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Originally published In Press as doi:10.1074/jbc.M209125200 on October 29, 2002

J. Biol. Chem., Vol. 278, Issue 1, 407-414, January 3, 2003
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Antitumor Effects of Photodynamic Therapy Are Potentiated by 2-Methoxyestradiol
A SUPEROXIDE DISMUTASE INHIBITOR*

Jakub GołabDagger §, Dominika NowisDagger , Michał Skrzycki, Hanna Czeczot, Anna Baranczyk-Kuzma, Grzegorz M. Wilczynski||, Marcin MakowskiDagger , Paweł MrózDagger , Katarzyna KozarDagger , Rafał KaminskiDagger , Ahmad JaliliDagger , Maciej Kopec'Dagger , Tomasz Grzela**Dagger Dagger , and Marek JakóbisiakDagger

From the Departments of Dagger  Immunology,  Biochemistry, || Pathology, and ** Histology and Embryology, Center of Biostructure Research, and the Dagger Dagger  Department of General and Vascular Surgery and Transplantation, The Medical University of Warsaw, 02-004 Warsaw, Poland

Photodynamic therapy (PDT), a promising therapeutic modality for the management of solid tumors, is a two-phase treatment consisting of a photosensitizer and visible light. Increasing evidence indicates that tumor cells in regions exposed to sublethal doses of PDT can respond by rescue responses that lead to insufficient cell death. We decided to examine the role of superoxide dismutases (SODs) in the effectiveness of PDT and to investigate whether 2-methoxyestradiol (2-MeOE2), an inhibitor of SODs, is capable of potentiating the antitumor effects of this treatment regimen. In the initial experiment we observed that PDT induced the expression of MnSOD but not Cu,Zn-SOD in cancer cells. Pretreatment of cancer cells with a cell-permeable SOD mimetic, Mn(II)-tetrakis(4-benzoic acid)porphyrin chloride, and transient transfection with the MnSOD gene resulted in a decreased effectiveness of PDT. Inhibition of SOD activity in tumor cells by preincubation with 2-MeOE2 produced synergistic antitumor effects when combined with PDT in 3 murine and 5 human tumor cell lines. The combination treatment was also effective in vivo producing retardation of the tumor growth and prolongation of the survival of tumor-bearing mice. We conclude that inhibition of MnSOD activity by 2-MeOE2 is an effective treatment modality capable of potentiating the antitumor effectiveness of PDT.

* This work was supported by Grant 1M19/M2/2000 from the Medical University of Warsaw, Poland, Grant 4 P05A 025 18 from the State Committee for Scientific Research (to K. B. N.), and a grant from the Foundation for Polish Science (to F. N. P.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ To whom correspondence should be addressed: Dept. of Immunology, Center of Biostructure Research, The Medical University of Warsaw, Chałubinskiego 5, 02-004 Warsaw, Poland. Tel./Fax: 48-22-622-6306; E-mail: jgolab@ib.amwaw.edu.pl.

Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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