Project summary/abstract
Cancer cells are in a state of increased basal oxidative stress due to their aberrant growth. As a
result, cancer cells have elevated levels of reactive oxygen species (ROS) compared to normal
cells. This feature has been employed to develop a class of ROS-activated prodrugs that only
become cytotoxic in the presence of ROS. The effectiveness of ROS-activated prodrugs as
monotherapy for cancer faces many challenges, including tumor heterogeneity, insufficient
prodrug activation, difficulty in targeted drug delivery, lack of therapeutic durability, etc. Novel
strategies are urgently needed to augment the efficacy and selectivity of ROS-activated prodrugs
to a wide variety of cancer. The H2O2-activated DNA alkylating agents developed by our group
exhibit selective toxicity towards cancer cells under oxidative stress but not normal cells,
suggesting their potential usage in combination with reagents or cancer therapies that amplify
ROS level specially in cancer cells. It has been reported that prooxidants such as vitC can act as
potent pro-oxidants to induce H2O2 specifically in cancer cells while normal cells are protected
due to higher Catalase expression that quenches H2O2. The non-toxic feature of the H2O2-
activated DNA cross-linking agents developed in our lab, together with the findings showing that
vitC selectively intensify H2O2 accumulation in cancer cells, provides a compelling rationale for
combining these two therapeutic modalities in a synergistic manner. The overarching hypothesis
of this project is that the combination of selected pro-oxidants with ROS-activated prodrugs can
achieve synergistic and durable antitumor effects while minimizing unwanted side-effects.
Specifically, we will develop novel ROS-activated anticancer prodrugs with improved tumor
specificity and drug like property (Aim 1), and identify ROS-activated prodrugs that synergize with
pro-oxidants to improve the efficacy of ROS-activated prodrugs (Aim 2). The significance of this
project is that targeting tumor redox through the combination of ROS-activated prodrugs and
prooxidants represents an effective cancer treatment strategy. The proposed research will identify
clinically applicable ROS-activated prodrugs that are compatible with prooxidant to confer
efficacious, selective, and durable therapeutic benefits. Successful completion of the project will
pave the way for repurposing ROS-activated DNA alkylating agents for cancer treatment.