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Epidemiology and Prevention |
Department of Pharmaceutical Sciences, School of Pharmacy [R. P. S., S. D., A. K. T., C. A., R. A.], Division of Medical Oncology, Department of Medicine [D. C. F. C.], University of Colorado Cancer Center [R. A.], University of Colorado Health Sciences Center, Denver, Colorado 80262
We have reported recently the anticancer effect of flavonoid antioxidant silymarin, the major part of milk thistle extract, against advanced human prostate carcinoma DU145 cells (X. Zi et al., Cancer Res., 58: 1920–1929, 1998) and later identified that silibinin is the main active component in silymarin responsible for its effect in cell culture studies. On the basis of these observations, here we assessed in vivo growth inhibitory potential of silibinin against advanced human prostate cancer (PCA). Dietary feeding of silibinin at 0.05 and 0.1% doses (w/w) for 60 days, 24 h after s.c. DU145 tumor xenograft implantation in athymic male nude mice, significantly inhibited tumor volume by 35 and 58% (P < 0.05), and wet weight of tumor by 29 and 40% (P < 0.05), respectively. In a second experiment where mice were fed with these test diets for 3 weeks before tumor xenograft implantation and continued on these diets for a total of 63 days, tumor volume and wet weight of tumor were reduced by 53–64% (P < 0.001–0.05) and 31–52% (P < 0.05), respectively. In both studies, animals did not show weight loss or reduced food consumption. These in vivo anticancer effects of silibinin were associated with an increased accumulation (up to 5.8 fold; P < 0.05) of human insulin-like growth factor-binding protein-3 in mouse plasma. In additional studies assessing biological availability of silibinin in nude mice and its antiproliferative activity at such doses in DU145 cells in culture, silibinin levels in plasma and prostate were found to be in the range of 7–13 µg/ml and 3.7–4.6 µg/g, respectively. At these biologically achievable silibinin concentrations, increased IGFBP-3 level in DU145 cell culture medium and a strong DU145 cell growth inhibition were observed that were irreversible in the absence of silibinin in culture medium. These findings extend and translate our observations on in vitro anticancer effect of silibinin/silymarin to an in vivo preclinical PCA model, which may form the basis for a Phase I clinical trial in PCA patients.
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A. Tyagi, C. Agarwal, G. Harrison, L. M. Glode, and R. Agarwal 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 Carcinogenesis, September 1, 2004; 25(9): 1711 - 1720. [Abstract] [Full Text] [PDF]
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S. Dhanalakshmi, G.U. Mallikarjuna, R. P. Singh, and R. Agarwal Silibinin prevents ultraviolet radiation-caused skin damages in SKH-1 hairless mice via a decrease in thymine dimer positive cells and an up-regulation of p53-p21/Cip1 in epidermis Carcinogenesis, August 1, 2004; 25(8): 1459 - 1465. [Abstract] [Full Text] [PDF]
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 R. P. Singh, G. Sharma, S. Dhanalakshmi, C. Agarwal, and R. Agarwal Suppression of Advanced Human Prostate Tumor Growth in Athymic Mice by Silibinin Feeding Is Associated with Reduced Cell Proliferation, Increased Apoptosis, and Inhibition of Angiogenesis Cancer Epidemiol. Biomarkers Prev., September 1, 2003; 12(9): 933 - 939. [Abstract] [Full Text] [PDF]
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A. K. Tyagi, R. P. Singh, C. Agarwal, D. C. F. Chan, and R. Agarwal Silibinin Strongly Synergizes Human Prostate Carcinoma DU145 Cells to Doxorubicin-induced Growth Inhibition, G2-M Arrest, and Apoptosis Clin. Cancer Res., November 1, 2002; 8(11): 3512 - 3519. [Abstract] [Full Text] [PDF]
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