Inhibition of heme oxygenase-1 by zinc protoporphyrin IX reduces tumor growth of LL/2 lung cancer in C57BL mice.
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 microg/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.
Hirai
Kaeko
K
Department of Molecular Pathology, Nara Medical University School of Medicine, Kashihara, Japan.
Sasahira
Tomonori
T
Ohmori
Hitoshi
H
Fujii
Kiyomu
K
Kuniyasu
Hiroki
H
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D018827:Carcinoma, Lewis Lung / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015151:Immunoblotting; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000473:pathology / Q000517:prevention & control; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D011524:Protoporphyrins / Q000494:pharmacology* / Q000627:therapeutic use; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D020030:Nitric Oxide Donors; D011524:Protoporphyrins; D042461:Vascular Endothelial Growth Factor A; C017803:zinc protoporphyrin; D009599:Nitroprusside; D051547:Heme Oxygenase-1