Parthenolide and sulindac cooperate to mediate growth suppression and inhibit the nuclear factor-κB pathway in pancreatic carcinoma cells
| Autor: | Michele T. Yip-Schneider, Harikrishna Nakshatri, C. Max Schmidt, Eric A. Wiebke, Christopher Sweeney, Mark S. Marshall |
|---|---|
| Rok vydání: | 2005 |
| Předmět: |
Cancer Research
Transcription Genetic endocrine system diseases Blotting Western Apoptosis Biology Pharmacology Transfection medicine.disease_cause Models Biological chemistry.chemical_compound Sulindac Cell Line Tumor Pancreatic cancer Antineoplastic Combined Chemotherapy Protocols medicine Humans Parthenolide Phosphorylation Cell Proliferation Dose-Response Relationship Drug Cell growth Anti-Inflammatory Agents Non-Steroidal Carcinoma NF-kappa B Drug Synergism medicine.disease digestive system diseases Pancreatic Neoplasms Oncology chemistry Cell culture Growth inhibition Carcinogenesis Sesquiterpenes Protein Binding medicine.drug |
| Zdroj: | Molecular Cancer Therapeutics. 4:587-594 |
| ISSN: | 1538-8514 1535-7163 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|