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Research Articles: Therapeutics, Targets, and Development

Suppression of pancreatic tumor growth by combination chemotherapy with sulindac and LC-1 is associated with cyclin D1 inhibition in vivo

Departments of ¹ Surgery, ² Biochemistry/Molecular Biology, ³ Hematology/Oncology, and ⁴ Biostatistics and ⁵ Walther Oncology Center, Indiana University School of Medicine; ⁶ Indiana University Cancer Center; ⁷ Richard L. Roudebush VA Medical Center, Indianapolis, Indiana; and ⁸ College of Pharmacy, University of Kentucky, Lexington, Kentucky

Requests for reprints: C. Max Schmidt or Michele T. Yip-Schneider, Department of Surgery, Indiana University School of Medicine, 1044 West Walnut Street, Building R4, Room 041, Indianapolis, IN 46202. Phone: 317-278-4739; Fax: 317-274-0396. E-mail: maxschmi{at}iupui.edu or myipschn{at}iupui.edu

Abstract

The design of novel targeted or combination therapies may improve treatment options for pancreatic cancer. Two targets of recent interest are nuclear factor-B (NF-B) and cyclooxygenase (COX), known to be activated or overexpressed, respectively, in pancreatic cancer. We have previously shown that parthenolide, a proapoptotic drug associated with NF-B inhibition, enhanced the growth suppression of pancreatic cancer cells by the COX inhibitor sulindac in vitro. In the present study, a bioavailable analogue of parthenolide, LC-1, and sulindac were evaluated in vivo using a xenograft model of human pancreatic cancer. Treatment groups included placebo, low-dose/high-dose LC-1 (20 and 40 mg/kg), low-dose/high-dose sulindac (20 and 60 mg/kg), and low-dose combination LC-1/sulindac (20 mg/kg each). In MiaPaCa-2 xenografts, tumor growth was inhibited by either high-dose sulindac or LC-1. In BxPC-3 xenografts, tumor size was significantly reduced by treatment with the low-dose LC-1/sulindac combination or high-dose sulindac alone (P < 0.05). Immunohistochemistry of BxPC-3 tumors revealed a significant decrease in Ki-67 and CD31 staining by high-dose sulindac, with no significant changes in COX-1/COX-2 levels or activity in any of the treatment groups. NF-B DNA-binding activity was significantly decreased by high-dose LC-1. Cyclin D1 protein levels were reduced by the low-dose LC-1/sulindac combination or high-dose sulindac alone, correlating with BxPC-3 tumor suppression. These results suggest that LC-1 and sulindac may mediate their antitumor effects, in part, by altering cyclin D1 levels. Furthermore, this study provides preclinical evidence for the therapeutic efficacy of these agents. [Mol Cancer Ther 2007;6(6):1736–44]

Grant support: AACR-PanCAN Career Development Award (C.M. Schmidt), Veterans Affairs Merit Award (C.M. Schmidt), and American Cancer Society grant RSG-06-267-01-CCE (C.M. Schmidt and M.T. Yip-Schneider).

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.

⁹ Personal communication.

Received 12/27/06; revised 3/29/07; accepted 4/27/07.

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				Mol. Cancer Ther., October 1, 2007; 6(10): 2816 - 2816. [Full Text] [PDF]