotherapy, radiotherapy, stem cell transplantation, patients with high-risk disease continue to experience poor long-term survival. Consequently, there is an urgent need for rationally designed targeted therapies that selectively impair oncogenic proliferation while minimizing systemic damage. Polo-like kinase 1 (PLK1), a serine/threonine kinase essential for mitotic entry, spindle assembly, chromosome alignment, and cytokinesis, is aberrantly overexpressed in neuroblastoma and contributes to unchecked cell-cycle progression and evasion of apoptotic cues. Onvansertib, a highly selective PLK1 inhibitor, has emerged as a promising therapeutic candidate due to its ability to disrupt mitotic fidelity and induce programmed cell death. Method: In this study, we evaluated the therapeutic potential of Onvansertib across multiple neuroblastoma cell lines using cell viability assays and molecular analyses. CCK-8 assays demonstrated a clear dose-dependent decrease in cell viability following 24-72 hours of treatment, indicating significant suppression of proliferation. To uncover the mechanisms underlying reduced viability, we conducted Western blot analyses assessing markers of DNA damage, apoptosis and cell-cycle disruption. Results: Onvansertib treatment resulted in substantial downregulation of PLK1 protein levels, consistent with effective pathway inhibition. Concurrently, we observed increased phosphorylation of H2AX, a hallmark of double-strand DNA breaks, indicating activation of DNA damage responses. Apoptotic signaling was strongly induced, as evidenced by elevated levels of cleaved PARP and cleaved caspase-3 across cell lines. Additionally, decreased phosphorylation of Cdc25c, a downstream regulator of mitotic entry, further supported disruption of normal mitotic progression. Conclusion: Together, these findings demonstrate that Onvansertib effectively compromises neuroblastoma cell survival through a multifaceted mechanism involving mitotic disruption, DNA damage accumulation and apoptotic activation. By targeting a fundamental regulator of the cell cycle, PLK1 inhibition represents a compelling therapeutic strategy for high-risk neuroblastoma. These data support further exploration of Onvansertib in preclinical models and provide a strong rationale for its advancement toward clinical evaluation in this very prevalent malignancy.