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Abstract
Pancreatic cancer is a complex disease, in need of new therapeutic approaches. In this study, we explored the effect and mechanism of action of epigallocatechin-3-gallate (EGCG), a major polyphenol in green tea, alone and in combination with current chemotherapeutics on pancreatic cancer cell growth, focusing on glycolysis metabolism. Moreover, we investigated whether EGCG’s effect is dependent on its ability to induce reactive oxygen species (ROS). EGCG reduced pancreatic cancer cell growth in a concentration-dependent manner and the growth inhibition effect was further enhanced under glucose deprivation conditions. Mechanistically, EGCG induced ROS levels concentration-dependently. EGCG affected glycolysis by suppressing the extracellular acidification rate through the reduction of the activity and levels of the glycolytic enzymes phosphofructokinase and pyruvate kinase. Cotreatment with catalase abrogated EGCG’s effect on phosphofructokinase and pyruvate kinase. Furthermore, EGCG sensitized gemcitabine to inhibit pancreatic cancer cell growth in vitro and in vivo. EGCG and gemcitabine, given alone, reduced pancreatic tumor xenograft growth by 40% and 52%, respectively, whereas the EGCG/gemcitabine combination reduced tumor growth by 67%. EGCG enhanced gemcitabine’s effect on apoptosis, cell proliferation, cell cycle and further suppressed phosphofructokinase and pyruvate kinase levels. In conclusion, EGCG is a strong combination partner of gemcitabine reducing pancreatic cancer cell growth by suppressing glycolysis.
Highlights
Pancreatic cancer is one of the top five causes of cancer-related death in the United States, with an overall five-year survival rate of approximately eight percent [1]
We explored the effect and mechanism of action of EGCG alone and in combination with current chemotherapeutics on pancreatic cancer cell growth, focusing on glycolysis metabolism involved in pancreatic cancer cell growth, and investigated whether it is dependent on the ability of EGCG to induce reactive oxygen species (ROS)
We compared the effect of EGCG in human pancreatic cancer cells to that of human pancreatic normal epithelial cells (HPNE)
Summary
Pancreatic cancer is one of the top five causes of cancer-related death in the United States, with an overall five-year survival rate of approximately eight percent [1]. While surgery, which offers the only realistic hope, is a viable option in a limited number of patients, current radiation therapy and chemotherapy regimens offer no significant clinical benefit [2]. Gemcitabine is an antimetabolite recognized as the current standard of care for unresectable locally advanced or metastatic pancreatic cancer, but its therapeutic effect for patients is limited [3]. An urgent need exists for new ways to combat pancreatic cancer, with the exploration of novel therapeutic strategies being a critical component. Deregulated energy metabolism is recognized as one of the hallmarks of cancer [4]. Tumor cells prefer to rely on aerobic glycolysis to produce energy and to obtain intermediate metabolites that can be directed to other biosynthetic pathways that promote tumor growth [5,6]
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