1. Tandutinib inhibits the Akt/mTOR signaling pathway to inhibit colon cancer growth.
- Author
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Ponnurangam S, Standing D, Rangarajan P, and Subramaniam D
- Subjects
- Animals, Antineoplastic Agents administration & dosage, Apoptosis drug effects, Cell Cycle drug effects, Cell Cycle Proteins genetics, Cell Cycle Proteins metabolism, Cell Line, Tumor, Cell Proliferation drug effects, Colonic Neoplasms genetics, Colonic Neoplasms pathology, Gene Expression Regulation, Neoplastic drug effects, Humans, Male, Mice, Neovascularization, Pathologic drug therapy, Neovascularization, Pathologic genetics, Neovascularization, Pathologic metabolism, Piperazines administration & dosage, Protein Kinase Inhibitors administration & dosage, Proto-Oncogene Proteins c-kit genetics, Proto-Oncogene Proteins c-kit metabolism, Quinazolines administration & dosage, Tumor Burden drug effects, Xenograft Model Antitumor Assays, Antineoplastic Agents pharmacology, Colonic Neoplasms metabolism, Piperazines pharmacology, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Proteins c-akt metabolism, Quinazolines pharmacology, Signal Transduction drug effects, TOR Serine-Threonine Kinases metabolism
- Abstract
The c-Kit receptor can activate distinct signaling pathways including phosphoinositide 3-kinase (PI3K)/Akt and mTOR. Aberrant c-Kit activation protects cells from apoptosis and enhances invasion of colon carcinoma cells. Tandutinib is a novel quinazoline-based inhibitor of the type III receptor tyrosine kinases including c-Kit. We determined the effect of tandutinib on colon cancer growth and identified a mechanism of action. Tandutinib inhibited phosphorylation of c-Kit, Akt, mTOR, and p70S6 kinase. In addition, tandutinib significantly inhibited the proliferation and colony formation ability of colon cancer cell lines but did not affect normal colonic epithelial cells. There were increased levels of activated caspase-3 and Bax/Bcl2 ratio, coupled with a reduction in cyclin D1, suggesting apoptosis. There was also a downregulation of COX-2, VEGF, and interleukin-8 expression, suggesting effects on cancer-promoting genes. In addition, overexpressing constitutively active Akt partially suppressed tandutinib-mediated colon cancer cell growth. In vivo, intraperitoneal administration of tandutinib significantly suppressed growth of colon cancer tumor xenografts. There was a reduction in CD31-positive blood vessels, suggesting that there was an effect on angiogenesis. Tandutinib treatment also inhibited the expression of cancer-promoting genes COX-2 and VEGF and suppressed the activation of Akt/mTOR signaling proteins in the xenograft tissues. Together, these data suggest that tandutinib is a novel potent therapeutic agent that can target the Akt/mTOR/p70S6K signaling pathway to inhibit tumor growth and angiogenesis., (©2013 AACR)
- Published
- 2013
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