Parthenolide and sulindac cooperate to mediate growth suppression and inhibit the nuclear factor-KB pathway in pancreatic carcinoma cells

Activation of the transcription factor nuclear factor-KB (NF-KB) has been implicated in pancreatic tumorigenesis. We evaluated the effect of a novel NF-KB 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 Mmol/L parthenolide in all three cell lines. Parthenolide treatment also dose-dependently increased the amount of the NF-KB inhibitory protein, IKB-A, and decreased NF-KB 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-KB 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 IKB-A protein were detected, especially in MIA PaCa-2 cells, after treatment with parthenolide and sulindac compared with each agent alone. Similarly, decreased NF-KB DNA binding and transcriptional activities were detected in cells treated with the combination compared with the single agents, demonstrating cooperative targeting of the NF-KB pathway. These data provide preclinical support for a combined chemotherapeutic approach with NF-KB inhibitors and NSAIDs for the treatment of pancreatic adenocarcinoma. [Mol Cancer Ther 2005;4(4):587–94]