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 A Nath, Gregory M. Vercellotti

Research output: Contribution to journalArticle

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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 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.

Original languageEnglish (US)
Pages (from-to)5308-5313
Number of pages6
JournalCancer Research
Volume53
Issue number21
StatePublished - Nov 1 1993
Externally publishedYes

Fingerprint

Ferritins
Heme
Oxidants
Drug Therapy
Hemin
Apoferritins
Iron
Neoplasms
Caco-2 Cells
Bleomycin
Hemeproteins
Messenger RNA
Chelating Agents
Colonic Neoplasms
Hydrogen Peroxide
Hemoglobins
Spleen
Breast Neoplasms
Hemorrhage
DNA

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Cermak, J., Balla, J., Jacob, H. S., Balla, G., Enright, H., Nath, K. A., & Vercellotti, G. M. (1993). Tumor cell heme uptake induces ferritin synthesis resulting in altered oxidant sensitivity: Possible role in chemotherapy efficacy. Cancer Research, 53(21), 5308-5313.

Tumor cell heme uptake induces ferritin synthesis resulting in altered oxidant sensitivity : Possible role in chemotherapy efficacy. / Cermak, Jaroslav; Balla, József; Jacob, Harry S.; Balla, György; Enright, Helen; Nath, Karl A; Vercellotti, Gregory M.

In: Cancer Research, Vol. 53, No. 21, 01.11.1993, p. 5308-5313.

Research output: Contribution to journalArticle

Cermak, J, Balla, J, Jacob, HS, Balla, G, Enright, H, Nath, KA & Vercellotti, GM 1993, 'Tumor cell heme uptake induces ferritin synthesis resulting in altered oxidant sensitivity: Possible role in chemotherapy efficacy', Cancer Research, vol. 53, no. 21, pp. 5308-5313.
Cermak, Jaroslav ; Balla, József ; Jacob, Harry S. ; Balla, György ; Enright, Helen ; Nath, Karl A ; Vercellotti, Gregory M. / Tumor cell heme uptake induces ferritin synthesis resulting in altered oxidant sensitivity : Possible role in chemotherapy efficacy. In: Cancer Research. 1993 ; Vol. 53, No. 21. pp. 5308-5313.
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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 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.",
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AU - Vercellotti, Gregory M.

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