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Heme oxygenase-1 protects tumor cells against photodynamic therapy-mediated cytotoxicity

Oncogene volume 25, pages 3365–3374 (2006)Cite this article

Abstract

Photodynamic therapy is a promising antitumor treatment modality approved for the management of both early and advanced tumors. The mechanisms of its antitumor action include generation of singlet oxygen and reactive oxygen species that directly damage tumor cells and tumor vasculature. A number of mechanisms seem to be involved in the protective responses to PDT that include activation of transcription factors, heat shock proteins, antioxidant enzymes and antiapoptotic pathways. Elucidation of these mechanisms might result in the design of more effective combination strategies to improve the antitumor efficacy of PDT. Using DNA microarray analysis to identify stress-related genes induced by Photofrin-mediated PDT in colon adenocarcinoma C-26 cells, we observed a marked induction of heme oxygenase-1 (HO-1). Induction of HO-1 with hemin or stable transfection of C-26 with a plasmid vector encoding HO-1 increased resistance of tumor cells to PDT-mediated cytotoxicity. On the other hand, zinc (II) protoporphyrin IX, an HO-1 inhibitor, markedly augmented PDT-mediated cytotoxicity towards C-26 and human ovarian carcinoma MDAH2774 cells. Neither bilirubin, biliverdin nor carbon monoxide, direct products of HO-1 catalysed heme degradation, was responsible for cytoprotection. Importantly, desferrioxamine, a potent iron chelator significantly potentiated cytotoxic effects of PDT. Altogether our results indicate that HO-1 is involved in an important protective mechanism against PDT-mediated phototoxicity and administration of HO-1 inhibitors might be an effective way to potentiate antitumor effectiveness of PDT.

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Abbreviations

CO:

carbon monoxide

COX:

cyclooxygenase

DFO:

desferrioxamine

HO-1:

heme oxygenase-1

Hsp:

heat shock protein

PBS:

phosphate-buffered saline

PDT:

photodynamic therapy

ROS:

reactive oxygen species

SOD:

superoxide dismutase

Zn(II)PPIX:

zinc (II) propoporphyrin IX

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Acknowledgements

This work was supported in part by Grants: 1M19/M2, 1M19/NK and 1M19/W1 from the Medical University of Warsaw; Grants PBZ-KBN-107-/P04/2004 and PBZ-KBN-091/P05/54 from the State Committee for Scientific Research, Poland. Marcin Makowski is a recipient of the Foundation for Polish Science Award.

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Authors and Affiliations

  1. Department of Immunology, Center of Biostructure Research, The Medical University of Warsaw, Warsaw, Poland

    D Nowis, M Legat, E Głodkowska, P Mrówka, T Issat, M Makowski, T Stokłosa, M Jakóbisiak & J Gołab

  2. Department of Histology and Embryology, Center of Biostructure Research, Warsaw, Poland

    T Grzela & J Niderla

  3. The Medical University of Warsaw, Warsaw, Poland

    T Grzela & J Niderla

  4. Department of Pathology, Center of Biostructure Research, The Medical University of Warsaw, Warsaw, Poland

    E Wilczek & G M Wilczynski

  5. Department of Medical Biotechnology, Faculty of Biotechnology, Jagiellonian University, Krakow, Poland

    J Dulak, A Józkowicz & H Waś

  6. Center for Laser Diagnostics and Therapy, Chair and Clinic of Internal Diseases and Physical Medicine, Silesian Medical University, Bytom, Poland

    M Adamek

  7. Department of Muscle Biochemistry, M Nencki Institute of Experimental Biology, Warsaw, Poland

    A Wrzosek

  8. Department of General and Vascular Surgery and Transplantation, The Medical University of Warsaw, Warsaw, Poland

    S Nazarewski

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  1. D Nowis
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  2. M Legat
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  16. M Makowski
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Correspondence to J Gołab.

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Nowis, D., Legat, M., Grzela, T. et al. Heme oxygenase-1 protects tumor cells against photodynamic therapy-mediated cytotoxicity. Oncogene 25, 3365–3374 (2006). https://doi.org/10.1038/sj.onc.1209378

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