Abstract LB-358: Heme oxygenase-1 and carbon monoxide arrest tumor growth via modulation of cellular respiration

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Heme oxygenase-1 (HO-1) and carbon monoxide (CO) are endogenous cytoprotective molecules yet their role in tumor growth, metastasis, cell death and DNA damage has not been elucidated. HO-1 expression was assessed in prostate cancer biopsies from 482 patients and strong nuclear staining, indicative of loss of enzymatic activity was observed in moderately differentiated tumors. Employing prostate cancer (PCa) as our model we treated PCa cells with the chemotherapeutics camptothecin or doxorubicin and observed an increase in cytosolic HO-1 activity that correlated with increased cell death. Overexpression of HO-1 or exogenous pretreatment with CO increased tumor cell sensitivity to chemotherapeutics one thousand fold. In contrast, CO blocked chemotherapeutic-induced cell death of normal prostate epithelial cells. In vivo, CO exposure of mice with established PC3 xenografts resulted in complete growth arrest and sensitization of tumors to doxorubicin with mitotic blockade and enhanced apoptosis of the tumor cells. Exposure to CO showed similar effects in a model of PC3 orthotopic tumors with significant inhibition in markers of invasion. Further, CO blocked development of PIN and prostate tumors in the model of TRAMP mice with concomitant targeting of mitochondria. Further, CO inhibited growth of lung adenocarcinoma in the inducible KRas model of carcinogenesis. Collectively, our data demonstrate the importance of cellular localization of HO-1 in human PCa progression and importantly that CO in part, regulates cellular sensitivity to DNA damaging agents and offers a novel therapeutic adjuvant for the treatment of cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-358. doi:1538-7445.AM2012-LB-358