Depletion of tumour glutathione in vivo by buthionine sulphoximine: modulation by the rate of cellular proliferation and inhibition of cancer growth

Abstract

We have investigated in Ehrlich-ascites-tumour-bearing mice the effect of buthionine sulphoximine (BSO), a selective inhibitor of GSH synthesis, on the rate of GSH depletion of tumour versus normal tissues and its relation to tumour cell proliferation. In normal tissues, GSH and GSSG remain unchanged or close to normal values during tumour growth, even at the last stage of growth when the animal is close to death. After administration of a single dose of BSO (4 mmol/kg), the rates of GSH depletion and recovery in the tumour and in several normal tissues are very different. BSO depletes GSH in cancer cells to a level of 0.3-0.4 mumol/g. The fall in GSH levels is faster when tumour cells do not proliferate actively. Four treatments of 4 mmol of BSO/kg at 48 h intervals induce a significant decrease (about 44%) in tumour growth. Our data show that the rate of BSO-induced GSH depletion in cancer cells depends on the stage of tumour growth, and that BSO administration also inhibits cancer-cell proliferation. A mechanism involving changes in protein kinase C activity and intracellular pH is proposed to explain the inhibition of cancer growth elicited by BSO.

Intertissue Flow of Glutathione (GSH) as a Tumor Growth-promoting Mechanism

“…As compared with non-tumor-bearing mice, GSH levels decrease in the liver and kidney of Ehrlich ascites tumor-bearing mice (32) and in the brain, lung, liver, and kidney of B16-F10-bearing mice (15). We also found that GGT overexpression in B16-F10 cells, by degrading extracellular GSH, facilitates their metastatic growth (15).…”

The Stance of Antioxidants in Brain Tumors

“…It has been reported that elevation of intracellular GSH in tumour cells is associated with mitogenic stimulation (Shaw & Chou, 1986), that GSH controls the onset of tumour-cell proliferation by regulating protein kinase C activity and intracellular pH (Terradez et al, 1993). GPx and GR decrease and protein oxidation increases in patients with glioblastoma multiforme and transitional meningioma and clear different oxidative status was found in the two kinds of tumors which represent specially one of the most malignant and most benign tumors respectively and it was shown that there is a complex relationship between pro-and anti-apoptotic molecules in glioblastoma multiforme pathogenesis, thus targeting multiple pathways with advanced chemotherapeutic agents or radiotheraupetic regimens following total resections might be helpful in patients with glioblastoma multiforme (Atukeren et al, 2010).…”

Regulation and measurement of oxidative stress in apoptosis

“…-buthionine-S,R-sulfoximine (BSO) is a cell permeable, selective and irreversible inhibitor of the enzyme γ glutamyl-cysteine synthetase, the first step in synthesising glutathione (Terradez et al, 1993). Glutathione-S-transferase (GST) substrates can also be used to deplete glutathione levels in cells.…”