Preclinical Research Center

Yongin Si, South Korea

Preclinical Research Center

Yongin Si, South Korea
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Zhu B.,University Park | Zhu B.,Pennsylvania State University | Bai R.,University Park | Kennett M.J.,University Park | And 4 more authors.
Molecular Cancer Therapeutics | Year: 2010

Ligand activation of peroxisome proliferator-activated receptor-β/ δ (PPARβ/δ) and inhibition of cyclooxygenase-2 (COX2) activity by nonsteroidal anti-inflammatory drugs (NSAID) can both attenuate skin tumorigenesis. The present study examined the hypothesis that combining ligand activation of PPARβ/δ with inhibition of COX2 activity will increase the efficacy of chemoprevention of chemically induced skin tumorigenesis over that observed with either approach alone. To test this hypothesis, wildtype and Pparβ/δ-null mice were initiated with 7,12-dimethylbenz[a]anthracene (DMBA), topically treated with 12-O-tetradecanoylphorbol-13-acetate to promote tumorigenesis, and then immediately treated with topical application of the PPARβ/δ ligand GW0742, dietary administration of the COX2 inhibitor nimesulide, or both GW0742 and nimesulide. Ligand activation of PPARβ/δ with GW0742 caused a PPARβ/δ-dependent delay in the onset of tumor formation. Nimesulide also delayed the onset of tumor formation and caused inhibition of tumor multiplicity (46%) in wild-type mice but not in Pparβ/δ-null mice. Combining ligand activation of PPARβ/δ with dietary nimesulide resulted in a further decrease of tumor multiplicity (58%) in wild-type mice but not in Pparβ/δ-null mice. Biochemical and molecular analysis of skin and tumor samples show that these effects were due to the modulation of terminal differentiation, attenuation of inflammatory signaling, and induction of apoptosis through both PPARβ/δ-dependent and PPARβ/δ-independent mechanisms. Increased levels and activity of PPARβ/δ by nimesulide were also observed. These studies support the hypothesis that combining ligand activation of PPARβ/δ with inhibition of COX2 activity increases the efficacy of preventing chemically induced skin tumorigenesis as compared with either approach alone. ©2010 AACR.


Zhu B.,Pennsylvania State University | Ferry C.H.,Pennsylvania State University | Blazanin N.,Pennsylvania State University | Bility M.T.,Pennsylvania State University | And 5 more authors.
Oncogene | Year: 2013

Peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) inhibits skin tumorigenesis through mechanisms that may be dependent on HRAS signaling. The present study examined the hypothesis that PPARβ/δ promotes HRAS-induced senescence resulting in suppression of tumorigenesis. PPARβ/δ expression increased p-ERK and decreased p-AKT activity. Increased p-ERK activity results from the dampened HRAS-induced negative feedback response mediated in part through transcriptional upregulation of RAS guanyl-releasing protein 1 (RASGRP1) by PPARβ/δ. Decreased p-AKT activity results from repression of integrin-linked kinase (ILK) and phosphoinositide-dependent protein kinase-1 (PDPK1) expression. Decreased p-AKT activity in turn promotes cellular senescence through upregulation of p53 and p27 expression. Both over-expression of RASGRP1 and shRNA-mediated knockdown of ILK partially restore cellular senescence in Pparβ/δ-null cells. Higher PPARβ/δ expression is also correlated with increased senescence observed in human benign neurofibromas and colon adenoma lesions in vivo. These results demonstrate that PPARβ/δ promotes senescence to inhibit tumorigenesis and provide new mechanistic insights into HRAS-induced cellular senescence.Oncogene advance online publication, 11 November 2013; doi:10.1038/onc.2013.477.


PubMed | Pennsylvania State University, Preclinical Research Center and U.S. National Cancer Institute
Type: Journal Article | Journal: Oncogene | Year: 2014

Peroxisome proliferator-activated receptor-/ (PPAR/) inhibits skin tumorigenesis through mechanisms that may be dependent on HRAS signaling. The present study examined the hypothesis that PPAR/ promotes HRAS-induced senescence resulting in suppression of tumorigenesis. PPAR/ expression increased p-ERK and decreased p-AKT activity. Increased p-ERK activity results from the dampened HRAS-induced negative feedback response mediated in part through transcriptional upregulation of RAS guanyl-releasing protein 1 (RASGRP1) by PPAR/. Decreased p-AKT activity results from repression of integrin-linked kinase (ILK) and phosphoinositide-dependent protein kinase-1 (PDPK1) expression. Decreased p-AKT activity in turn promotes cellular senescence through upregulation of p53 and p27 expression. Both over-expression of RASGRP1 and shRNA-mediated knockdown of ILK partially restore cellular senescence in Ppar/-null cells. Higher PPAR/ expression is also correlated with increased senescence observed in human benign neurofibromas and colon adenoma lesions in vivo. These results demonstrate that PPAR/ promotes senescence to inhibit tumorigenesis and provide new mechanistic insights into HRAS-induced cellular senescence.


Walkowiak K.J.,Research Animal Resources | Graham M.L.,Preclinical Research Center | Graham M.L.,University of Minnesota
Journal of the American Association for Laboratory Animal Science | Year: 2015

Buprenorphine is a potent analgesic commonly administered to alleviate pain in sheep used in research. Sustained-release buprenorphine (SRB) is an alternative to conventional buprenorphine hydrochloride (which must be injected repeatedly). To compare SRB with a typical conventional buprenorphine regimen (0.03 mg/kg every 8 h for 72 h), we used a simple 1:1 conversion to calculate a total SRB dose of 0.27 mg/kg per injection. The pharmacokinetics and thermal nociceptive effects of SRB were analyzed in 4 healthy adult sheep after a single intramuscular injection plus a washout period then a single subcutaneous injection. For both routes in all 4 sheep, plasma buprenorphine concentrations exceeded 0.1 ng/mL, considered the minimal threshold for therapeutic benefit, after 12 h and maintained a steady state for at least 72 h Likewise, for both routes in all sheep, thermal thresholds increased significantly between baseline and 12 h; lack of response persisted for at least 72 h. The average maximal plasma buprenorphine concentrations and bioavailability were similar for both routes. No clinical adverse effects occurred. Using a dose equivalent to the total course of conventional buprenorphine, this pilot study suggests that SRB is a well-tolerated, effective, and long-acting analgesic that can be administered as a single intramuscular or subcutaneous injection. SRB confers steady plasma concentrations and continuous analgesia in thermal nociception for at least 72 h. When compared with conventional buprenorphine, SRB has considerable advantages in improving wellbeing by minimizing handling-associated stress of repeated injection and limiting the likelihood of end-of-dose breakthrough pain.

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