Investigation into the distinct subcellular effects of docosahexaenoic acid loaded low-density lipoprotein nanoparticles in normal and malignant murine liver cells

Biochim Biophys Acta. 2016 Nov;1860(11 Pt A):2363-2376. doi: 10.1016/j.bbagen.2016.07.004. Epub 2016 Jul 11.


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.

Keywords: Lipid peroxidation; Liver cancer; Lysosome membrane permeability; Mitochondrial membrane potential; Omega-3 fatty acid.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / toxicity
  • Cell Line
  • Cell Line, Tumor
  • Cells, Cultured
  • DNA Damage
  • Docosahexaenoic Acids / pharmacology*
  • Docosahexaenoic Acids / toxicity
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism*
  • Humans
  • Lipoproteins, LDL / pharmacology
  • Lipoproteins, LDL / toxicity
  • Mice
  • Mice, Inbred BALB C
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Nanoparticles*
  • Oxidative Stress


  • Antineoplastic Agents
  • Lipoproteins, LDL
  • Docosahexaenoic Acids