27 February 2007 Tumor cell hyperresistance to photodynamic killing arising from nitric oxide preconditioning
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Abstract
Relatively little is known about how nitric oxide (NO) generated by tumor vascular cells or tumor cells themselves might affect the outcome of photodynamic therapy (PDT). Using a breast tumor epithelial line (COH-BR1) metabolically sensitized with protoporphyrin IX (PpIX) by pre-treating with 5-aminolevulinic acid (ALA), we have recently shown that NO from chemical donors can elicit both an immediate (NO-now) and delayed (NO-then) hyperresistance to photokilling. Cell death was mainly apoptotic when PpIX was confined to mitochondria, but mainly necrotic when it was allowed to diffuse to the cell periphery. We found that NO-now operates primarily by scavenging lipid-derived free radicals, whereas NO-then "preconditions" cells by some other mechanism. In addressing this, we have used a biologically relevant NO donor/tumor target model, viz. RAW 264.7 macrophages grown on microporous membrane inserts and COH-BR1 cells grown in culture plate wells. The RAW cells were activated with lipopolysaccharide, and 15 h later (when NO output was ~ 2 &mgr;M/h) placed over the tumor cells for 20 h, after which the latter were ALA-treated and then irradiated. Prior exposure to activated RAW macrophages reduced tumor cell photokilling by >50 %. This effect was completely lost when the RAW cells were pre-treated with the nitric oxide synthase inhibitor L-NAME, confirming that NO was involved in the hyperresistance. Results from other experiments suggest that heme oxygenase-1 and ferritin play a role in the preconditioning effect described. These studies provide new insights into how NO might modulate PDT efficacy.
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Magdalena Niziolek-Kierecka, Witold Korytowski, Albert W. Girotti, "Tumor cell hyperresistance to photodynamic killing arising from nitric oxide preconditioning", Proc. SPIE 6427, Optical Methods for Tumor Treatment and Detection: Mechanisms and Techniques in Photodynamic Therapy XVI, 642705 (27 February 2007); doi: 10.1117/12.701334; https://doi.org/10.1117/12.701334
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