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Departments of ¹ Surgery, ² Biochemistry/Molecular Biology, and ³ Hematology/Oncology; ⁴ Walther Oncology Center, Indiana University School of Medicine; ⁵ Indiana University Cancer Center; ⁶ Lilly Research Laboratories; and ⁷ Richard L. Roudebush VA Medical Center, Indianapolis, Indiana

Requests for reprints: C. Max Schmidt or Michele T. Yip-Schneider, Department of Surgery, Indiana University School of Medicine, Room 041, Building R4, 1044 West Walnut Street, Indianapolis, IN 46202. Phone: 317-278-3324; Fax: 317-278-4325. E-mail: maxschmi{at}iupui.edu or myipschn{at}iupui.edu

Activation of the transcription factor nuclear factor-B (NF-B) has been implicated in pancreatic tumorigenesis. We evaluated the effect of a novel NF-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 µmol/L parthenolide in all three cell lines. Parthenolide treatment also dose-dependently increased the amount of the NF-B inhibitory protein, IB-, and decreased NF-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-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 IB- protein were detected, especially in MIA PaCa-2 cells, after treatment with parthenolide and sulindac compared with each agent alone. Similarly, decreased NF-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-B pathway. These data provide preclinical support for a combined chemotherapeutic approach with NF-B inhibitors and NSAIDs for the treatment of pancreatic adenocarcinoma.

Key Words: NF-B • parthenolide • pancreatic cancer • NSAIDs • sulindac

Grant support: American Cancer Society institutional research grant IRG-84-002-19 and Eli Lilly Co. research grant.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

⁸ Unpublished data.

⁹ Unpublished data.

Received 8/20/04; revised 1/21/05; accepted 2/ 3/05.