The Effect of Indomethacin on the Cytotoxicity of Phenylboronic Acid Nitrogen Mustards in Triple Negative Breast Cancer
Mentor 1
Xiaohua Peng
Start Date
28-4-2023 12:00 AM
Description
Triple Negative Breast Cancer (TNBC) lacks hormonal receptors such as progesterone, estrogen receptors, and human epidermal growth factor (HER2 protein). TNBC is unaffected by hormonal treatments that target these three growth factors. After diagnosis, there is less time treat TNBC than other breast cancers. TNBC showed poorest prognosis among all types of breast cancer. Therefore, there is an urgent need for a better understanding of TNBC and development of better treatment options. Our previous study showed that the phenylboronic acid nitrogen mustard prodrug, FAN-NM-CH3 is effective in reducing tumor sizes without obvious toxicity due to the prodrug’s enhanced activity in the presence of hydrogen peroxide (H2O2). This prodrug is initially inactive but can be converted into an active species upon metabolism in cancer cells with high level of H2O2. Many TNBC cells are under oxidative stress and produced high level of reactive oxygen species (ROS), such as H2O2 that can act as a target for developing cancer-specific therapy for TNBC treatment. We propose that these issues can be resolved by combining ROS-activated prodrugs with the agents that can create H2O2 selectively in cancer cells. Indomethacin is a ROS generating NSAID (non-steroidal anti-inflammatory drug), which can produce ROS selectively in cancer cells. Thus, we expect that combination of indomethacin and ROS-activated prodrugs can enhance the anticancer efficacy and selectively, therefore reducing the effective drug doses, minimizing off target effects. My work is focusing on investigation of the cytotoxicity of indomethacin and its combination with FAN-NM-CH3 in TNBC cells and its correlation with ROS levels. We determined the optimum doses of indomethacin to improve the efficacy of the prodrug by cytotoxicity assays. The use of a lower dose of the prodrug would minimize any adverse effects that may result from the chemotherapy.
The Effect of Indomethacin on the Cytotoxicity of Phenylboronic Acid Nitrogen Mustards in Triple Negative Breast Cancer
Triple Negative Breast Cancer (TNBC) lacks hormonal receptors such as progesterone, estrogen receptors, and human epidermal growth factor (HER2 protein). TNBC is unaffected by hormonal treatments that target these three growth factors. After diagnosis, there is less time treat TNBC than other breast cancers. TNBC showed poorest prognosis among all types of breast cancer. Therefore, there is an urgent need for a better understanding of TNBC and development of better treatment options. Our previous study showed that the phenylboronic acid nitrogen mustard prodrug, FAN-NM-CH3 is effective in reducing tumor sizes without obvious toxicity due to the prodrug’s enhanced activity in the presence of hydrogen peroxide (H2O2). This prodrug is initially inactive but can be converted into an active species upon metabolism in cancer cells with high level of H2O2. Many TNBC cells are under oxidative stress and produced high level of reactive oxygen species (ROS), such as H2O2 that can act as a target for developing cancer-specific therapy for TNBC treatment. We propose that these issues can be resolved by combining ROS-activated prodrugs with the agents that can create H2O2 selectively in cancer cells. Indomethacin is a ROS generating NSAID (non-steroidal anti-inflammatory drug), which can produce ROS selectively in cancer cells. Thus, we expect that combination of indomethacin and ROS-activated prodrugs can enhance the anticancer efficacy and selectively, therefore reducing the effective drug doses, minimizing off target effects. My work is focusing on investigation of the cytotoxicity of indomethacin and its combination with FAN-NM-CH3 in TNBC cells and its correlation with ROS levels. We determined the optimum doses of indomethacin to improve the efficacy of the prodrug by cytotoxicity assays. The use of a lower dose of the prodrug would minimize any adverse effects that may result from the chemotherapy.
