title: Parthenolide and sulindac cooperate to mediate growth suppression and inhibit the nuclear factor-kappa B pathway in pancreatic carcinoma cells.
abstract: Activation of the transcription factor nuclear factor-kappa B (NF-kappa B) has been implicated in pancreatic tumorigenesis. We evaluated the effect of a novel NF-kappa B 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 micromol/L parthenolide in all three cell lines. Parthenolide treatment also dose-dependently increased the amount of the NF-kappa B inhibitory protein, I kappa B-alpha, and decreased NF-kappa B 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-kappa B 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 I kappa B-alpha protein were detected, especially in MIA PaCa-2 cells, after treatment with parthenolide and sulindac compared with each agent alone. Similarly, decreased NF-kappa B DNA binding and transcriptional activities were detected in cells treated with the combination compared with the single agents, demonstrating cooperative targeting of the NF-kappa B pathway. These data provide preclinical support for a combined chemotherapeutic approach with NF-kappa B inhibitors and NSAIDs for the treatment of pancreatic adenocarcinoma.
authors.affiliation: Department of Surgery, Indiana University School of Medicine, Room 041, Building R4, 1044 West Walnut Street, Indianapolis, IN 46202, USA. myipschn@iupui.edu <myipschn@iupui.edu>
authors.forename: Michele T
authors.initials: MT
authors.lastname: Yip-Schneider
authors.forename: Harikrishna
authors.initials: H
authors.lastname: Nakshatri
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Sweeney
authors.forename: Mark S
authors.initials: MS
authors.lastname: Marshall
authors.forename: Eric A
authors.initials: EA
authors.lastname: Wiebke
authors.forename: C Max
authors.initials: CM
authors.lastname: Schmidt
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis; D015153:Blotting, Western; D002277:Carcinoma / Q000188:drug therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006801:Humans; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D010766:Phosphorylation; D011485:Protein Binding; D012717:Sesquiterpenes / Q000008:administration & dosage*; D013467:Sulindac / Q000008:administration & dosage*; D014158:Transcription, Genetic; D014162:Transfection
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016328:NF-kappa B; D012717:Sesquiterpenes; D013467:Sulindac; C002669:parthenolide