Abstract
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.
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