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

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

^* To whom correspondence should be addressed. E-mail: maxschmi{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):OF1-9]

Key Words: sulindac, cyclooxygenase (COX), pancreatic cancer, NF-B, cyclin D1

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