A novel combination therapy with arsenic trioxide and parthenolide against pancreatic cancer cells

To investigate the anticancer effect and potential mechanism of combination treatment with arsenic trioxide (ATO) and parthenolide (PTL) in human pancreatic cancer cells.

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.

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.

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.