Carcinogenesis Advance Access published online on April 29, 2004
Carcinogenesis, doi:10.1093/carcin/bgh180
© 2004 by Oxford University Press
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1 Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Health Sciences Center, Denver, CO 80262, USA
* To whom correspondence should be addressed. E-mail: Rajesh.Agarwal{at}UCHSC.edu.
Bladder cancer is the fourth and eighth most common cancer in men and women in the United States, respectively. Flavonoid phytochemicals are being studied for both prevent ion and therapy of various human malignancies including bladder cancer. One such naturally occurring flavonoid is silibinin isolated from milk thistle. Here, we assessed the effect of silibinin on human bladder transitional cell carcinoma (TCC) cell growth, cell cycle modulation and apoptosis induction, and associated molecular alterations, employing two different cell lines representing high-grade invasive tumor (TCC-SUP) and high-grade TCC (T-24) human bladder cancer. Silibinin treatment of these cells resulted in a significant dose- and time-dependent growth inhibition together with a G1 arrest only at lower doses in TCC-SUP cells but at both lower and higher doses in T-24 cells; higher silibinin dose showed a G2/M arrest in TCC-SUP cells. In other studies, silibinin treatment strongly induced the expression of Cip1/p21 and Kip1/p27, but resulted in a decrease in cyclin dependent kinases (CDKs) and cyclins involved in G1 progression. Silibinin treatment also showed an increased interaction between CDKIs-CDKs and a decreased CDK kinase activity. Further, the G2/M arrest by silibinin in TCC-SUP cells was associated with a decrease in pCdc25c (Ser216), Cdc25c, pCdc2 (Tyr15), Cdc2 and cyclin B1 protein levels. In additional studies, silibinin showed a dose- and a time-dependent apoptotic death only in TCC-SUP cells that was associated with cleaved forms of caspase 3 and PARP. Together, these results suggest that silibinin modulates CDKI-CDK-cyclin cascade and activates caspase 3 causing growth inhibition and apoptotic death of human TCC cells, providing a strong rationale for future studies evaluating preventive and/or intervention strategies for silibinin in bladder cancer pre-clinical models. Key Words:
Silibinin, bladder cancer, cell cycle, apoptosis, CDKI, CDK, cyclin, caspases
Revised April 12, 2004
Accepted April 23, 2004
MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION
Silibinin causes cell cycle arrest and apoptosis in human bladder transitional cell carcinoma cells by regulating CDKI-CDK-cyclin cascade, and caspase 3 and PARP cleavages
2 Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Health Sciences Center, Denver, CO 80262, USA; University of Colorado Cancer Center, University of Colorado Health Sciences Center, Denver, CO 80262, USA
3 Division of Medical Oncology, Department of Medicine, University of Colorado Health Sciences Center, Denver, CO 80262, USA
4 University of Colorado Cancer Center, University of Colorado Health Sciences Center, Denver, CO 80262, USA; Division of Medical Oncology, Department of Medicine, University of Colorado Health Sciences Center, Denver, CO 80262, USA
Abstract 
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  T.-T. Ou, C.-J. Wang, G.-U. Hung, C.-H. Wu, and H.-J. Lee Aqueous Extract of Shi-Liu-Wei-Liu-Qi-Yin Induces G2/M Phase Arrest and Apoptosis in Human Bladder Carcinoma Cells via Fas and Mitochondrial Pathway Evid. Based Complement. Altern. Med., May 25, 2009; (2009) nep016v2. [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]
|
|
|
|
 |
|
 A. Tyagi, K. Raina, R. P. Singh, M. Gu, C. Agarwal, G. Harrison, L. M. Glode, and R. Agarwal Chemopreventive effects of silymarin and silibinin on N-butyl-N-(4-hydroxybutyl) nitrosamine induced urinary bladder carcinogenesis in male ICR mice Mol. Cancer Ther., December 1, 2007; 6(12): 3248 - 3255. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E.-R. Hahm and S. V. Singh Honokiol causes G0-G1 phase cell cycle arrest in human prostate cancer cells in association with suppression of retinoblastoma protein level/phosphorylation and inhibition of E2F1 transcriptional activity Mol. Cancer Ther., October 1, 2007; 6(10): 2686 - 2695. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Roy, M. Kaur, C. Agarwal, M. Tecklenburg, R. A. Sclafani, and R. Agarwal p21 and p27 induction by silibinin is essential for its cell cycle arrest effect in prostate carcinoma cells Mol. Cancer Ther., October 1, 2007; 6(10): 2696 - 2707. [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. Provinciali, F. Papalini, F. Orlando, S. Pierpaoli, A. Donnini, P. Morazzoni, A. Riva, and A. Smorlesi Effect of the Silybin-Phosphatidylcholine Complex (IdB 1016) on the Development of Mammary Tumors in HER-2/neu Transgenic Mice Cancer Res., March 1, 2007; 67(5): 2022 - 2029. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Tyagi, R. P. Singh, C. Agarwal, and R. Agarwal Silibinin activates p53-caspase 2 pathway and causes caspase-mediated cleavage of Cip1/p21 in apoptosis induction in bladder transitional-cell papilloma RT4 cells: evidence for a regulatory loop between p53 and caspase 2 Carcinogenesis, November 1, 2006; 27(11): 2269 - 2280. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Zhang, S. Loganathan, I. Humphreys, and S. K. Srivastava Benzyl Isothiocyanate-Induced DNA Damage Causes G2/M Cell Cycle Arrest and Apoptosis in Human Pancreatic Cancer Cells J. Nutr., November 1, 2006; 136(11): 2728 - 2734. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. F. McCarty and K. I. Block Multifocal Angiostatic Therapy: An Update Integr Cancer Ther, December 1, 2005; 4(4): 301 - 314. [Abstract] [PDF]
|
|
|
|
|
|
L. Varghese, C. Agarwal, A. Tyagi, R. P. Singh, and R. Agarwal Silibinin Efficacy against Human Hepatocellular Carcinoma Clin. Cancer Res., December 1, 2005; 11(23): 8441 - 8448. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Gu, S. Dhanalakshmi, S. Mohan, R. P. Singh, and R. Agarwal Silibinin inhibits ultraviolet B radiation-induced mitogenic and survival signaling, and associated biological responses in SKH-1 mouse skin Carcinogenesis, August 1, 2005; 26(8): 1404 - 1413. [Abstract] [Full Text] [PDF]
|
|