The Therapeutic Rroles And Mechanism Of Embelin In Pancreatic Cancer

Pancreatic cancer is an aggressive malignancy that is frequently diagnosed at an advanced stage with a poor prognosis.Moreover,it is often unresponsive to conventional radiation and chemotherapies.Therefore,novel therapeutic strategies,such as immunotherapeutic approaches,are urgently needed to improve the clinical outcome of pancreatic cancer patients.Objective:To explore whether embelin(2,5-dihydroxy-3-undecyl-1,4-benzoquinone)can attenuate the progression of pancreatic tumours by directly exerting cytotoxicity,including inhibition of cell proliferation,cell migration and induced apoptosis in pancreatic cancer cells,and indirectly modulating the tumour immune micro-environment,including improving anti-tumor immunity and suppressing pro-tumor immunity.Methods:The anti-tumour and immunomodulatory effects of embelin on pancreatic cancer were investigated in vitro and in vivo.In the in vitro study,murine pancreatic cancer cells H7 and Pane 02 were treated with embelin,and the effects of embelin on cell invasion,proliferation and apoptosis were assessed.In the in vivo study,H7 and Pane 02 cells were subcutaneously and orthotropic implanted in C57BL/6 mice and then treated with embelin or vehicle daily by intraperitoneal injection.Following treatment,the inhibitory effects of embelin on the development of pancreatic cancer were evaluated and the effects of embelin on the immune system were explored by assessing the immune cell subpopulations in splenocytes,mesenteric lymph nodes and tumour-infiltrating lymphocytes(TILs),including CTL,γδT,NKT,NK,Treg,MDSCs,Th and IFN-γ-,IL-17A-,IL-6-,IL-4-,GM-CSF-,IL-1β-producing cells.Results:Our results show that embelin significantly attenuated cell invasion and proliferation and induced apoptosis in a dose-and time-dependent manner by upregulating p53 and downregulating the STAT3 signalling pathway.Furthermore,our in vivo study showed that embelin substantially reduced the tumourigenicity of the H7 and Pane 02 cells in C57BL/6 mice,and this reduction was associated with(ⅰ)the inhibition of cell proliferation;(ⅱ)the inhibition of cellular invasion;(ⅲ)the induction of cellular apoptosis;(ⅳ)the modulation of the tumour immune micro-environment via the accumulation of CTL,γδT,NKT,NK,IFN-γ+Th1 cells and reduction of myeloid-derived suppressor cells(MDSCs),Treg;and(ⅴ)the reduction of inflammatory cells such as Th17,GM-CSF,IL-1β and IL-6-producing cells in the mouse pancreatic cancer model.Conclusions:Embelin elicits an effective therapeutic effect by directly exerting cytotoxicity,including inhibition of cell proliferation,cell migration and induced apoptosis in pancreatic cancer cells,and indirectly modulate the tumour immune micro-environment,including increasing the infiltration of CTL,γδT,NKT,NK,IFN-γ+Th1 cells and decreasing the infiltration of Treg,MDSCs on mouse pancreatic cancer model.Embelin represents a novel therapeutic drug candidate for the clinical treatment of pancreatic cancer.