Acid sphingomyelinase enhances the anti-neoplastic effects of irradiation in vitro and in vivo.

摘要

Exposure of cells or animals to stress frequently induces acid sphingomyelinase (ASM) mediated ceramide production, leading to cell death. Consistent with this, over-expression of ASM in subcutaneous B16-F10 mouse melanomas, in combination with irradiation, resulted in tumors that were up to 12-fold smaller than irradiated control melanomas. Similarly, when irradiated melanomas were pre-treated with a single, peritumoral injection of recombinant ASM (rhASM), the tumors were up to 3-fold smaller. The in vivo effect of ASM was likely due to enhanced cell death of the tumor cells themselves, as well as the surrounding microvascular endothelial cells. In vitro, rhASM had little or no effect on the growth of tumor cells, even in combination with irradiation. However, when the culture media was acidified to mimic the acidic microenvironment of solid tumors, rhASM-mediated cell death was markedly enhanced when combined with irradiation. Microscopic analysis suggested that this was associated with an increase in autophagy. rhASM has been produced for the treatment of the lysosomal storage disorder, type B Niemann-Pick disease, and is currently being evaluated in a phase-1 clinical trial. Based on the data presented in this dissertation, we propose that further investigation of this protein and gene as antineoplastic agents is warranted.