Margaret Briehl

My laboratory's research objective is to elucidate relationships between oxidative stress and disease processes, particularly cancer. Specifically, we are investigating the regulation of apoptosis by the redox state of the cell. Cellular redox state is determined by the sum of prooxidants (e.g., the levels of reactive oxygen species) and antioxidants (e.g., proteins like catalase and small molecules like vitamin E) in the cell. Cancer cells have frequently undergone changes consistent with an altered ability to handle oxidative stress. Genetic differences in proteins that protect cells against oxidative stress have been associated with an increased risk of cancer. Epidemiological studies suggest that a diet rich in fruits and vegetables confers a lower risk of cancer. One idea is that the high antioxidants content of fruits and vegetables is protective, although definitive studies to prove this have not yet been conducted. Another untested idea is that cancer patients should avoid taking antioxidant supplements while undergoing chemotherapy, as the antioxidants may oppose the action of the anticancer drugs. Based on our research with model systems for lymphoma, breast and skin cancer, we have accumulated evidence that a cell's ability to handle oxidative stress does influence its susceptibility to apoptosis. Lymphocytes that have acquired resistance to oxidative stress simultaneously acquire resistance to glucocorticoid-induced apoptosis. The basic metabolism of the resistant cells is also fundamentally altered. These findings clearly have implications for the development and treatment of cancer. They potentially have a broader impact, since dysregulation of apoptosis and cellular redox state are common to other major diseases. We are now working towards determining the mechanism by which an altered cellular redox state contributes to the control of apoptotic signaling and identifying molecules that sense oxidative stress, are involved in the mechanism of apoptosis and may be dysfunctional in cancer cells. Using gene expression and tissue arrays from lymphoma patient samples, we are investigating whether the expression of antioxidant enzymes predicts response to therapy. Understanding how key processes like apoptosis can be affected by resistance to oxidative stress will make an important contribution towards teasing out key relationships between genetics, diet, control of oxidative stress and effective cancer prevention and treatment.