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.