Effect of Silibinin on the Growth and Progression of Primary Lung Tumors in Mice

• Published in: JNCI : Journal of the National Cancer Institute Vol. 98; no. 12; pp. 846 - 855
• Main Authors: Singh, Rana P., Deep, Gagan, Chittezhath, Manesh, Kaur, Manjinder, Dwyer-Nield, Lori D., Malkinson, Alvin M., Agarwal, Rajesh
• Format: Journal Article
• Language: English
• Published: Cary, NC Oxford University Press 21-06-2006; Oxford Publishing Limited (England)
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents - pharmacology; Antioxidants; Apoptosis - drug effects; Biological and medical sciences; Biomarkers, Tumor - metabolism; Blotting, Western; Carcinogens; Cell Proliferation - drug effects; Chemotherapy; Cyclin D1 - drug effects; Cyclooxygenase 2 - drug effects; Diet; Disease Models, Animal; Fibroblast Growth Factor 2 - drug effects; Immunohistochemistry; Inflammation - drug therapy; Lung cancer; Lung Neoplasms - blood supply; Lung Neoplasms - chemically induced; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Medical sciences; Mice; Microcirculation - drug effects; Neovascularization, Pathologic - drug therapy; Nitric Oxide Synthase Type II - drug effects; Pharmacology. Drug treatments; Platelet Endothelial Cell Adhesion Molecule-1 - drug effects; Proliferating Cell Nuclear Antigen - metabolism; Rodents; Silymarin - pharmacology; Tumors; Urethane; Vascular Endothelial Growth Factor A - drug effects; Antineoplastic agent; Lung disease; Chemoprophylaxis; Respiratory disease; Lung cancer; Rodentia; Malignant tumor; Flavonoid; Prevention; Polyphenol; Vertebrata; Mammalia; Cancerology; Mouse; Animal; Silibinin; Phenols; Bronchus disease; Antiangiogenic agent
• ISSN: 0027-8874; 1460-2105
• DOI: 10.1093/jnci/djj231

Background: Silibinin, a flavanone from milk thistle, inhibits the growth of tumors in several rodent models. We examined the effects of dietary silibinin on the growth, progression, and angiogenesis of urethane-induced lung tumors in mice. Methods: A/J mice (15 per group) were injected with urethane (1 mg/g body weight) or saline alone and fed normal diets for 2 weeks, after which they were fed diets containing different doses of silibinin (0%–1% [wt/wt] silibinin) for 18 or 27 weeks. Immunohistochemistry and Western blot analysis were used to examine angiogenesis and enzymatic markers of inflammation, proliferation, and apoptosis. All statistical tests were two-sided. Results: Urethane-injected mice exposed to silibinin had statistically significantly lower lung tumor multiplicities than urethane-injected mice fed the control diet lacking silibinin (i.e., control mice). Mice that received urethane and 1% (wt/wt) dietary silibinin for 18 weeks had 93% fewer large (i.e., 1.5–2.5-mm-diameter) lung tumors than control mice (mean number of tumors/mouse: 27 in the urethane group versus 2 in the urethane + 1% silibinin group, difference = 25 tumors/mouse, 95% confidence interval [CI] = 13 to 37 tumors/mouse, P = .005). Lung tumors of silibinin-fed mice had 41%–74% fewer cells positive for the cell proliferation markers proliferating cell nuclear antigen and cyclin D1 than lung tumors of control mice. Tumor microvessel density was reduced by up to 89% with silibinin treatment (e.g., 56 microvessels/400× field in tumors from control mice versus 6 microvessels/400× field in tumors from urethane + 1% silibinin-treated mice [difference = 50 microvessels/400× field, 95% CI = 46 to 54 microvessels/400× field; P<.001]). Silibinin decreased lung tumor expression of vascular endothelial growth factor (VEGF) and of inducible nitric oxide synthase and cyclooxygenase-2, two enzymes that promote lung tumor growth and progression by inducing VEGF expression. Conclusions: Silibinin inhibits lung tumor angiogenesis in an animal model and merits investigation as a chemopreventive agent for suppressing lung cancer progression.