Abstract
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.
Highlights
61 eliminates the intrinsic GTPase catalytic activity of the Ras protein.[1]
We found that death induced by the combination of farnesylthiosalicylic acid (FTS) and 2-DG was significantly inhibited by QVD-OPH (Figure 3b), suggesting that the cell death induced by FTS þ 2-DG was, at least in part, apoptotic in nature and dependent on caspase activation
Whereas monotherapy with FTS or with a low dose of the glycolysis inhibitor 2-DG was incapable of causing significant death in this pancreatic tumor cell line, combined administration of the two agents prompted their synergistic effect resulting in significant cell death, as demonstrated in vitro by Hoechst labeling and in vivo by TUNEL
Summary
61 eliminates the intrinsic GTPase catalytic activity of the Ras protein.[1]. A large percentage of all cancer types either express one of the mutationally activated Ras isoforms or harbor a chronically activated Ras isoform owing to overexpression of growth-factor receptors.[9,10] Ras has long been considered an appropriate potential target for directed therapy, but attempts to target Ras with agents, such as farnesyltransferase or methyltransferase inhibitors, have so far been unsuccessful.[1]. Over the last 15 years, we have elaborated a new concept and developed a new class of Ras inhibitors that affect the active form of Ras. The concept is based on the knowledge that the farnesyl moiety common to all Ras proteins[11,12] serves as a lipophilic lipid anchor, and confers functional specificity on Ras.[1,11,12] Those findings raised the possibility that the farnesyl group might act as part of a recognition unit for specific anchorage lipids or protein(s) that interact with Ras in the cell membrane. N-Ras and the epidermal growth factor receptor was recently shown to synergistically support N-Ras transformation in vitro.[20] Taken together, and assuming that compounds that block farnesyl-binding sites would act as Ras inhibitors, these findings point to the farnesyl-binding pockets as excellent potential targets for Ras-directed therapy. FTS inhibits tumor growth, cell migration, and energy metabolism in numerous cancer cell lines and many types of cancer cells that exhibit high Ras GTP levels.[22,23,24,25,26] The most recent clinical trials showed that oral salirasib treatment of patients with pancreatic cancer increases survival rates (http://www.concordiapharma.com)
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