Antitumor effects of photodynamic therapy are potentiated by 2-methoxyestradiol. A superoxide dismutase inhibitor.
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-MeOE(2)), 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-MeOE(2) 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-MeOE(2) is an effective treatment modality capable of potentiating the antitumor effectiveness of PDT.
Golab
Jakub
J
Department of Immunology, The Medical University of Warsaw, 02-004 Warsaw, Poland. jgolab@ib.amwaw.edu.pl
Nowis
Dominika
D
Skrzycki
Michal
M
Czeczot
Hanna
H
Baranczyk-Kuzma
Anna
A
Wilczynski
Grzegorz M
GM
Makowski
Marcin
M
Mroz
Pawel
P
Kozar
Katarzyna
K
Kaminski
Rafal
R
Jalili
Ahmad
A
Kopec'
Maciej
M
Grzela
Tomasz
T
Jakobisiak
Marek
M
D000077584:2-Methoxyestradiol; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017323:Dihematoporphyrin Ether / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology; D004958:Estradiol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008815:Mice, Inbred Strains; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010778:Photochemotherapy; D013482:Superoxide Dismutase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015996:Survival Rate; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D004958:Estradiol; D000077584:2-Methoxyestradiol; D017323:Dihematoporphyrin Ether; D013482:Superoxide Dismutase