Effects of the inhibitors of energy metabolism, lonidamine and levamisole, on 5-aminolevulinic-acid-induced photochemotherapy.
The ability of endogenously synthesized protoporphyrin IX (PpIX) to damage Chinese hamster lung fibroblasts of the line V79 by exposure to light was examined. This treatment induced reduction of cellular ATP, GTP, of the NADH/NAD+ ratio and of oxygen consumption. The present results indicate a close relationship between inhibition of respiration of irradiated cells and their ability to survive, e.g. 1 min of light exposure induced 90% inhibition of oxygen consumption and inactivation of approximately 95% of the cells, while the cellular content of ATP was reduced by only 15%. This indicates that the mitochondria are one of the primary targets of 5-aminolevulinic acid (ALA)-mediated photochemotherapy (PCT). In the present study, ALA-PCT was combined with the modulators of the glycolysis and the respiration chain, levamisole (LEV) and lonidamine (LND). A synergistic effect of combining ALA-PCT with non-toxic concentrations of LND was observed when LND was given prior to light exposure. This synergism was observed despite a substantial LND-induced inhibition of PpIX formation. At increasing doses of LND (>0.15 mM) the combination treatment becomes less efficient. This is due to the inhibition of PpIX synthesis induced by LND. A synergistic effect of ALA-PDT and LEV was found when LEV was given prior to light exposure. This was at least partly due to an LEV-stimulated effect on ALA-induced PpIX formation. However, it is not clear from the present results whether LEV may perturb energy metabolism in V79 cells since LEV alone did not reduce the energy charge or the NADH/NAD+ ratio. When LEV or LND were given after ALA-PCT, these 2 treatment modalities acted in an additive or slightly synergistic manner.
Shevchuk
I
I
Institute of Chemistry, Estonian Academy Science, Talinn.
Chekulayev
V
V
Moan
J
J
Berg
K
K
D000622:Aminolevulinic Acid / Q000627:therapeutic use*; D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D004734:Energy Metabolism / Q000187:drug effects*; D007191:Indazoles / Q000494:pharmacology*; D007978:Levamisole / Q000494:pharmacology*; D009243:NAD / Q000378:metabolism; D009711:Nucleotides / Q000378:metabolism; D010778:Photochemotherapy; D011524:Protoporphyrins / Q000096:biosynthesis*
D007191:Indazoles; D009711:Nucleotides; D011524:Protoporphyrins; D009243:NAD; D007978:Levamisole; D000622:Aminolevulinic Acid; C028025:protoporphyrin IX; C016371:lonidamine