Reduced cellular glutathione levels do not affect the cytotoxicity or photocytotoxicity of the cationic photosensitiser Victoria Blue BO.
Victoria Blue BO (VBBO) is thought to exert its photocytotoxic effects via free radical generation. Glutathione and related enzymes are associated with the protection of normal tissues against free-radical damage and have also been implicated in multiple drug resistance. It might, therefore, be expected that cells containing higher levels of glutathione would be resistant to the cytotoxic effects of VBBO. The total glutathione content for a murine mammary tumour cell line, EMT6-S, was found to be lower than in a multi-drug resistant cell line, EMT6-R, 21.84+/-2.54 microg (mg protein)(-1) and 18.79+/-2.7 microg (mg protein)(-1), respectively; however, this was not found to be a significant difference (p > 0.05, Student t-test). Buthionine sulfoximine, a potent inhibitor of gamma-glutamyl cysteine synthetase, brought about a reduction in glutathione levels in both EMT6-S and EMT6-R cell lines in a concentration-dependent manner. Buthionine sulfoximine administration was effective in reducing intracellular glutathione levels by up to 90% in both types of cells. Interestingly, glutathione depletion of EMT6-S and EMT6-R cells did not enhance the photocytotoxic effect of VBBO, suggesting that the primary site of action of VBBO may be at an intracellular site not protected by glutathione or that the mechanism of action is not via the in situ generation of free radical species.
Burrow
S M
SM
Department of Biological Sciences, University of Central Lancashire, Preston, UK.
Phoenix
D A
DA
Wainwright
M
M
Waring
J J
JJ
D000818:Animals; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D004347:Drug Interactions; D005609:Free Radicals / Q000378:metabolism; D005721:Glutamate-Cysteine Ligase / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism*; D051379:Mice; D017319:Photosensitizing Agents / Q000494:pharmacology* / Q000633:toxicity*; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology* / Q000633:toxicity*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000494:pharmacology
D005609:Free Radicals; D017319:Photosensitizing Agents; D000644:Quaternary Ammonium Compounds; D011838:Radiation-Sensitizing Agents; C084160:Victoria blue BO; D019328:Buthionine Sulfoximine; D004317:Doxorubicin; D014700:Verapamil; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione