Abstract
Epithelial ovarian carcinoma is the most lethal gynecological cancer due to its silent onset and recurrence with resistance to chemotherapy. Overexpression of oncogene c-Myc is one of the most frequently encountered events present in ovarian carcinoma. Disrupting the function of c-Myc and its downstream target genes is a promising strategy for cancer therapy. Our objective was to evaluate the potential effects of small-molecule c-Myc inhibitor, 10058-F4, on ovarian carcinoma cells and the underlying mechanisms by which 10058-F4 exerts its actions. Using MTT assay, colony formation, flow cytometry and Annexin V FITC assays, we found that 10058-F4 significantly inhibited cell proliferation of both SKOV3 and Hey ovarian cancer cells in a dose dependent manner through induction of apoptosis and cell cycle G1 arrest. Treatment with 10058-F4 reduced cellular ATP production and ROS levels in SKOV3 and Hey cells. Consistently, primary cultures of ovarian cancer treated with 10058-F4 showed induction of caspase-3 activity and inhibition of cell proliferation in 15 of 18 cases. The response to 10058-F4 was independent the level of c-Myc protein over-expression in primary cultures of ovarian carcinoma. These novel findings suggest that the growth of ovarian cancer cells is dependent upon c-MYC activity and that targeting c-Myc-Max heterodimerization could be a potential therapeutic strategy for ovarian cancer.
Highlights
Among gynecologic cancers worldwide, epithelial ovarian carcinoma is the leading cause of death and the fifth most frequent cause of cancer related death across all cancers in women in the United States
This study provides cellular and molecular evidence for the impact of 10058-F4 on ovarian carcinoma cells through its inhibition of cell proliferation, and the induction of apoptosis and cell cycle arrest, and it offers the targeting of the c-Myc-Max interaction as a potential and viable strategy in ovarian cancer chemotherapy
10058-F4 induces apoptosis To verify that 10058-F4 treatment inhibits cell proliferation by inducing apoptosis, we investigated apoptotic cells by applying an Annexin-V and propidium iodide (PI) double staining assay after a 24 hours treatment
Summary
Epithelial ovarian carcinoma is the leading cause of death and the fifth most frequent cause of cancer related death across all cancers in women in the United States. Platinum/taxane chemotherapy and cytoreductive surgery have proven effective as primary treatments in patients with advanced stage ovarian carcinoma, with a positive initial response in approximately 75-80% of Genetic alterations and deregulation of oncogene and tumor suppressor gene expressions are known to correlate with and promote the carcinogenesis of ovarian carcinoma. Deregulation of the expression of oncogene cMyc is one of the most frequently encountered events present in epithelial ovarian carcinoma [4]. The transcriptionally active c-Myc-Max dimer promotes proliferation, cell adhesion, apoptosis, and angiogenesis in cancer cells through its control on the transcription of Myc target genes [5,6]. Small-molecule c-Myc inhibitor, 10058-F4, is a cell-permeable thiazolidinone that disrupts the formation and function of the c-Myc-Max heterodimer and prevents transactivation of c-Myc target genes [7]. Understanding the molecular mechanisms of 10058-F4 in ovarian carcinoma cells may facilitate the development of improved therapeutic strategies for ovarian carcinoma
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