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.
Kaweesa et al. (Mon,) studied this question.