Effective sequential combined therapy with carboplatin and a CDC7 inhibitor in ovarian cancer
**Background:** DNA damage repair enhancement is a key mechanism contributing to platinum resistance. The cell division cycle 7 (CDC7) protein, a conserved serine/threonine kinase, plays a critical role in initiating DNA replication and has been linked to chemotherapy resistance in ovarian cancer. However, the potential antitumor effects of the CDC7 inhibitor XL413 against ovarian cancer and its impact on chemosensitivity remain unclear.
**Methods:** The antitumor activity of combining carboplatin with XL413 was evaluated both in vitro and in vivo in ovarian cancer models. Experiments assessed cell viability, colony formation, and apoptosis. Key molecules involved in DNA repair and damage responses were examined. The combined effects of carboplatin and XL413 were further tested in SKOV-3 and OVCAR-3 xenografts using subcutaneous and intraperitoneal tumor models.
**Results:** Sequential administration of XL413 following carboplatin treatment significantly inhibited cell proliferation and induced apoptosis in ovarian cancer cells. Compared to carboplatin alone, the combination treatment led to a marked reduction in RAD51 expression and an increase in γH2AX expression. This sequential combination also significantly suppressed tumor growth in both subcutaneous and intraperitoneal xenograft models, with reduced levels of RAD51 and Ki67 and elevated γH2AX expression observed.
**Conclusions:** Administering the CDC7 inhibitor XL413 after carboplatin enhances the chemotherapeutic efficacy of carboplatin in ovarian cancer cells. This effect may be attributed to XL413’s ability to amplify chemotherapy-induced DNA damage by inhibiting homologous recombination repair.