A Novel Combination Therapy With Arsenic Trioxide and Parthenolide Against Pancreatic Cancer Cells

Objectives: To investigate the anticancer effect and potential mechanism of combination treatment with arsenic trioxide (ATO) and parthenolide (PTL) in human pancreatic cancer cells. Methods: The effects of PTL/ATO on 2 pancreatic carcinoma cell lines, PANC-1 and BxPC-3, were determined by trypan blue exclusion, annexin V/propidium iodide, 4',6-diamidino-2-phenylindole HCl, terminal deoxynucleotidyltransferase-mediated nick-end labeling, flow cytometry, Western blot, and clonogenic assay. In vivo study was performed in PANC-1 tumor xenografts in nude mice. Results: The combination of PTL and ATO inhibited the growth of pancreatic tumor cell lines much greater than each agent alone. The PTL/ATO treatment induced apoptosis and reactive oxygen species generation. Both of them were inhibited by L-N-acetylcysteine and diphenylene iodonium chloride. During ATO/PTL-mediated apoptosis, the collapse of mitochondrial transmembrane potential occurred with cytochrome c release, which was reversed by L-N-acetylcysteine. The combination treatment significantly reduced tumor growth rates of PANC-1 xenografts compared with those treated with either PTL or ATO alone. Conclusions: Combination therapy with ATO and PTL has an augmented anticancer effect on pancreatic cancer in vitro and in vivo, which provides a novel promising approach in the treatment of pancreatic cancer. The mechanism of growth-suppressive effect of combination therapy was correlated with its ability to induce reactive oxygen species generation and apoptosis via the mitochondrial pathway.