title: Suppression of pancreatic tumor growth by combination chemotherapy with sulindac and LC-1 is associated with cyclin D1 inhibition in vivo.
abstract: The design of novel targeted or combination therapies may improve treatment options for pancreatic cancer. Two targets of recent interest are nuclear factor-kappaB (NF-kappaB) 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-kappaB 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-kappaB 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.
authors.affiliation: Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA. myipschn@iupui.edu
authors.forename: Michele T
authors.initials: MT
authors.lastname: Yip-Schneider
authors.forename: Huangbing
authors.initials: H
authors.lastname: Wu
authors.forename: Matthew
authors.initials: M
authors.lastname: Ralstin
authors.forename: Constantin
authors.initials: C
authors.lastname: Yiannoutsos
authors.forename: Peter A
authors.initials: PA
authors.lastname: Crooks
authors.forename: Sundar
authors.initials: S
authors.lastname: Neelakantan
authors.forename: Stephen
authors.initials: S
authors.lastname: Noble
authors.forename: Harikrishna
authors.initials: H
authors.lastname: Nakshatri
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Sweeney
authors.forename: C Max
authors.initials: CM
authors.lastname: Schmidt
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000037:antagonists & inhibitors*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D012717:Sesquiterpenes / Q000494:pharmacology*; D013467:Sulindac / Q000494:pharmacology*
chemical_list: D016328:NF-kappa B; D012717:Sesquiterpenes; D019938:Cyclin D1; D013467:Sulindac; C002669:parthenolide; D011451:Prostaglandin-Endoperoxide Synthases