Inhibition of heme oxygenase-1 by zinc protoporphyrin IX reduces tumor growth of LL/2 lung cancer in C57BL mice
Kaeko Hirai
Department of Molecular Pathology, Nara Medical University School of Medicine, Kashihara, Japan
Search for more papers by this authorTomonori Sasahira
Department of Molecular Pathology, Nara Medical University School of Medicine, Kashihara, Japan
Search for more papers by this authorHitoshi Ohmori
Department of Molecular Pathology, Nara Medical University School of Medicine, Kashihara, Japan
Department of Food and Nutrition, Okayama Gakuin University, Kurashiki, Japan
Search for more papers by this authorKiyomu Fujii
Department of Molecular Pathology, Nara Medical University School of Medicine, Kashihara, Japan
Search for more papers by this authorCorresponding Author
Hiroki Kuniyasu
Department of Molecular Pathology, Nara Medical University School of Medicine, Kashihara, Japan
Fax: +81-722-25-7308.
Department of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 734-8521, JapanSearch for more papers by this authorKaeko Hirai
Department of Molecular Pathology, Nara Medical University School of Medicine, Kashihara, Japan
Search for more papers by this authorTomonori Sasahira
Department of Molecular Pathology, Nara Medical University School of Medicine, Kashihara, Japan
Search for more papers by this authorHitoshi Ohmori
Department of Molecular Pathology, Nara Medical University School of Medicine, Kashihara, Japan
Department of Food and Nutrition, Okayama Gakuin University, Kurashiki, Japan
Search for more papers by this authorKiyomu Fujii
Department of Molecular Pathology, Nara Medical University School of Medicine, Kashihara, Japan
Search for more papers by this authorCorresponding Author
Hiroki Kuniyasu
Department of Molecular Pathology, Nara Medical University School of Medicine, Kashihara, Japan
Fax: +81-722-25-7308.
Department of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 734-8521, JapanSearch for more papers by this authorAbstract
Heme oxygenase (HO)-1 is a key player reducing cytotoxicity and enhancing protumoral effects of nitric oxide (NO). We examined zinc protoporphyrin (ZnPP) IX, an HO-1 inhibitor, to affect tumor growth of LL/2 mouse lung cancer cells. ZnPPIX reduced HO-1 expression and HO activity in LL/2 cells, whereas cobalt PPIX (CoPPIX), an HO-1 activator, increased both. LL/2 cells treated with sodium nitropurusside, an NO donor, showed growth inhibition dose-dependently, which was enhanced by ZnPPIX cotreatment, but was reduced by CoPPIX. In mice tumors, ZnPPIX decreased HO-1 expression. LL/2-tumors were found in 88% (7/8) vehicle-treated mice, whereas tumors were found in 38% (3/8) and 25% (2/8) mice treated with 5 and 20 μg/mouse ZnPPIX, respectively (p = 0.0302). Tumor growth was inhibited dose-dependently by ZnPPIX. Vascular endothealial growth factor concentration in tumors was reduced by ZnPPIX (p = 0.0341). Microvessel density (MVD) in ZnPPIX-treated tumors was lower than that in vehicle-treated tumors (p = 0.0362). Apoptotic cell count in ZnPPIX-treated tumors was higher than that in vehicle-treated tumors (p = 0.0003). In contrast, CoPPIX treatment increased HO-1 expression, enhanced tumorigenicity and MVD and reduced apoptosis. From these findings, inhibition of HO-1 by ZnPPIX provides relevant antitumoral effects. © 2006 Wiley-Liss, Inc.
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