Date of Award

12-15-2014

Document Type

Open Access Thesis

Department

Biomedical Science

First Advisor

Ugra Singh

Abstract

Neuroblastoma is one of the most common solid neoplasms in children, which affects sympathetic neurons with a wide range of genetic abnormalities, especially MYCN amplification, a molecular marker of poor prognosis. Despite advance therapy, still the mortality rate for advance disease is high with frequent relapse and resistance to cytotoxic therapy with evidence of p53 mutation. Metformin, an oral hypoglycemic medication, is a relatively safe and cost effective drug with wide clinical applications, mainly for treatment of Type 2 diabetes. Recent studies have showed promising anticancer effect of metformin on various cancer types, especially on p53 mutant cells. In our research, we performed in vitro study testing the effect of metformin on neuroblastoma cells, as little is known about its effect on this disease. Our results demonstrate that metformin at 10 and 20 mM has significant growth and survival inhibitory effects on both N-myc amplified and N-myc non-amplified and p53 mutant cells. Metformin induces apoptosis in both cell types revealed by morphological changes and detection of cleaved caspase3 by western blot analysis. Metformin’s anticancer effect may be independent on AMPK and AKT pathways as our initial results show no marked change relative to control. Metformin decreases total RhoA protein expression in both cell lines and total Rac1 protein expression in N-myc amplified cells. Our results suggest that metformin can be a good and safe candidate for treatment of neuroblastoma.

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