Eicosapentaenoic acid and docosahexaenoic acid effects on tumour mitochondrial metabolism, acyl CoA metabolism and cell proliferation

Abstract

In order to investigate the effects of high-fat diets rich in eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), Wistar rats bearing subcutaneous implants of the Walker 256 tumour were fed pelleted chow containing low DHA/EPA or high DHA/EPA. The presence of n-3 polyunsaturated fatty acids (PUFAs) led to a marked suppression (35-46%) of tumour growth over a 12 day period. Both the whole tumour homogenate and the Percoll-purified mitochondrial fraction presented significant changes in fatty acid composition. The levels of EPA increased in both n-3 dietary groups while the levels of DHA increased only in the high DHA/EPA group, in comparison with the control chow-fed group. The presence of n-3 PUFAs led to an increase in mitochondrial acyl CoA synthetase activity, but neither the cytoplasmic acyl CoA content nor the n-3 fatty acid composition of the cytoplasmic acyl CoAs was altered by the diet. The content of thiobarbituric acid-reactive substances (TBARS) was increased in the low DHA/EPA group but was unchanged in the high DHA/EPA group. In vitro studies with the Walker 256 cell line showed a 46% decrease in cell growth in the presence of either EPA or DHA which was accompanied by a large decrease in the measured mitochondrial membrane potential. The TBARS content was increased only in the EPA-exposed cells. Cell cycle analysis identified a decrease in G0-G1 phase cells and an increase in G2-M phase cells and apoptotic cells, for both EPA and DHA-exposed cells. The data show that the presence of n-3 PUFAs in the diet is able to significantly after the growth rate of the Walker 256 tumour. The involvement of changes in mitochondrial membrane composition and membrane potential have been indicated for both EPA and DHA, while changes in lipid peroxidation have been identified in the presence of EPA but not of DHA.

Neuroblastoma cell death in response to docosahexaenoic acid: Sensitization to chemotherapy and arsenic‐induced oxidative stress

“…Similarly, treatment of Walker 256 tumor cells with DHA results in a decreased mitochondrial transmembrane potential. 32 To assess the relative importance of mitochondrial stress in response to DHA, we performed experiments employing CsA, an inhibitor of the mitochondrial transition pore. 33,34 CsA inhibited DHA-induced mitochondrial depolarization and subsequent neuroblastoma cell death (Figs.…”

Regulation of human lymphocyte proliferation by fatty acids

“…26 Polyunsaturated fatty acids (PUFA) of the n-6 family (linoleic and arachidonic acids at 300 mM) reduce the number of these cells in S and G2/M phases. Colquhoun et al 27 observed a decrease in G0-G1 phase cells and an increase in G2-M phase and apoptotic Walker tumour 256 cells, after treatment with both EPA and DHA.…”

Maternal supply of omega-3 polyunsaturated fatty acids alter mechanisms involved in oocyte and early embryo development in the mouse

“…Eicosanoid-independent mechanisms, such as modulation of intracellular signaling pathways, transcription factor activity, and altered gene expression, also are involved (11,14,37), as well as the modulation of oxidative stress and mitochondrial function (9). In addition, recent evidence suggests that oocyte fatty acids are utilized during oocyte maturation and that they are incorporated into the oocyte cytoplasm during this process (18,23), perhaps for a role in oocyte development.…”

“…Hong et al (22) also have shown that n-3 PUFAs increase apoptosis in colonocytes when coincubated with butyrate, because of the increase in oxidative stress. Furthermore, EPA increases oxidative stress via changes in lipid peroxidation in Walker 256 rat tumor cells, in addition to altering the mitochondria via a decrease in mitochondrial membrane potential (9). This is of particular interest, since changes in mitochondrial membrane potential have been measured in oocytes as a consequence of metabolic inhibitors (44) and have been correlated with developmental arrest in mouse two-cell embryos (2), increased fragmentation (2), and the rate of embryo development in the human (45).…”