NSC606985 induces apoptosis, exerts synergistic effects with cisplatin, and inhibits hypoxia-stabilized HIF-1alpha protein in human ovarian cancer cells

Abstract

The camptothecins, which target the intranuclear enzyme topoisomerase I, have advanced to the forefront of several areas of developmental chemotherapy of cancers. In the present study, we investigated the potential anti-human ovarian cancer effects of NSC606985, a novel and rarely studied camptothecin analog, and its combination with cisplatin (CDDP). Human ovarian cancer cell line COC1 cells were treated with different nanomolar of NSC606985 with or without CDDP, and cell growth and apoptosis were evaluated, respectively, by MTT assay and annexin-V assay on flow cytometry. Chou-Talalay analysis was used to evaluate combined effect of NSC606985 and CDDP. Western blot was used to detect protein kinase Cdelta (PKCdelta), caspase-3 and hypoxia-inducible factor-1alpha (HIF-1alpha) proteins. Our results showed that NSC606985 at nanomolar concentration induced apoptosis with the activation of PKCdelta in COC1 cells. Especially, NSC606985 presented the significant combined effects on COC1 cells in terms of growth inhibition and apoptosis induction. In addition, NSC606985 significantly antagonized the accumulation of HIF-1alpha stabilized by hypoxia or hypoxia-mimetic agent. These results suggest that NSC606985 and its combination with CDDP present the therapeutic potential on ovarian cancer, and deserve further preclinical and clinical studies.