Investigation into the distinct subcellular effects of docosahexaenoic acid loaded low-density lipoprotein nanoparticles in normal and malignant murine liver cells.
BACKGROUND
Recent studies have shown that low density lipoproteins reconstituted with the natural omega 3 fatty acid docosahexaenoic acid (LDL-DHA) is selectively cytotoxic to liver cancer cells over normal hepatocytes. To date, little is known about the subcellular events which transpire following LDL-DHA treatment.


METHODS
Herein, murine noncancer and cancer liver cells, TIB-73 and TIB-75 respectively, were investigated utilizing confocal microscopy, flow cytometry and viability assays to demonstrate differential actions of LDL-DHA nanoparticles in normal versus malignant cells.


RESULTS
Our studies first showed that basal levels of oxidative stress are significantly higher in the malignant TIB-75 cells compared to the normal TIB-73 cells. As such, upon entry of LDL-DHA into the malignant TIB-75 cells, DHA is rapidly oxidized precipitating global and lysosomal lipid peroxidation along with increased lysosomal permeability. This leakage of lysosomal contents and lipid peroxidation products trigger subsequent mitochondrial dysfunction and nuclear injury. The cascade of LDL-DHA mediated lipid peroxidation and organelle damage was partially reversed by the administration of the antioxidant, N-acetylcysteine, or the iron-chelator, deferoxamine. LDL-DHA treatment in the normal TIB-73 cells was well tolerated and did not elicit any cell or organelle injury.


CONCLUSION
These studies have shown that LDL-DHA is selectively cytotoxic to liver cancer cells and that increased levels of ROS and iron catalyzed reactions promote the peroxidation of DHA which lead to organelle dysfunction and ultimately the demise of the cancer cell.


GENERAL SIGNIFICANCE
LDL-DHA selectively disrupts lysosomal, mitochondrial and nuclear function in cancer cells as a novel pathway for eliminating cancer cells.
['Moss|Lacy R|LR|', 'Mulik|Rohit S|RS|', 'Van Treuren|Tim|T|', 'Kim|Soo Young|SY|', 'Corbin|Ian R|IR|']
D000818:Animals D000970:Antineoplastic Agents D002460:Cell Line D045744:Cell Line, Tumor D002478:Cells, Cultured D004249:DNA Damage D004281:Docosahexaenoic Acids D022781:Hepatocytes D006801:Humans D008077:Lipoproteins, LDL D051379:Mice D008807:Mice, Inbred BALB C D008928:Mitochondria D053758:Nanoparticles D018384:Oxidative Stress
Liver cancer Lipid peroxidation Lysosome membrane permeability Mitochondrial membrane potential Omega-3 fatty acid