A Differentiation Therapy for the N2a Neuroblastoma through the Cholesterol Synthesis Pathway

Abstract

Neuroblastomas are the second most common childhood cancer, claiming 15% of all childhood cancer deaths. To discover a differentiation therapy to treat the cancerous neuroblastoma cell, the elevated activity of the cholesterol synthesis pathway has been investigated. Statin drugs are aggressive inhibitors of the rate limiting enzyme, HMG-CoA reductase, of the cholesterol synthesis pathway. Inhibition of this enzyme eliminates the production of downstream intermediates, along with their entire non-sterol and sterol end products. Add-back experiments exposed that mevinolin co-treatment with cholesterol intermediates mevalonate, farnesyl pyrophosphate, and geranylgeranyl pyrophosphate, blocked neurite outgrowths and cells appear unable to differentiate, exhibiting the typical morphology of neuroblastoma cells. However, the add-back of cholesterol (dissolved in 95% ethanol) triggered differentiation of the N2a neuroblastoma cell. This study demonstrates that the N2a neuroblastoma cell differentiates after add-back of cholesterol, implying that the agent(s) of differentiation lies above the production of cholesterol.