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 non-toxic conditions.