Methemoglobin contributes to the growth of human tumor cells

Methemoglobin (metHb) has been reported to be present in areas surrounding solid tumors. The effects of human metHb on the growth of one human hepatocellular carcinoma cell line and one human glioma cell line that simply replicate in Ham's nutrient mixture F12 (F12) were investigated. MetHb, depending on its concentration, stimulated or inhibited the in vitro growth of both cancer cell lines. The stimulatory or inhibitory effect was due to the release of hemin from metHb, which was recognized by its characteristic light absorption spectrum. The possibility of metHb or hemin acting initially through a 3', 5'-cyclic guanosine monophosphate- (cGMP-) or prostaglandin E2- (PGE2-) mediated pathway to enhance cell growth was excluded. Ferric iron derived from the catabolic degradation of hemin increased cell growth, whereas biliverdin (Bv) and its reduction product, bilirubin (Br), decreased cell growth. Hemoglobin oxidized to metHb in conditions found in tumors showing neovascularization and hemorrhage may contribute significantly to increased proliferation of cancerous cells.