Growth reduction in glioma cells after treatment with tetradecylthioaceticacid: changes in fatty acid metabolism and oxidative status

During aerobic metabolism, a small amount of partially reduced oxygen is pr oduced, yielding reactive oxygen species (ROS). Peroxisomes and mitochondri a are major contributors to cellular ROS production, which is normally bala nced by consumption by antioxidants. The fatty acid analogue tetradecylthio acetic acid (TTA) promotes mitochondrial and peroxisomal proliferation, and may induce oxidative stress and change the growth potential of cancer cell s. In the present study, we found that TTA reduced [H-3]thymidine incorpora tion in the glioma cell lines BT4Cn (rat), D54Mg (human), and GaMg (human) in a dose- and time-dependent manner. The 50% inhibitory TTA doses were app roximately 125 muM for BT4Cn and D54Mg cells and 40 muM for GaMg cells afte r 4 days. alpha -Tochopherol counteracted this inhibition in GaMg cells. TT A enhanced the oxidation of [1-C-14]palmitic acid, which could be explained by stimulation of enzymes involved in peroxisomal (fatty acyl-CoA oxidase) and/or mitochondrial (carnitine palmitoyltransferase) fatty acid oxidation . The glutathione content and the activities of glutathione peroxidase, glu tathione reductase, and glutathione S-transferase were differentially affec ted. Increased malondialdehyde: (MDA) production was seen in TTA-treated Ga Mg and D54Mg cells, but not in BT4Cn cells, in vitro. In BT4Cn tumor tissue from TTA-treated rats, MDA was increased while the alpha -tocopherol conte nt tended to decrease. TTA increased the level of cytosolic cytochrome c in BT4Cn cells, which suggests induction of apoptotic cascades. Although seve ral mechanisms are likely to be involved in the TTA-mediated effects on gro wth, we propose that modulation of cellular redox conditions caused by chan ges in fatty acid metabolism may be of vital importance. (C) 2001 Elsevier Science Inc. All rights reserved.