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INHIBITION OF HO‐1 INCREASES RESPONSIVENESS OF MELANOMA CELLS TO ALA‐PDT
Author(s) -
Frank Juergen,
Flaccus Andrea,
Biesalski Hans Konrad
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a1082-c
Subject(s) - protoporphyrin ix , photodynamic therapy , melanoma , chemistry , intracellular , heme oxygenase , heme , photosensitizer , cancer research , downregulation and upregulation , oxidative stress , cell , apoptosis , pharmacology , microbiology and biotechnology , biochemistry , biology , gene , enzyme , organic chemistry
Based on the observation that 5‐aminolevulinic acid (ALA) induced the expression of heme oxygenase‐1 (HO‐1) in cultured melanoma cells, we examined the role of HO‐1 on the effectiveness of ALA‐based photodynamic therapy (ALA‐PDT). Transcriptional activation of the HO‐1 gene is considered as an adaptive response to oxidative and cellular stress and confers a protective capacity to cell and tissue injury, which may affect the responsiveness to ALA‐PDT. A time dependent accumulation (0h‐16h) of protoporphyrin IX (PPIX) within melanoma cells was seen after ALA supply (0.5 mM ALA). In the same time interval a significant increase (up to 25‐fold) in HO‐1 protein expression was observed. Thus, production and degradation of PPIX (by HO‐1) were simultaneously enabled, leading to a reduced intracellular concentration of PPIX. Diminishing of HO‐1 activity by the HO‐1 inhibitor tin protoporphyrin IX (SnPPIX) significantly enhanced the formation of PPIX up to 1.8 fold. A further strong increase in HO‐1 protein expression (up to 128‐fold) was seen after ALA‐PDT treatment. The inhibition of HO‐1 activity by SnPPIX made tumor cells considerably more sensitive to ALA‐PDT treatment. At low radiation doses (0.42 J/cm2) the death rate increased significantly from 9.8 ± 5.0 % to 50.7 ± 19.7 %. Therefore, specific inhibition of HO‐1 activity may be used to increase the effectiveness of ALA‐PDT.