BACKGROUND: Actinic keratoses (AKs) are a precancerous condition of the skin that have the potential to become squamous cell cancer (SCC). Sulindac is a Food and Drug Administration (FDA)-approved nonsteroidal anti-inflammatory drug (NSAID) that has been shown to have clinically significant anticancer effects. Malignant cells may have a different response to oxidative stress than normal cells. OBJECTIVE: To establish a role of increased reactive oxygen species (ROS) in the mechanism of cancer killing by sulindac in the presence of an oxidizing agent. To assess the tolerability and efficacy of the combination of gels containing sulindac and hydrogen peroxide in the treatment of patients with AKs. METHODS: Cell culture studies were performed using a skin SCC cell line and normal human epidermal keratinocytes. After treatment with sulindac and an oxidizing agent, cell viability, and intracellular ROS levels were measured. An open-label clinical trial was performed using sulindac and hydrogen peroxide gels daily for 3 weeks on AKs involving the upper extremities. RESULTS: In SCC cells, a combination of sulindac and an oxidizing agent lead to 400 to 500% increases in intracellular ROS, which resulted in significant cell death. In sharp contrast, normal keratinocytes did not show increases in ROS levels and were not killed. A clinical trial using the combination of sulindac and hydrogen peroxide therapy in 5 patients with AKs revealed that 60% of the treated AKs responded and 50% showed no residual AK on histopathology specimens after skin biopsy. LIMITATIONS: The small number of patients and the lack of a placebo group. CONCLUSION: Increased levels of ROS appear to be important in the selective killing of cancer cells in the presence of sulindac and oxidizing agents. Further studies are necessary to define the role of the combination of sulindac and oxidizing agent therapy in patients with AKs and skin cancer.
BACKGROUND: Actinic keratoses (AKs) are a precancerous condition of the skin that have the potential to become squamous cell cancer (SCC). Sulindac is a Food and Drug Administration (FDA)-approved nonsteroidal anti-inflammatory drug (NSAID) that has been shown to have clinically significant anticancer effects. Malignant cells may have a different response to oxidative stress than normal cells. OBJECTIVE: To establish a role of increased reactive oxygen species (ROS) in the mechanism of cancer killing by sulindac in the presence of an oxidizing agent. To assess the tolerability and efficacy of the combination of gels containing sulindac and hydrogen peroxide in the treatment of patients with AKs. METHODS: Cell culture studies were performed using a skin SCC cell line and normal human epidermal keratinocytes. After treatment with sulindac and an oxidizing agent, cell viability, and intracellular ROS levels were measured. An open-label clinical trial was performed using sulindac and hydrogen peroxide gels daily for 3 weeks on AKs involving the upper extremities. RESULTS: In SCC cells, a combination of sulindac and an oxidizing agent lead to 400 to 500% increases in intracellular ROS, which resulted in significant cell death. In sharp contrast, normal keratinocytes did not show increases in ROS levels and were not killed. A clinical trial using the combination of sulindac and hydrogen peroxide therapy in 5 patients with AKs revealed that 60% of the treated AKs responded and 50% showed no residual AK on histopathology specimens after skin biopsy. LIMITATIONS: The small number of patients and the lack of a placebo group. CONCLUSION: Increased levels of ROS appear to be important in the selective killing of cancer cells in the presence of sulindac and oxidizing agents. Further studies are necessary to define the role of the combination of sulindac and oxidizing agent therapy in patients with AKs and skin cancer.
Authors: Anindita Das; David Durrant; Clint Mitchell; Eric Mayton; Nicholas N Hoke; Fadi N Salloum; Margaret A Park; Ian Qureshi; Ray Lee; Paul Dent; Rakesh C Kukreja Journal: Proc Natl Acad Sci U S A Date: 2010-09-30 Impact factor: 11.205