6-C-(E-phenylethenyl)-naringenin suppresses colorectal cancer growth by inhibiting cyclooxygenase-1.
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.
Authors' Affiliations: The Hormel Institute, University of Minnesota, Austin, Minnesota; The National Institutes of Health, National Cancer Institute, Bethesda, Maryland; and School of Biological Sciences, The University of Hong Kong, Hong Kong, China.
Haitao
H
Li
Feng
F
Zhu
Hanyong
H
Chen
Ka Wing
KW
Cheng
Tatyana
T
Zykova
Naomi
N
Oi
Ronald A
RA
Lubet
Ann M
AM
Bode
Mingfu
M
Wang
Zigang
Z
Dong
D000818:Animals; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control; D051545:Cyclooxygenase 1 / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004195:Disease Models, Animal; D005260:Female; D044950:Flavanones / Q000494:pharmacology*; D019073:HT29 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
D016861:Cyclooxygenase Inhibitors; D044950:Flavanones; D051545:Cyclooxygenase 1; C005273:naringenin