regression of panc cancer in mice from Sulindac / parthenolide combo

regression of panc cancer in mice from Sulindac / parthenolide combo

* w w w .ncbi.nlm.nih.gov/pubmed/17541034?ordinalpos=5&itool=EntrezSystem2
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Mol Cancer Ther. 2007 Jun;6(6):1736-44. Epub 2007 May 31.

Erratum in:
Mol Cancer Ther. 2007 Oct;6(10):2816.

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

Yip-Schneider MT, Wu H, Ralstin M, Yiannoutsos C, Crooks PA, Neelakantan S,
Noble S, Nakshatri H, Sweeney CJ, Schmidt CM.
Department of Surgery, Indiana University School of Medicine, Indianapolis,
IN 46202, USA. myipschn@iupui.edu

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.