RGD Reference Report - Suppression of pancreatic tumor growth by combination chemotherapy with sulindac and LC-1 is associated with cyclin D1 inhibition in vivo. - Rat Genome Database

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

Authors: Yip-Schneider, Michele T  Wu, Huangbing  Ralstin, Matthew  Yiannoutsos, Constantin  Crooks, Peter A  Neelakantan, Sundar  Noble, Stephen  Nakshatri, Harikrishna  Sweeney, Christopher J  Schmidt, C Max 
Citation: Yip-Schneider MT, etal., Mol Cancer Ther. 2007 Jun;6(6):1736-44. doi: 10.1158/1535-7163.MCT-06-0794. Epub 2007 May 31.
RGD ID: 13462059
Pubmed: PMID:17541034   (View Abstract at PubMed)
DOI: DOI:10.1158/1535-7163.MCT-06-0794   (Journal Full-text)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
pancreatic cancer treatmentIDA 13462059human cells in a mouse modelRGD 
pancreatic cancer treatmentISOCCND1 (Homo sapiens)13462059; 13462059human cells in a mouse modelRGD 

Objects Annotated

Genes (Rattus norvegicus)
Ccnd1  (cyclin D1)

Genes (Mus musculus)
Ccnd1  (cyclin D1)

Genes (Homo sapiens)
CCND1  (cyclin D1)


Additional Information