Nitrogen mustard containing compound are known well-known for their high reactivity towards different types of cancers. This reactivity also introduces a higher risk of off-targets and lower selectivity. Using the unique oxidative stress environment of tumors to chemically convert boronic acid derivatives into active nitrogen mustards represents a tissue-specific cancer therapy with reduced adverse effects. Recently, we have reported a potent and selective drug candidate, which is effective in vivo against MDA-MB-468 derived triple negative breast cancer tumor in xenograft mice model. The prodrug FAN-NM-CH3 can be activated in vitro by H2O2 leading to formation of active nitrogen mustards that alkylate DNA. Compound FAN-NM-CH3 was 10 times more cytotoxic than chlorambucil and 16 times more active than melphalan, which are known for their lowest-limiting toxicity within its class of compounds. A combination strategy to enhance H2O2 levels using ascorbic acid was implemented that further improved cytotoxicity 3-folds and lowers drug dose to highest safest dose that inhibits cancer cell growth by 90%. These findings pave the way to investigate the potential of ROS-activated drugs in combination therapy. Although the exact mechanism of its superior activity and selectivity in vivo is yet to be determined. In this work, we measure extracellular H2O2 production level in MDA-MB-468 cells, evaluate effects of ROS quencher/enhancer on prodrug toxicity to define correlation between H2O2 level and efficacy. Additionally understand drug’s mechanism of action as a DNA alkylating agent through evaluation of gene expression.

Reactive oxygen species (ROS) mediated prodrugs: mechanism and combination strategy.

Fall 2022 abstracts, posters, and presentations will launch in mid-September.

ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.