TUMOR-CELL HEME UPTAKE INDUCES FERRITIN SYNTHESIS RESULTING IN ALTERED OXIDANT SENSITIVITY - POSSIBLE ROLE IN CHEMOTHERAPY EFFICACY

Neovascularization and hemorrhage are common features of malignant tum ors. We wondered whether hemoglobin derived from extravasated RBC depo sits heme-derived iron into the tumor, which could modulate the sensit ivity of cancer cells to oxidant-mediated injury. A brief exposure (1 h) of Cr-51-radiolabeled breast cancer cells (BT-20) but not colon can cer cells (Caco-2) to hemin (10 muM) or FeSO4 (10 muM) significantly e nhances cytotoxicity mediated by 0.5 mM hydrogen peroxide (H2O2). Asso ciated with Caco-2 resistance, these cells were found to be enriched i n the endogenous iron chelator, ferritin. If cellular ferritin is even further increased through 1 h incubation (24 h prior to H2O2 exposure ) of both cell types with hemin, FeSO4, or exogenous spleen apoferriti n itself (24 h), marked resistance to H2O2-mediated cytotoxicity is ma nifest. Under several conditions, the sensitivity of tumor cells to ox idant-mediated lysis is inversely proportional to their ferritin conte nt. Pretreatment of BT-20 and Caco-2 cells with hemin or FeSO4 rapidly increases H-ferritin mRNA but only slightly increases L-ferritin mRNA ; nevertheless, large increases in overall ferritin content of iron-ex posed cells result. Data analogous to those with H2O2-mediated cytotox icity were obtained in studies of bleomycin-engendered DNA strand brea kage and cell damage, i.e., brief treatment of BT-20 cells with both h emin or FeSO4 significantly increases their sensitivity to bleomycin ( 100 mug/ml), whereas treatment followed by 24 h incubation with media alone significantly protects against bleomycin toxicity. We speculate that acute exposure of tumors to iron (e.g., derived from heme-protein s in hemorrhagic cancerous lesions) may increase sensitivity of some c ancer cells, particularly those relatively low in endogenous ferritin, to oxidant-mediated lysis. In contrast, repeated, more chronic, expos ure may result in resistance of various tumors to oxidant-producing im mune effector cells or chemotherapeutic agents, an effect derived from their increased synthesis and accumulation of the intracellular iron scavenger, ferritin.