© The Author 2006. Published by Oxford University Press.
ARTICLE |
Effect of Silibinin on the Growth and Progression of Primary Lung Tumors in Mice
Affiliations of authors: Department of Pharmaceutical Sciences, School of Pharmacy (RPS, GD, MC, MK, LDDN, AMM, RA), University of Colorado Cancer Center (AMM, RA), University of Colorado Health Sciences Center, Denver, CO
Correspondence to: Rajesh Agarwal, PhD, 4200 E. 9th Ave., Box C238, Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Cancer Center, Denver, CO 80262 (e-mail: rajesh.agarwal{at}uchsc.edu).
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/400x field in tumors from control mice versus 6 microvessels/400x field in tumors from urethane + 1% silibinin-treated mice [difference = 50 microvessels/400x field, 95% CI = 46 to 54 microvessels/400x 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.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  C.-X. Xu, D. Jere, H. Jin, S.-H. Chang, Y.-S. Chung, J.-Y. Shin, J.-E. Kim, S.-J. Park, Y.-H. Lee, C.-H. Chae, et al. Poly(ester amine)-mediated, Aerosol-delivered Akt1 Small Interfering RNA Suppresses Lung Tumorigenesis Am. J. Respir. Crit. Care Med., July 1, 2008; 178(1): 60 - 73. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Chittezhath, G. Deep, R. P. Singh, C. Agarwal, and R. Agarwal Silibinin inhibits cytokine-induced signaling cascades and down-regulates inducible nitric oxide synthase in human lung carcinoma A549 cells Mol. Cancer Ther., July 1, 2008; 7(7): 1817 - 1826. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. P. Singh, M. Gu, and R. Agarwal Silibinin Inhibits Colorectal Cancer Growth by Inhibiting Tumor Cell Proliferation and Angiogenesis Cancer Res., March 15, 2008; 68(6): 2043 - 2050. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. P. Singh, A. Tyagi, G. Sharma, S. Mohan, and R. Agarwal Oral Silibinin Inhibits In vivo Human Bladder Tumor Xenograft Growth Involving Down-Regulation of Survivin Clin. Cancer Res., January 1, 2008; 14(1): 300 - 308. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. P. Singh, G. Deep, M.-J. Blouin, M. N. Pollak, and R. Agarwal Silibinin suppresses in vivo growth of human prostate carcinoma PC-3 tumor xenograft Carcinogenesis, December 1, 2007; 28(12): 2567 - 2574. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y.-g. Son, E. H. Kim, J. Y. Kim, S. U. Kim, T. K. Kwon, A-R. Yoon, C.-O. Yun, and K. S. Choi Silibinin Sensitizes Human Glioma Cells to TRAIL-Mediated Apoptosis via DR5 Up-regulation and Down-regulation of c-FLIP and Survivin Cancer Res., September 1, 2007; 67(17): 8274 - 8284. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. C. Comelli, U. Mengs, C. Schneider, and M. Prosdocimi Toward the Definition of the Mechanism of Action of Silymarin: Activities Related to Cellular Protection From Toxic Damage Induced by Chemotherapy Integr Cancer Ther, June 1, 2007; 6(2): 120 - 129. [Abstract] [PDF]
|
|
|
|
|
|
G. Deep and R. Agarwal Chemopreventive Efficacy of Silymarin in Skin and Prostate Cancer Integr Cancer Ther, June 1, 2007; 6(2): 130 - 145. [Abstract] [PDF]
|
|
|
|
|
|
S. M. Sagar Future Directions for Research on Silybum marianum for Cancer Patients Integr Cancer Ther, June 1, 2007; 6(2): 166 - 173. [Abstract] [PDF]
|
|
|
|
 |
|
 E. F. Redente, D. J. Orlicky, R. J. Bouchard, and A. M. Malkinson Tumor Signaling to the Bone Marrow Changes the Phenotype of Monocytes and Pulmonary Macrophages during Urethane-Induced Primary Lung Tumorigenesis in A/J Mice Am. J. Pathol., February 1, 2007; 170(2): 693 - 708. [Abstract] [Full Text] [PDF]
|
|