Modifications in mitochondrial metabolism and ultrastructure and their relationship to tumour growth inhibition by gamma-linolenic acid.
Walker 256 tumour-bearing rats were fed pelleted chow containing low-gamma-linolenic acid (GLA) (2.98%) or high-GLA (5.55%) during the twelve-day period after subcutaneous implantation of the tumour. The presence of n-6, polyunsaturated GLA in the diet caused a concentration-dependent decrease in tumour growth, reaching an almost 50% reduction in final tumour weight in the high-GLA group. The eicosatrienoic acid content of the whole tumour homogenate and of the Percoll-purified mitochondrial fraction was increased by the GLA-rich diets. Changes in the fatty acid composition of the cytoplasmic acyl CoA pool were also found, with increases in GLA content in both the low- and high-GLA groups. Additionally, increases in eicosatrienoic acid and arachidonic acid were found in the high-GLA group. Both the cytoplasmic acyl CoA content and the mitochondrial acyl CoA synthetase activity were increased by GLA in the diet and lipid peroxidation was also increased as determined by an increase in TBARS content. Changes in mitochondrial fatty acid composition were accompanied by a decrease in the mitochondrial membrane potential in the high-GLA group. Tumours from the control and GLA groups were examined by transmission electron microscopy. This revealed an increase in mitochondrial area and volume in the high-GLA group, in comparison with the control group, as well as a change in general cell ultrastructure, with many cells found in an apoptotic state or in a necrotic state, possibly secondary to apoptosis. The data presented show that the addition of GLA to the diet of Walker 256 tumour-bearing rats can greatly decrease the rate of development of the tumour burden. This may be, in part, due to the accumulation of poorly metabolised acyl CoA's within the tumour cell cytoplasm which, when coupled with altered mitochondrial composition, membrane potential and ultrastructure, may be a signal for cell death.
Colquhoun
A
A
Departamento de Histologia e Embriologia, Instituto de Ciencias Biomédicas, Universidade de São Paulo, São Paulo, Brasil.
Schumacher
R I
RI
D015126:8,11,14-Eicosatrienoic Acid / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D016718:Arachidonic Acid / Q000378:metabolism; D002279:Carcinoma 256, Walker / Q000201:enzymology / Q000378:metabolism* / Q000648:ultrastructure; D003066:Coenzyme A Ligases / Q000378:metabolism; D004041:Dietary Fats / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008854:Microscopy, Electron; D008928:Mitochondria / Q000378:metabolism* / Q000648:ultrastructure*; D051381:Rats; D017208:Rats, Wistar; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D017965:gamma-Linolenic Acid / Q000494:pharmacology*
D004041:Dietary Fats; D017392:Thiobarbituric Acid Reactive Substances; D016718:Arachidonic Acid; D017965:gamma-Linolenic Acid; D003066:Coenzyme A Ligases; D015126:8,11,14-Eicosatrienoic Acid