ToxSci Advance Access published online on March 16, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm060
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Nicotine Promotes Colon Tumor Growth and Angiogenesis Through ß-Adrenergic Activation
,
,1
* Department of Pharmacology, The University of Hong Kong, Hong Kong, China
Department of Pharmacology, The Chinese University of Hong Kong, Hong Kong, China
Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
1 To whom correspondence should be address: Professor Chi-Hin Cho, Department of Pharmacology, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China. Phone: 852-2609-6886; Fax: 852-2603-5139; Email: chcho{at}cuhk.edu.hk
Received December 28, 2006;
revision received February 26, 2007; revision received February 26, 2007;
 |
Abstract |
|---|
Cigarette smoking is a putative environmental risk factor for colon cancer. Nicotine, an active alkaloid in tobacco, has been implicated in carcinogenesis. In the present study, we demonstrated that oral nicotine administration (50 or 200 µg/ml) for 25 days stimulated growth of human colon cancer xenograft in nude mice. It also increased vascularization in the tumors and elevated cotinine and adrenaline plasma levels. ß-adrenoceptors, cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2) and vascular endothelial growth factor (VEGF) in tumor tissues were also increased by nicotine. Intraperitoneal injection of ß1-selective antagonist (atenolol, 5 or 10 mg/kg) or ß2-selective antagonist (ICI 118,551, 5 or 10 mg/kg) blocked the nicotine-stimulated tumor growth dose-dependently, in which ß2-selective antagonist produced a more prominent effect. ß-adrenoceptors blockade also abrogated the stimulatory action of nicotine on microvessel densities as well as cell expression of COX-2, PGE2 and VEGF, in which ß2-selective antagonist produced a significant effect. These findings provide a direct evidence that nicotine can enhance colon tumor growth mediated partly by stimulation of ß-adrenoceptors, preferentially the ß2-adrenoceptors. Activation of ß-adrenoceptors and the subsequent stimulation of COX-2, PGE2 and VEGF expression is perhaps an important mechanism in the tumorigenic action of nicotine on colon tumor growth. These data suggest that ß-adrenoceptors play a modulatory role in the development of colon cancer and partly elucidate the carcinogenic action of cigarette smoke.
Key Words: colon cancer; nicotine; ß-adrenoceptors; smoking.