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 tumors. We wondered whether hemoglobin derived from extravasated RBC deposits heme-derived iron into the tumor, which could modulate the sensitivity of cancer cells to oxidant-mediated injury. A brief exposure (1 h) of ⁵¹Cr-radiolabeled breast cancer cells (BT-20) but not colon cancer cells (Caco-2) to hemin (10 μM) or Fe-SO₄ (10 μM) significantly enhances cytotoxicity mediated by 0.5 mM hydrogen peroxide (H₂O₂). Associated with Caco-2 resistance, these cells were found to be enriched in the endogenous iron chelator, ferritin. If cellular ferritin is even further increased through l h incubation (24 h prior to H₂O₂ exposure) of both cell types with hemin, FeSO₄, or exogenous spleen apoferritin itself (24 h), marked resistance to H₂O₂-mediated cytotoxicity is manifest. Under several conditions, the sensitivity of tumor cells to oxidantmediated lysis is inversely proportional to their ferritin content. Pretreat ment of BT-20 and Caco-2 cells with hemin or FeSO₄ rapidly increases H-ferritin mRNA but only slightly increases L-ferritin iiiUN V: neverthe less, large increases in overall ferritin content of iron-exposed cells result. Data analogous to those with H₂O₂-imidiate cytotoxicity were obtained in studies of bleomycin-engendered DNA strand breakage and cell damage, i.e., brief treatment of BT-20 cells with both hemin or FeSO₄ significantly increases their sensitivity to bleomycin (100 μg/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-proteins in hemorrhagic cancerous lesions) may increase sensitivity of some cancer cells, particularly those relatively low in endogenous In filili, to oxidant-mediated lysis. In contrast, repeated, more chronic, ex posure may result in resistance of various tumors to oxidant-producing immune effector cells or chemotherapeutic agents, an effect derived from their increased synthesis and accumulation of the intracellular iron scav enger, ferritin.