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Tumor Cell Heme Uptake Induces Ferritin Synthesis Resulting in Altered Oxidant Sensitivity: Possible Role in Chemotherapy Efficacy¹

Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota 55455

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 FeSO₄ (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 1 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 oxidant-mediated lysis is inversely proportional to their ferritin content. 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-exposed cells result. Data analogous to those with H₂O₂-mediated 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 ferritin, to oxidant-mediated lysis. In contrast, repeated, more chronic, exposure 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 scavenger, ferritin.

¹ Supported by NIH Grants HL33793 and 4R37-HL28935; J. C. was supported by the Charles Proshek Fellowship from the Minnesota Medical Foundation.

² To whom requests for reprints should be addressed, at the University of Minnesota Department of Medicine, Box 480 UMHC, 420 Delaware St. SE, Minneapolis, MN 55455.

Received 4/13/93. Accepted 8/24/93.

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