Activation of the transcription factor nuclear factor-κB (NF-κB) has been implicated in pancreatic tumorigenesis. We evaluated the effect of a novel NF-κB inhibitor, parthenolide, a sesquiterpene lactone isolated from the herb feverfew, in three human pancreatic tumor cell lines (BxPC-3, PANC-1, and MIA PaCa-2). Parthenolide inhibited pancreatic cancer cell growth in a dose-dependent manner with substantial growth inhibition observed between 5 and 10 μmol/L parthenolide in all three cell lines. Parthenolide treatment also dose-dependently increased the amount of the NF-κB inhibitory protein, IκB-α, and decreased NF-κB DNA binding activity. We have previously shown that nonsteroidal anti-inflammatory drugs (NSAID) suppress the growth of pancreatic cancer cells. To determine whether inhibition of the NF-κB pathway by parthenolide could sensitize pancreatic cancer cells to NSAID inhibition, BxPC-3, PANC-1, and MIA PaCa-2 cells were treated with parthenolide and the NSAID sulindac, either alone or in combination. Treatment with the combination of parthenolide and sulindac inhibited cell growth synergistically in MIA PaCa-2 and BxPC-3 cells and additively in PANC-1 cells. In addition, treatment with the parthenolide/sulindac combination lowered the threshold for apoptosis. Increased levels of IκB-α protein were detected, especially in MIA PaCa-2 cells, after treatment with parthenolide and sulindac compared with each agent alone. Similarly, decreased NF-κB DNA binding and transcriptional activities were detected in cells treated with the combination compared with the single agents, demonstrating cooperative targeting of the NF-κB pathway. These data provide preclinical support for a combined chemotherapeutic approach with NF-κB inhibitors and NSAIDs for the treatment of pancreatic adenocarcinoma.
ASJC Scopus subject areas
- Cancer Research