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

Abstract

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 hormonerefractory 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 signalregulated 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]

CXCR3-B Can Mediate Growth-inhibitory Signals in Human Renal Cancer Cells by Down-regulating the Expression of Heme Oxygenase-1

“…On the other hand, it has been demonstrated that HO-1 is overexpressed in different types of human tumors (27)(28)(29), and this enzyme can facilitate tumor progression through different mechanism(s). It has been suggested that HO-1 may be used as one of the potential targets in antitumor therapy to increase the level of ROS within the tumor and promote effective killing of the tumor cells (30,32). Many antitumor agents, such as vinblastine, cisplatin, mitomycin C, doxorubicin, camptothecin, inostamycin, and neocarzinostatin, exhibit antitumor activity via ROS-dependent activation of apoptotic cell death (37).…”

Heme Oxygenase-1 Promotes Survival of Renal Cancer Cells through Modulation of Apoptosis- and Autophagy-regulating Molecules

“…Revelation of its effects on tumor growth and metastasis has undoubtedly increased the significance of HO-1 in the field of cancer biology. Many studies have targeted inhibition of this enzyme as an approach to sensitize cancer cells to therapies (14,17).…”

Structural insights into human heme oxygenase-1 inhibition by potent and selective azole-based compounds

“…As such, we have concluded that this class of azole-based HO-1 inhibitors, originally derived from azalanstat, inhibit heme oxidation through a non-competitive, yet heme-dependent, mechanism by disrupting the ordered solvent structure integral to the critical hydrogen-bond network involving Asp140 and displacing the catalytically critical distal water ligand. Moreover, from a physiological point of view, this inhibitory mechanism has already demonstrated potential therapeutic applications as some of our imidazole-based HO-1 inhibitors have shown the ability to attenuate the growth of prostate [89] and breast cancer cells in vivo. The relevance of HO in various experimental situations has been explored by other laboratories through administration of these novel imidazole-based drugs to both cultured cells and intact animals.…”