Evaluation of the antitumor effects of c-Myc-Max heterodimerization inhibitor 100258-F4 in ovarian cancer cells

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.

Let-7 Suppresses B Cell Activation through Restricting the Availability of Necessary Nutrients

“…c-Myc in cells (Lucas et al, 2015;Muller et al, 2014;Wang et al, 2014;Zirath et al, 2013). We found that c-Myc inhibition blocked the let-7adf cluster's regulatory effects on the expression of Slc1a5 and Gls ( Figure 6E), and on glutaminolysis, indicated by comparable levels of glutamine consumption and ammonium production in B cells (Figures 6F and 6G).…”

Inhibition of c-Myc by 10058-F4 induces growth arrest and chemosensitivity in pancreatic ductal adenocarcinoma

“…14], the cell viability of both cancer 142 cell lines was reduced after exposure to 10058-F4 for 5 days 143 (Fig. 1B).…”

“…Among all currently available 13 treatments, surgical resection is the option with most potential for 14 cure. However, 80-85% of PDAC patients are unresectable by the 15 time of diagnosis due to aggressive growth, early local invasion and 16…”

Human prostate luminal cell differentiation requires NOTCH3 induction by p38-MAPK and MYC

“…S3B). These doses are at or below common usage for 10058-F4 (Guo et al, 2009;Wang et al, 2014). As an alternative approach, we used JQ-1, a BET bromodomain inhibitor, to block transcription of MYC (Delmore et al, 2011).…”