Journal
CANCER RESEARCH
Volume 74, Issue 1, Pages 243-252Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-13-2245
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Funding
- Hormel Foundation
- National Institutes of Health [R37 CA081064, ES016548]
- NCI [HHSN-261200533001C-NO1-CN-53301, N01-CN-43309-18018-01WA 13B]
- NATIONAL CANCER INSTITUTE [R37CA081064] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES [R01ES016548] Funding Source: NIH RePORTER
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Recent clinical trials raised concerns regarding the cardiovascular toxicity of selective cyclooxygenase-2 (COX-2) inhibitors and cyclooxygenase-1 (COX-1) is now being reconsidered as a target for chemoprevention. Our aims were to determine whether selective COX-1 inhibition could delay or prevent cancer development and also clarify the underlying mechanisms. Data clearly showed that COX-1 was required for maintenance of malignant characteristics of colon cancer cells or tumor promoter-induced transformation of preneoplastic cells. We also successfully applied a ligand-docking computational method to identify a novel selective COX-1 inhibitor, 6-C-(E-phenylethenyl)-naringenin (designated herein as 6CEPN). 6CEPN could bind to COX-1 and specifically inhibited its activity both in vitro and ex vivo. In colorectal cancer cells, it potently suppressed anchorage-independent growth by inhibiting COX-1 activity. 6CEPN also effectively suppressed tumor growth in a 28-day colon cancer xenograft model without any obvious systemic toxicity. Taken together, COX-1 plays a critical role in human colorectal carcinogenesis, and this specific COX-1 inhibitor merits further investigation as a potential preventive agent against colorectal cancer. (C)2013 AACR.
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