Effects of the inhibitors of energy metabolism, lonidamine and levamisole, on 5-aminolevulinic-acid-induced photochemotherapy

Abstract

The ability of endogenously synthesized protoporphyrin IX (PplX) to damage Chinese hamster lung fibroblasts of the line W 9 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. I 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 PplX formation. At increasing doses of LND (>0.15 mM) the combination treatment becomes less efficient. This is due to the inhibition of PplX 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 PplX formation. However, it is not clear from the present results whether LEV may perturb energy metabolism in W 9 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.o 1996 Wilqv-Liss, Inc.

2‐deoxy‐D‐glucose augments photodynamic therapy induced mitochondrial caspase‐independent apoptosis and energy‐mediated autophagy

“…Optimizing these variables results in cytotoxic levels of reactive oxygen species (ROS), mainly singlet oxygen, that damage the cellular components [12]. Recent, studies show that individual metabolic inhibitors such as 2-DG, 3-bromopyruvate or lonidamine can significantly improve the anticancer effects of PDT [13][14][15]. However, the underlying pathways involved are not completely understood.…”

Bioluminescence Imaging of the Response of Rat Gliosarcoma to ALA‐PpIX‐mediated Photodynamic Therapy¶

“…Hence, as the first step we compared the levels of ALA‐induced PpIX between 9L and 9L luc cells. This is particularly important because PpIX synthesis in the mitochondria is itself an ATP‐dependent process (40). For each experiment, 2 × 10 3 cells were grown in the dark on coverslips incubated for 0 (control), 1, 2 or 4 h in serum‐free media containing 1 m M of ALA (Frontier Scientific Corp., Logan, UT) without pH buffer.…”

Bioluminescence Imaging of the Response of Rat Gliosarcoma to ALA-PpIX Mediated Photodynamic Therapy

“…Hence, as the first step we compared the levels of ALA-induced PpIX between 9L and 9L'"" cells. This is particularly important because PpIX synthesis in the mitochondria is itself an ATP-dependent process (40). For each experiment, 2 X lo3 cells were grown in the dark on coverslips incubated for 0 (control), 1 , 2 or 4 h in serum-free media containing 1 mM of ALA (Frontier Scientific Corp., Logan, UT) without pH buffer.…”