Modified peroxamide-based reactive oxygen species (ROS)-responsive doxorubicin prodrugs

Reactive oxygen species (ROS) plays a pivotal physiological role in intracellular signaling of any living organism. Due to the elevated levels of ROS in tumor microenvironment than normal tissues, an increasing number of ROSresponsive probes and prodrugs is being studied for the fight against cancer. This study describes the design and synthesis of a panel of novel modified peroxamide-based ROS-responsive prodrugs of doxorubicin, among which the OH-mOX-Dox prodrug showed very stable and highly specific ROS sensitivity. This novel Dox prodrug exerted potent anti-proliferation effects against the two breast cancer cell lines of MDA-MB-468 and MDA-MB231 while it showed minimal toxicity toward the normal breast cell line, MCF-12A. The cytotoxicity of the OH-mOX-Dox prodrug was significantly enhanced at elevated ROS levels after co-incubation with L-buthionine sulfoximine (BSO). Our clonogenic assay data validated that enhanced intracellular ROS level upon X-ray irradiation resulted in an increase in the efficacy of the OH-mOX-Dox prodrug against the two breast cancer cell lines.

Automated summary

ROS plays a crucial role in intracellular signaling and is elevated in tumor microenvironment. This study developed a series of novel ROS-responsive prodrugs of doxorubicin, among which the OH-mOX-Dox prodrug showed potent anti-proliferation effects against breast cancer cells with minimal toxicity towards normal cells. Enhanced cytotoxicity of OH-mOX-Dox prodrug was observed at elevated ROS levels, especially when co-incubated with BSO. Clonogenic assay validated the increased efficacy of OH-mOX-Dox prodrug against breast cancer cells with enhanced intracellular ROS levels after X-ray irradiation.