TY - JOUR
T1 - Acid sphingomyelinase overexpression enhances the antineoplastic effects of irradiation in vitro and in vivo
AU - Smith, Eric L.
AU - Schuchman, Edward H.
N1 - Funding Information:
We thank Xingxuan He and Chien-Ling Huang for help with the ceramide quantification assay, and Yu Zhou for help with bioluminescent imaging. We also thank John Martignetti and Goutham Narla for careful reading of the manuscript. This research was supported by a grant from the NIH (2 R01 HD28607) to E.H.S. E.L.S. was supported, in part, by a Medical Scientist Training Program Grant from the NIH (5 T32 GM007280).
PY - 2008
Y1 - 2008
N2 - Exposure of cells or animals to stress frequently induces acid sphingomyelinase (ASM)-mediated ceramide production that leads to cell death. Consistent with this, overexpression 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 pretreated with a single, peritumoral injection of recombinant ASM (rhASM), the tumors were up to threefold 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 article, we propose that further investigation of this protein and gene as antineoplastic agents also is warranted.
AB - Exposure of cells or animals to stress frequently induces acid sphingomyelinase (ASM)-mediated ceramide production that leads to cell death. Consistent with this, overexpression 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 pretreated with a single, peritumoral injection of recombinant ASM (rhASM), the tumors were up to threefold 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 article, we propose that further investigation of this protein and gene as antineoplastic agents also is warranted.
UR - http://www.scopus.com/inward/record.url?scp=50549083676&partnerID=8YFLogxK
U2 - 10.1038/mt.2008.145
DO - 10.1038/mt.2008.145
M3 - Article
C2 - 18628757
AN - SCOPUS:50549083676
SN - 1525-0016
VL - 16
SP - 1565
EP - 1571
JO - Molecular Therapy
JF - Molecular Therapy
IS - 9
ER -