Activity of Didesmethylrocaglamide in High Grade Serous Ovarian Cancer Using Preclinical In Vitro and In Vivo Models
High grade serous ovarian cancer (HGSOC) is the most lethal gynecological cause of death in women and requires new treatments to help tackle chemoresistance. Rocaglamides, a promising class of anticancer natural products, function as protein translation inhibitors and trigger apoptosis in other types of solid tumors. Didesmethylrocaglamide ((±)-DDR), a derivative of rocaglamide with potent antitumor activity, was synthesized, including three additional rocaglamide derivatives, (±)-DDR01, (±)-DDR03, and (±)-DDR04, to evaluate their cytotoxicity in HGSOC. Using in vitro models, it was determined that (±)-DDR induced cytotoxicity in ovarian cancer cell lines as early as 24 h after application and activated caspase-3, indicating pro-apoptotic activity. In addition, (±)-DDR was cytotoxic in the PE04 and MCF7-ADR (OVCAR8-RES) cell lines that are resistant to cisplatin and paclitaxel, respectively. Evaluation of each enantiomer revealed the minus enantiomer to be ∼18-fold more potent compared to the plus enantiomer in the OVCAR8 cell line. (-)-DDR was further evaluated using an OVCAR8 xenograft model in mice, and a reduction in tumor burden was observed. Its effective cytotoxicity in drug-sensitive and -resistant cell models suggests that (±)-DDR and its corresponding minus enantiomer may have potential as a new therapeutic strategy against HGSOC.