Depletion of tumour glutathione in vivo by buthionine sulphoximine: modulation by the rate of cellular proliferation and inhibition of cancer growth.
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.
Departamento de Fisiología, Universidad de Valencia, Spain.
P
P
Terradez
M
M
Asensi
M C
MC
Lasso de la Vega
I R
IR
Puertes
J
J
Viña
J M
JM
Estrela
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D019328:Buthionine Sulfoximine; D002286:Carcinoma, Ehrlich Tumor / Q000188:drug therapy / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005978:Glutathione / Q000378:metabolism*; D008297:Male; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051379:Mice
D000964:Antimetabolites, Antineoplastic; D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; D005978:Glutathione