PTPS-16DEVELOPMENT OF NOVEL THERAPEUTIC STRATEGY FOR NEUROBLASTOMA THROUGH IRON AND CHOLESTEROL METABOLISM PATHWAYS

Abstract

Neuroblastoma (NB) is the most common extracranial solid cancer in childhood and about 50% are metastatic at the time of diagnosis. Therefore, it is difficult to treat successfully. We studied the relationship between iron and cholesterol metabolisms in human NB cell lines with the goal of identifying novel therapeutic targets. In general, iron levels in human NB cells increased during the time they were cultured (∼ 3 days) while cholesterol levels of cells maintained in medium containing 1% fetal bovine serum (FBS) or 10% lipoprotein deficient serum decreased. The drug resistant human NB CHLA-171 cells had the higher levels of total iron than other cells as well as significantly more total cholesterol than the other cells during the first 48 hours in culture. Among iron chelators, DpC showed the strongest cytotoxicity to drug resistant NB cells. In general, the drug resistant NB cells are more sensitive to simvastatin than drug sensitive NB cells. In addition, the drug resistant CHLA-171 cells are more vulnerable to serum deprivation or combination of cholesterol inhibitors compare to the other NB cells. The HFE genotype is known to impact both cholesterol and iron metabolism. When HFE expression was decreased by HFE siRNA, cholesterol levels were also decreased in CHLA-171 cells. There is a mild anti-tumor effect at 20 mg/kg (3 times a week) of simvastatin in subcutaneous NB tumor model. In summary, the current data suggest that the need for iron is enhanced during cell proliferation, while cellular cholesterol is used for building new cells or synthesized more slowly during cell growth. The present data also indicates that iron/cholesterol is essential for the growth of drug resistant NB cells, and the effect of inhibition of its synthesis has a significant impact on cell viability.