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

Jaroslav Cermak, József Balla, Harry S. Jacob, György Balla, Helen Enright, Karl Nath, Gregory M. Vercellotti

Research output: Contribution to journalArticlepeer-review

64 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)5308-5313
Number of pages6
JournalCancer research
Volume53
Issue number21
StatePublished - Nov 1993

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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