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 microM) or FeSO4 (10 microM) 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 micrograms/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 effector cells or chemotherapeutic agents, an effect derived from their increased synthesis and accumulation of the intracellular iron scavenger, ferritin.
Cermak
J
J
Department of Medicine, University of Minnesota Medical School, Minneapolis 55455.
Balla
J
J
Jacob
H S
HS
Balla
G
G
Enright
H
H
Nath
K
K
Vercellotti
G M
GM
D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001692:Biological Transport; D001943:Breast Neoplasms; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003110:Colonic Neoplasms; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005293:Ferritins / Q000096:biosynthesis*; D005296:Ferrous Compounds / Q000494:pharmacology; D006427:Hemin / Q000378:metabolism* / Q000494:pharmacology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity*; D007700:Kinetics; D016877:Oxidants / Q000633:toxicity*; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014471:Umbilical Veins
D000970:Antineoplastic Agents; D005296:Ferrous Compounds; D016877:Oxidants; D012333:RNA, Messenger; C020748:ferrous sulfate; D006427:Hemin; D005293:Ferritins; D006861:Hydrogen Peroxide