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A Novel Experimental Heme Oxygenase-1–Targeted Therapy for Hormone-Refractory Prostate Cancer

¹ Lady Davis Institute of Medical Research, Segal Cancer Centre, and Centre for Neurotranslational Research of the Sir Mortimer B. Davis Jewish General Hospital, Department of Medicine, Oncology, and Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada; ² Southern Alberta Cancer Institute, Departments of Pathology & Laboratory Medicine and Oncology, University of Calgary, Calgary, Alberta, Canada; ³ Osta Biotechnologies, Inc., Dollard-des-Ormeaux, Quebec, Canada; and ⁴ Department of Chemistry, Queen's University, Kingston, Ontario, Canada

Requests for reprints: Moulay A. Alaoui-Jamali and Hyman M. Schipper, Lady Davis Institute for Medical Research of the Jewish General Hospital, 3755 Chemin de la Côte-Ste-Catherine, Montreal, Quebec, Canada H3T 1E2. Phone: 514-340-8260 or 8222 Ext. 3438; Fax: 1-514-340-7502; E-mail: moulay.alaoui-jamali{at}mcgill.ca and hyman.schipper{at}mcgill.ca.

Key Words: Prostate cancer • hormone-refractory prostate cancer • heme oxygenase-1 • inhibitor • anti-tumor • anti-metastasis

Heme oxygenase-1 (HO-1), a member of the heat shock protein family, plays a key role as a sensor and regulator of oxidative stress. Herein, we identify HO-1 as a biomarker and potential therapeutic target for advanced prostate cancer (PCA). Immunohistochemical analysis of prostate tissue using a progression tissue microarray from patients with localized PCA and across several stages of disease progression revealed a significant elevation of HO-1 expression in cancer epithelial cells, but not in surrounding stromal cells, from hormone-refractory PCA (HRPCA) compared with hormone-responsive PCA and benign tissue. Silencing the ho-1 gene in HRPCA cells decreased the HO-1 activity, oxidative stress, and activation of the mitogen-activated protein kinase–extracellular signal-regulated kinase/p38 kinase. This coincided with reduced cell proliferation, cell survival, and cell invasion in vitro, as well as inhibition of prostate tumor growth and lymph node and lung metastases in vivo. The effect of ho-1 silencing on these oncogenic features was mimicked by exposure of cells to a novel selective small-molecule HO-1 inhibitor referred to as OB-24. OB-24 selectively inhibited HO-1 activity in PCA cells, which correlated with a reduction of protein carbonylation and reactive oxygen species formation. Moreover, OB-24 significantly inhibited cell proliferation in vitro and tumor growth and lymph node/lung metastases in vivo. A potent synergistic activity was observed when OB-24 was combined with Taxol. Together, these results establish HO-1 as a potential therapeutic target for advanced PCA. [Cancer Res 2009;69(20):8017–24]