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D‐galactose induces necroptotic cell death in neuroblastoma cell lines

D‐Galactose (D‐gal) can induce oxidative stress in non‐cancer cells and result in cell damage by disturbing glucose metabolism. However, the effect of D‐gal on cancer cells is yet to be explored. In this study, we investigated the toxicity of D‐gal to malignant cells specifically neuroblastoma cells. As the results, high concentrations of D‐gal had significant toxicity to cancer cells, whereas the same concentrations of glucose had no; the viability loss via D‐gal treatment was prominent to malignant cells (Neuro2a, SH‐SY5Y, PC‐3, and HepG2) comparing to non‐malignant cells (NIH3T3 and LO2). Differing from the apoptosis induced by H2O2, D‐gal damaged cells showed the characters of necrotic cell death, such as trypan blue‐tangible and early phase LDH leakage. Further experiments displayed that the toxic effect of D‐gal can be alleviated by necroptosis inhibitor Necrostatin (Nec‐1) and autophagy inhibitor 3‐methyladenine (3‐MA) but not by caspase inhibitor z‐VAD‐fmk. D‐Gal treatment can transcriptionally up‐regulate the genes relevant to necroptosis (Bmf, Bnip3) and autophagy (Atg5, TIGAR) but not the genes related to apoptosis (Caspase3, Bax, and p53). D‐Gal did not activate Caspase‐3, but prompted puncta‐like GFP–LC3 distribution, an indicator for activated autophagy. The involvement of aldose reductase (AR)‐mediated polyol pathway was proved because the inhibitor of AR can attenuate the toxicity of D‐gal and D‐gal treatment elevates the expression of AR. This study demonstrates for the first time that D‐gal can induce non‐apoptotic but necroptotic cell death in neuroblastoma cells and provides a new clue for developing the strategy against apoptosis‐resistant cancers. J. Cell. Biochem. 112: 3834–3844, 2011. © 2011 Wiley Periodicals, Inc.