Repurposing colforsin daropate to treat MYC-driven high-grade serous ovarian carcinomas
High-grade serous ovarian cancer (HGSOC) is one of the deadliest cancers for women, with a low survival rate, no early markers, a high rate of recurrence, and few therapeutic options. Forskolin, an activator of cyclic AMP signaling, has several anticancer activities, including against HGSOC, but has limited use in vivo. Its water-soluble derivative, colforsin daropate, has the same mechanism of action as forskolin and is used to treat acute heart failure. Here, we investigated the potential of colforsin daropate as a treatment for HGSOC. We found that colforsin daropate induced cell cycle arrest and apoptosis in cultured HGSOC cells and spheroids, but not in normal fallopian tube secretory cells and ovarian surface epithelial cells. Colforsin daropate also prevented HGSOC cells from invading ovarian surface cell layers in culture. In vivo, colforsin daropate reduced tumor growth, synergized with cisplatin (a standard chemotherapy in ovarian cancer care), and improved host survival in a subcutaneous xenograft model. These anti-tumor effects of colforsin daropate were mediated in part by its reduction in the abundance and transcriptional activity of the oncoprotein c-MYC, which is often increased in HGSOC. Our findings demonstrate that colforsin daropate may be a promising therapeutic that could be combined with conventional therapies to treat HGSOC. Overall design: To investigate the effects of colforsin daropate on HGSOC, HEYA8 ovarian cancer cells were treated with either vehicle, 1 uM colforsin daropate, 5 uM colforsin daropate, or 10 uM colforsin daropate for 48 hr. We then performed gene expression profiling analysis using data obtained from RNAseq of N=3 biological replicates for each HEYA8 cell treatment condition.