Abstract C41: Heme oxygenase‐1 and carbon monoxide modulate responses to DNA damage in prostate cancer

Heme oxygenase (HO) and carbon monoxide (CO), a product of HO activity generated during heme catalysis, exert differential effects on the apoptotic response dependently on the environmental milieu and cell types involved. The role of HO‐1 and CO in modulating chemotherapeutic treatment in prostate cancer has not been tested. Our focus in this work explored the role of HO‐1 and CO in modulating PCa cell death via DNA damage mechanisms. We examined HO‐1 expression in PCa samples from 482 patients and found strong nuclear staining in moderately differentiated tumors (Gleason grade 3). Treatment of PCa cells with the chemotherapeutic agents, camptothecin or doxorubicin increased HO‐1 activity in the cytosol, which correlated with increased cell death. Nuclear translocation of HO‐1 resulted in decreased enzymatic activity. Low activity of HO‐1 in the nucleus may confer resistance to chemotherapy due to the antiapoptotic effects of HO‐1. Overexpression of cytosolic and active HO‐1 or exogenous delivery of CO at low non‐toxic concentrations (250 parts per million) in combination with a chemotherapeutic led to enhanced tumor cell death via caspase‐3 activation. CO exposure of mice with established PC3 xenografts delayed tumor growth via accelerated apoptosis (TUNEL staining) and mitotic catastrophe of cancer cells as well as strong inhibition of angiogenesis (CD31 staining). Further, CO sensitized tumors to doxorubicin treatment with enhanced apoptosis and blockage of mitosis. In contrast, CO blocked chemotherapeutic‐induced cell death in normal cells supporting a new function for HO‐1/CO as cellular sensors of DNA damage. Taken together, our data demonstrate the importance of cellular localization of HO‐1 in PCa progression and importantly that CO, in part regulates cellular sensitivity to DNA damaging agents. We propose a novel strategy to overcome resistance to chemotherapy as well as reducing the chemotherapeutic burden by employing CO at safe, non‐toxic concentrations that permits preservation of normal cells and tissue. Citation Information: Cancer Res 2009;69(23 Suppl):C41.