Background: Methods: Results: Conclusion:

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.

The clinical relevance of the receptor for advanced glycation end products (RAGE) and amphoterin expression was examined in 119 non-diabetic patients with colorectal carcinoma. Expression of RAGE was examined by immunohistochemistry and that of amphoterin by in situ hybridization. RAGE expression was observed in 55% (64/119) of the cases. RAGE positivity in Dukes' B, C and D cases was 19, 81 and 100%, respectively (p<0.0001). Amphoterin was expressed in most cases regardless of tumor stage. Survival analysis of Dukes' B and C cases showed a significantly poorer prognosis for patients with co-expression of RAGE and amphoterin than for patients without co-expression. The results suggest that co-expression of RAGE and amphoterin is closely associated with invasion and metastasis of colorectal cancer.