Abstract
Introductions:
Adrenoleukodystrophy (ALD) is a disease caused by the accumulation of very long chain fatty acids in adrenal and cerebral tissues. For the treatment of ALD, a mixture of omega-9 fatty acids (oleic and erucic) is being used. Erucic acid (EA) also significantly exists in the Asian diet. At first, the safety of EA was largely debated partly due to the Spanish Toxic Oil Syndrome (STOS), when severe cardiomyopathy was observed among consumers of rapeseed oils rich in EA. It was proposed that EA is highly toxic to cardiac mitochondria. But several studies showed that STOS cases were only seen among consumers of rapeseed oils, which were refined with carcinogenic aniline dyes. Furthermore, opponents of mitochondrial toxicity theory have applied EA at unapplicable doses. Since EA also binds transcription factor PPAR-delta capable to induce oligodendroglial differentiation of glial progenitors, we aimed to define EA effects on C6 glioma growth in vitro. PPARs also involve in induction of nitric oxide synthases (NOs) and in mitochondrial-proliferation. We also studied in vivo interactions of EA with the toxicity of doxorubicine (Dox) which is a chemotherapeutic causing prominent mitochondrial injury.
Materials and Methods:
Effects of EA at different dosages (10, 100, 250 ve 500 μM) were tested on cell proliferation, agar colony formation, S-phase fraction, iNOS and eNOS immunopositivity. EA-interference with Dox toxicity was analyzed on mouse liver and heart via light and transmission electron microscopy.
Results:
While EA reduced monolayer and colony growth of C6 glioma cells at 10 μM, its inhibition of S-phase occured dose-dependently. However, the efficacy of Dox to suppress glioma S-phase was diminished with EA. EA and Dox additively induced iNOS and eNOS in tumor spheroids. Unexpectedly, EA significantly reduced Dox-induced toxicity and hyalinization in mouse liver and heart tissues analyzed by light microscopy. Furthermore, mitochondrial morphology was better when EA was added to Dox treatment as assessed with transmission electron microscopy. On the other hand, it was witnessed that intercalated disc morphology was more deteriorated with EA addition to Dox-treatment.
Conclusions:
EA reduces glial tumor growth in vitro and its cardiac toxicity - if ever exists at low applicable doses - is not due to mitochondrial injury. It may be a novel biological modifier to enhance chemotherapy-efficacy in glial tumor treatment.