TY - JOUR
T1 - FTS and 2-DG induce pancreatic cancer cell death and tumor shrinkage in mice
AU - Goldberg, L.
AU - Israeli, R.
AU - Kloog, Y.
N1 - Funding Information:
Acknowledgements. This work was supported in part by The Israel Science Foundation (YK), the Prajs-Drimmer Institute for the Development of Anti-Degenerative Drugs (LG), and the SFAHO Foundation (a private Foundation; YK). Y Kloog is the incumbent of the Jack H Skirball Chair in Applied Neurobiology and Head of the Prajs-Drimmer Institute.
PY - 2012/3
Y1 - 2012/3
N2 - The Ras inhibitor S-trans-trans farnesylthiosalicylic acid (FTS) inhibits active Ras, which controls cell proliferation, differentiation, survival, and metabolism. FTS also inhibits HIF1α expression in cancer cells, leading to an energy crisis. The synthetic glucose analog 2-deoxy-D-glucose (2-DG), which inhibits glycolysis, is selectively directed to tumor cells that exhibit increased glucose consumption. The 2-DG enters tumor cells, where it competes with glucose for glycolytic enzymes. In cancer models, as well as in human phase 1 trials, 2-DG inhibits tumor growth without toxicity. We postulated that under normoxic conditions, tumor cells treated with FTS would be more sensitive than normal cells to 2-DG. We show here that combined treatment with FTS and 2-DG inhibited cancer cell proliferation additively, yet induced apoptotic cell death synergistically both in vitro and in vivo. The induced apoptosis was inferred from QVD-OPH inhibition, an increase in cleaved caspase 3, and loss of survivin. FTS and 2-DG when combined, but not separately, also induced an increase in fibrosis of the tumor tissue, chronic inflammation, and tumor shrinkage. Overall, these results suggest a possible new treatment of pancreatic tumors by the combined administration of FTS and 2-DG, which together induce pancreatic tumor cell death and tumor shrinkage under nontoxic conditions.
AB - The Ras inhibitor S-trans-trans farnesylthiosalicylic acid (FTS) inhibits active Ras, which controls cell proliferation, differentiation, survival, and metabolism. FTS also inhibits HIF1α expression in cancer cells, leading to an energy crisis. The synthetic glucose analog 2-deoxy-D-glucose (2-DG), which inhibits glycolysis, is selectively directed to tumor cells that exhibit increased glucose consumption. The 2-DG enters tumor cells, where it competes with glucose for glycolytic enzymes. In cancer models, as well as in human phase 1 trials, 2-DG inhibits tumor growth without toxicity. We postulated that under normoxic conditions, tumor cells treated with FTS would be more sensitive than normal cells to 2-DG. We show here that combined treatment with FTS and 2-DG inhibited cancer cell proliferation additively, yet induced apoptotic cell death synergistically both in vitro and in vivo. The induced apoptosis was inferred from QVD-OPH inhibition, an increase in cleaved caspase 3, and loss of survivin. FTS and 2-DG when combined, but not separately, also induced an increase in fibrosis of the tumor tissue, chronic inflammation, and tumor shrinkage. Overall, these results suggest a possible new treatment of pancreatic tumors by the combined administration of FTS and 2-DG, which together induce pancreatic tumor cell death and tumor shrinkage under nontoxic conditions.
KW - 2-DG
KW - FTS
KW - Pancreatic cancer
KW - Ras
KW - Ras-oncogenes
UR - http://www.scopus.com/inward/record.url?scp=84859363762&partnerID=8YFLogxK
U2 - 10.1038/cddis.2012.24
DO - 10.1038/cddis.2012.24
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AN - SCOPUS:84859363762
SN - 2041-4889
VL - 3
SP - e284
JO - Cell Death and Disease
JF - Cell Death and Disease
IS - 3
ER -
