| Role of Oxidative Stress in Killing of Cancer Cells | |
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| Normal cells usually function under a low and steady level of oxidative stress. They have a strong anti-oxidant capacity which protects them against prolonged and excessive levels of reactive oxygen species (ROS). Cancer cells operate at a much higher level of oxidative stress than normal cells and have a greatly reduced anti-oxidant capacity. This diminished capacity to clear ROS makes them susceptible to further increases in oxidative stress. When ROS levels exceed a natural limit, mitochondria program the cell to die by apoptosis. The diminished anti-oxidant capacity of cancer cells, relative to normal cells, makes them vulnerable to agents that increase ROS levels beyond their limit. To date, we are unaware of any drugs that have been approved whose primary mechanism of action is based on making cancer cells more sensitive to oxidative stress. Sulindac in Combination with Oxidative Stress (Peroxide) has an Enhanced and Selective Anti-Cancer Effect Dr. Herbert Weissbach and colleagues from our group have discovered that the anti-cancer effect of our lead candidate, sulindac, proceeds by sensitizing the cancer cells to oxidative stress. Sulindac is an FDA-approved drug (marketed as Clinoril by Merck) that has been widely used in patients with arthritis since the 1970s. Unexpectedly, about 10 years ago, it was found to have anti-cancer effects. Our research shows that the combination of sulindac and an oxidizing agent, such as hydrogen peroxide, will act synergistically and selectively to target and kill cancer cells while exhibiting a protective effect on normal cells. This effect occurs at concentrations of sulindac and hydrogen peroxide that individually have little or no activity directed against cancer cells. Thus, this drug combination can be useful for the treatment of cancer and precancerous conditions such as actinic keratoses (AKs) of the skin. A skin cream has been developed and used in a human clinical trial to treat skin cancer and AKs that effectively removes the skin growths while having no effect on the surrounding normal skin.  |  |