Inhibition of Glycolysis: Novel Therapy for Ovarian Cancer
Angela Kueck, Lijun Tan, Milheon Choi, J. Rebecca Liu.
University of Michigan, Ann Arbor, MI and University of Michigan Medical Ctr., Ann Arbor, MI.
Objectives: Resveratrol (3,5,4’-trihydroxystilbene), a natural phytoalexin found in red wine, grapes, and other dietary sources, has anti-neoplastic activity. We have previously demonstrated that resveratrol induces autophagic cell death (type II programmed cell death) in ovarian cancer cells.
Autophagy is induced in mammalian cells in response to amino acid or glucose deprivation. Cancer cells exhibit increased rates of glycolysis as compared to normal cells, and have increased susceptibility to cell death induced by glucose deprivation.
The purpose of this study was to determine if resveratrol induced autophagy in ovarian cancer cells is due to inhibition of glucose uptake, and to determine the therapeutic effect of resveratrol in vivo.
Methods: Eight ovarian cancer cell lines were incubated with media containing glucose, resveratrol, or 2-deoxyglucose (2-DOG). Growth inhibition was determined using the sulforhodamine assay. Glucose uptake was analyzed with the 3H-2-DOG assay. Activation of AKT and translocation of the Glut1 receptor was determined by immunoblotting.
A bioluminescent ovarian cancer xenograft model was used to determine the effect of resveratrol in vivo. A2780 ovarian cancer cells stably expressing green fluorescent protein were injected into the peritoneal cavity of female nu/nu mice. After tumor establishment, mice were treated with vehicle control, cisplatin, or resveratrol. Tumor response was monitored on a light box.
Results: Glucose deprivation and resveratrol induced cell death in all ovarian cell lines by 24 h. Resveratrol inhibited glucose uptake, AKT activation and translocation of the Glut1 receptor to the plasma membrane.
Mice treated with cisplatin and resveratrol had a complete response to treatment, whereas control mice developed carcinomatosis.
Conclusions: Resveratrol inhibits glucose uptake in ovarian cancer cells and induces autophagocytosis. The majority of conventional chemotherapeutic agents induce apoptotic cell death.
Because resveratrol can circumvent chemoresistance due to alterations in apoptotic signaling, it has the potential to be effective against chemoresistant disease.
Furthermore, because ovarian cancer cells are dependent upon glucose for survival, agents that inhibit glycolysis, such as resveratrol, may have significant therapeutic benefit for ovarian cancer patients.
AACR 2005 Abstract #3085
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