Effects of low-density lipoprotein docosahexaenoic acid nanoparticles on cancer stem cells isolated from human hepatoma cell lines.

Docosahexaenoic acid (DHA) is an omega-3 polyunsaturated fatty acid with anti-cancer properties. Recently, DHA packaged within low-density lipoprotein (LDL) nanoparticles (LDL-DHA) was demonstrated to be effective in a murine model of hepatocellular carcinoma (HCC). Cancer stem cells (CSCs) are a subpopulation of tumor cells that are resistant to most cancer therapies and thereby, contribute to tumor recurrences. To determine whether LDL-DHA is effective against CSCs derived from human HCC cell lines and tumor bearing rats. Epithelial cellular adhesion molecule positive and CD133 negative (EpCAM+CD133-) CSCs were isolated from HuH-7 and HepG2 human HCC lines and exposed to varying concentrations (1-60 µM) of LDL-DHA nanoparticles for 0-72 h. HCC tumor bearing rats were treated with 2 mg/kg LDL-DHA nanoparticles for 3 days. Regardless of the cell line employed, LDL-DHA nanoparticles achieved 70-100% killing of EpCAM+CD133- CSCs at a concentration of 40 µM after 48 h of exposure while DHA and LDL alone had minimal or no cytotoxic effects. Similar results were obtained with LDL-DHA nanoparticle treatment of EpCAM-CD133- adult cancer cells (ACCs). In keeping with these findings were similar levels of low density lipoprotein receptor expression and LDL-DHA nanoparticle induced lipid peroxidation activity and reactive oxygen species in the CSC and ACC populations. However, differences in sensitivity to LDL-DHA treatment were observed in vivo experiments where LDL-DHA nanoparticle treated tumors had a higher percent of surviving CSCs relative to ACCs. Further research on LDL-DHA nanoparticle therapy for human HCC is warranted.