Activity of Didesmethylrocaglamide in High Grade Serous Ovarian Cancer Using Preclinical In Vitro and In Vivo Models

Area of Science:

• Oncology
• Pharmacology
• Natural Products Chemistry

Background:

• High-grade serous ovarian cancer (HGSOC) is a leading cause of cancer death in women.
• Chemoresistance is a major challenge in treating HGSOC, necessitating novel therapeutic approaches.
• Rocaglamides are natural products with protein translation inhibitory and apoptosis-inducing properties.

Purpose of the Study:

• To synthesize and evaluate the cytotoxicity of didesmethylrocaglamide ((±)-DDR) and related derivatives against HGSOC.
• To assess the potential of (±)-DDR as a treatment for both drug-sensitive and drug-resistant ovarian cancer.
• To investigate the in vivo efficacy of the more potent enantiomer of (±)-DDR.

Main Methods:

• Synthesis of (±)-DDR and derivatives (±)-DDR01, (±)-DDR03, (±)-DDR04.
• In vitro cytotoxicity assays using HGSOC cell lines, including cisplatin- and paclitaxel-resistant models.
• Caspase-3 activation assays to confirm apoptosis induction.
• Enantiomeric evaluation of (±)-DDR's potency.
• In vivo efficacy study using an OVCAR8 xenograft mouse model.

Main Results:

• (±)-DDR demonstrated significant cytotoxicity in ovarian cancer cell lines within 24 hours.
• (±)-DDR induced apoptosis, evidenced by caspase-3 activation.
• (±)-DDR was effective against cisplatin-resistant (PE04) and paclitaxel-resistant (MCF7-ADR/OVCAR8-RES) cell lines.
• The minus enantiomer ((-)-DDR) was approximately 18-fold more potent than the plus enantiomer in OVCAR8 cells.
• (-)-DDR treatment led to a reduction in tumor burden in the OVCAR8 xenograft mouse model.

Conclusions:

• (±)-DDR exhibits potent and rapid cytotoxicity against HGSOC cell lines.
• (±)-DDR overcomes chemoresistance to cisplatin and paclitaxel.
• The potent minus enantiomer, (-)-DDR, warrants further investigation as a novel therapeutic agent for HGSOC.
• Didesmethylrocaglamide derivatives represent a promising new strategy for treating ovarian cancer, including resistant forms.