The enhanced antitumor effect of combined triptolide and paclitaxel on pancreatic cancer cell lines.

Abstract

335 Background: Pancreatic cancer is a disease with dismal prognosis and its treatment options are limited. Recently albumin-bound paclitaxel (nab-paclitaxel) was approved by FDA for advanced pancreatic cancer patients. This study aims to explore the enhancement of therapeutic effect on human pancreatic cancer cell lines (AsPC-1 and PANC-1) via the combination of triptolide, derived from the herb Tripterygium wilfordii, and paclitaxel. Methods: Pancreatic cells were treated with paclitaxel or triptolide alone, and the combination of them. Cell proliferation was measured by sulforhodamine B (SRB). Apoptotic cells were assessed by flow cytometry and western blot for cleaved caspase-3, 8, 9 and PARP. To explore the role of nuclear factor kappaB (NF-kB) activity in pancreatic cancer cell lines, AsPC-1/IkBaM and PANC-1/IkBaM cells (NF-kB activity of cells was silenced by IkB-a mutation) were treated with triptolide plus paclitaxel and NF-kB activity were analyzed. Results: Triptolide demonstrated cytotoxicity on pancreatic cancer cell lines with the IC50 of 25-40nM. The combination of triptolide (IC30 concentration) and paclitaxel enhanced the cytotoxicity significantly . Combination index (CI) indicated that the effect of triptolide plus paclitaxel was synergistic. Furthermore, pancreatic cancer cells treated with triptolide plus paclitaxel exhibited increased apoptosis, as evidenced by stronger Annexin V/ PI staining, higher levels of pro-apoptotic proteins including cleaved caspases and activated PARP compared to cells treated with paclitaxel or gemcitabine alone. In the mechanism study, the combination of triptolide and paclitaxel did not demonstrate synergistic effect on AsPC-1/IkBaM and PANC-1/IkBaM cells. It indicated that the enhanced effect of triptolide plus paclitaxel was correlated with NF-kB activity. Conclusions: (1) the combination of triptolide and paclitaxel enhances the apoptosis in vitro, low concentration of triptolide showed synergistic effect with paclitaxel; (2) the antitumor effect of triptolide plus paclitaxel on pancreatic cancer is mediated by the induction of apoptosis and triptolide enhances paclitaxel-mediated apoptosis via suppression of NF-kB activity.