Enhanced antitumor effect via combination of triptolide with 5-fluorouracil in pancreatic cancer

Abstract

Background: Pancreatic cancer is one of the most aggressive types of cancer, and lack of effective treatment results with a very low 6-month survival rate. This study explores the enhancement of therapeutic effect on human pancreatic cancer cell line (AsPC-1) via combination of triptolide (TPL) and 5-fluorouracil (5-FU). Methods: Cell proliferation was measured by sulforhodamine B (SRB), apoptotic cells were assessed by flow cytometry and western blot for cleaved caspase-3 and vimentin to explore the role of vimentin protein in pancreatic cancer cell line. In vivo , AsPC-1 xenografts were treated by TPL, 5-FU and combination respectively and tumor samples were tested by western blot. Results: The results showed that TPL and 5-FU had the effects on AsPC-1 cell line with the dose dependence individually. The combination of TPL and 5-FU enhanced the cytotoxicity significantly compared to 5-FU or TPL alone. Combination index (CI) indicated the effect of TPL combined with 5-FU was highly synergistic. Furthermore, pancreatic cancer cells treated with TPL plus 5-FU exhibited increased apoptosis and higher levels of pro-apoptotic proteins including caspase-3 activity compared to cells treated with TPL or 5-FU alone. In the mechanism study, high vimentin expression was involved in the enhanced apoptosis induced by TPL plus 5-FU. It indicated that the vimentin expression was inhibited by TPL plus 5-FU significantly. In vivo , the tumor growth of AsPC-1 xenografts was much slower in the group treated with TPL plus 5-FU compared to the group treated with TPL or 5-FU alone. Conclusions: (I) TPL has a potent therapeutic effect on pancreatic cancer cell lines; (II) the combination of TPL with 5-FU enhances the therapeutic effect in vitro and in vivo TPL showed high synergistic effect with 5-FU; (III) the inhibitory effect of TPL plus 5-FU on pancreatic cancer is mediated by the induction of apoptosis and TPL enhanced the apoptosis via inhibition of vimentin expression.