Ethyl Pyruvate Inhibits Pancreatic Tumor Growth In Mice

Background:Pancreatic cancer is the fourth leading cause of cancer-related deaths in the world and has a poor prognosis; the5-year survival rate of patients remains less than5%and a median survival time after diagnosed is only6months. Up till now, surgical resection still remains the only curative treatment for pancreatic cancer. But, due to this aggressive disease, most pancreatic cancer patients have early metastasis by the time of diagnosis, and only a few cases can undergo surgical resection. Even among cases undergoing resection, the long-term outcome remains unsatisfactory because of early recurrence and metastasis. Although significance advances have been made in the understanding the biology of pancreatic cancer, the molecular and cellular mechanisms involved in the metastasis and recurrence in the early stage or after resection remain poorly understood. Recent literature has highlighted an important role of inflammation in inducing and promoting cancer, chronic inflammation has been linked with the development and growth of cancer and even tumor metastasis. The previous study has highlighted those innate immune cells, such as macrophages, NK cells, dendritic cells, granulocytes, drive cancer development through the production of proinflammatory cytokines such as tumor necrosis factor (TNF), interleukin (IL)-1, IL-6and high mobility group box1(HMGB1), and these cytokines create inflammatory micro-environment of tumor growth and play an important role in inducing and promoting tumor development and metastasis.Ethyl pyruvate (EP), a kind of chemical materials, has recently been reported to prevent lethality in mice with established lethal sepsis and systemic inflammation. Other investigators reported that treatment with EP ameliorate organ injury or dysfunction in animal models of myocardial, intestinal, and severe acute pancreatitis. EP inhibits activation of NF-kB in a variety of in vitro and in vivo systems and the release of inflammatory cytokines such as TNF-a, IL-1β, IL-6and HMGB1. Previously, our study demonstrated EP inhibited cell proliferation and induced cell apoptosis by inhibiting HMGB1expression in pancreatic carcinoma cells. Therefore, we reasoned that EP also might suppress growth of pancreatic tumor in vivo through inhibition of inflammatory cytokines release. Here, we investigated the effects of EP administration on pancreatic cancer development.Objective:We evaluate the anti-tumor effect of Ethyl Pyruvate (EP) on the human pancreatic cancer xenograft in nude mice.Methods:Human pancreatic cancer cell line SW1990was used in vivo to investigate the effect of EP on the human pancreatic cancer in mice. The mice were treated with different doses of EP (100mg/kg,50mg/kg, i. p.) initiating1hour (early treatment) after tumor cells injection daily for14days, and EP(100mg/kg, i. p.) was administered beginning12days (delayed treatment) after tumor cells injection daily for14days. Tumor volumes were measured biweekly. ELISA was used to measure tumor necrosis factor (TNF)-a, interleukin (IL)-1(3, IL-6and high mobility group box1(HMGB1).Results:EP administration inhibited pancreatic tumor growth significantly. The differences in tumor volumes were statistical significant (P=0.0001) and in tumor weights (P=0.0028) between treatment and untreated groups. Treatment with the higher (100mg/kg) dose of EP conferred better efficacy than lower (50mg/kg) group (P=0.024). Early treatment with EP inhibited tumor significantly than delayed treatment (P=0.001). Early administration of EP inhibits TNF-a, IL-1β, IL-6and HMGB1release.Conclusions:EP may have potential as a therapeutic candidate for the treatment of pancreatic cancer.