TY - JOUR
T1 - Oncogenic targets Mmp7, S100a9, Nppb and Aldh1a3 from transcriptome profiling of FAP and Pirc adenomas are downregulated in response to tumor suppression by Clotam
AU - Ertem, Furkan U.
AU - Zhang, Wenqian
AU - Chang, Kyle
AU - Mohaiza Dashwood, Wan
AU - Rajendran, Praveen
AU - Sun, Deqiang
AU - Abudayyeh, Ala
AU - Vilar, Eduardo
AU - Abdelrahim, Maen
AU - Dashwood, Roderick H.
N1 - Funding Information:
The authors are grateful to Lindsey Chew, Ahsan Khan and Li Li for help with breeding, genotyping and animal treatments. These individuals, plus Ying-Shiuan Chen, Gavin Johnson and Nhung Nguyen also are acknowledged for their assistance during necropsies.
Publisher Copyright:
© 2016 UICC
PY - 2017/1/15
Y1 - 2017/1/15
N2 - Intervention strategies in familial adenomatous polyposis (FAP) patients and other high-risk colorectal cancer (CRC) populations have highlighted a critical need for endoscopy combined with safe and effective preventive agents. We performed transcriptome profiling of colorectal adenomas from FAP patients and the polyposis in rat colon (Pirc) preclinical model, and prioritized molecular targets for prevention studies in vivo. At clinically relevant doses in the Pirc model, the drug Clotam (tolfenamic acid, TA) was highly effective at suppressing tumorigenesis both in the colon and in the small intestine, when administered alone or in combination with Sulindac. Cell proliferation in the colonic crypts was reduced significantly by TA, coincident with increased cleaved caspase-3 and decreased Survivin, β-catenin, cyclin D1 and matrix metalloproteinase 7. From the list of differentially expressed genes prioritized by transcriptome profiling, Mmp7, S100a9, Nppb and Aldh1a3 were defined as key oncogene candidates downregulated in colon tumors after TA treatment. Monthly colonoscopies revealed the rapid onset of tumor suppression by TA in the Pirc model, and the temporal changes in Mmp7, S100a9, Nppb and Aldh1a3, highlighting their value as potential early biomarkers for prevention in the clinical setting. We conclude that TA, an “old drug” repurposed from migraine, offers an exciting new therapeutic avenue in FAP and other high-risk CRC patient populations.
AB - Intervention strategies in familial adenomatous polyposis (FAP) patients and other high-risk colorectal cancer (CRC) populations have highlighted a critical need for endoscopy combined with safe and effective preventive agents. We performed transcriptome profiling of colorectal adenomas from FAP patients and the polyposis in rat colon (Pirc) preclinical model, and prioritized molecular targets for prevention studies in vivo. At clinically relevant doses in the Pirc model, the drug Clotam (tolfenamic acid, TA) was highly effective at suppressing tumorigenesis both in the colon and in the small intestine, when administered alone or in combination with Sulindac. Cell proliferation in the colonic crypts was reduced significantly by TA, coincident with increased cleaved caspase-3 and decreased Survivin, β-catenin, cyclin D1 and matrix metalloproteinase 7. From the list of differentially expressed genes prioritized by transcriptome profiling, Mmp7, S100a9, Nppb and Aldh1a3 were defined as key oncogene candidates downregulated in colon tumors after TA treatment. Monthly colonoscopies revealed the rapid onset of tumor suppression by TA in the Pirc model, and the temporal changes in Mmp7, S100a9, Nppb and Aldh1a3, highlighting their value as potential early biomarkers for prevention in the clinical setting. We conclude that TA, an “old drug” repurposed from migraine, offers an exciting new therapeutic avenue in FAP and other high-risk CRC patient populations.
KW - colorectal cancer
KW - polyposis in rat colon
KW - prevention
KW - tolfenamic acid
KW - β-catenin/Tcf
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U2 - 10.1002/ijc.30458
DO - 10.1002/ijc.30458
M3 - Article
C2 - 27706811
AN - SCOPUS:84991624938
SN - 0020-7136
VL - 140
SP - 460
EP - 468
JO - International journal of cancer
JF - International journal of cancer
IS - 2
ER -