2-Deoxyglucose treatment complements the cisplatin- or BH3-only mimetic-induced suppression of neuroblastoma cell growth

Neuroblastoma (NB) is characterized by pleomorphic molecular characteristics, which may influence cellular metabolism as well as the efficacy of glycolytic inhibitors in suppressing NB cell growth. We studied the metabolic profile of four NB cell lines without or with MYCN amplification and found no unanimous metabolic characteristics. The two NB cell lines with MYCN amplification exhibited a significantly higher HIF-1α expression level and ATP content compared to the two cell lines without MYCN amplification. MYCN amplification was associated with significantly greater inhibition of cellular proliferation and more apoptosis after treatment with the glycolytic inhibitor 2-deoxyglucose (2DG). Further analysis showed that 2DG increased PDK1 but decreased the ATP content and increased expression of the proapoptotic BH3-only protein Bad in both SK-N-AS (without MYCN amplification) and SK-N-DZ (with MYCN amplification) cells. In addition, 2DG decreased hexokinase II expression in SK-N-DZ cells and increased HIF-1α, Noxa, and PUMA expression in SK-N-AS cells. Pretreating SK-N-DZ cells with 2DG or cisplatin for 24 h, followed by cisplatin or 2DG for another 24 h, resulted in significantly greater suppression of cellular proliferation compared to treatment with 2DG or cisplatin for 48 h alone. Effective suppression of SK-N-AS proliferation occurred only when the cells were pretreated with cisplatin. Pretreatment of SK-N-DZ, but not SK-N-AS, with 2DG followed by the BH3-only mimetic ABT737 also resulted in significantly greater suppression of cellular proliferation compared to treatment with ABT737 or 2DG alone. A low dose of 2DG (2 mM) was as effective as a high dose (20 mM) in SK-N-DZ cells. In conclusion, the glycolytic inhibitor 2DG complemented the cisplatin- or ABT737-induced suppression of growth in NB cells, which are sensitive to glycolytic inhibition.