Silibinin may help prevent or slow lung cancer development

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June 23, 2006

Silibinin may help prevent or slow lung cancer development

The June 21, 2006 issue of the Journal of the National Cancer Institute reported the finding of Rajesh Agarwal, PhD and his colleagues at the University of Colorado Health Sciences Center in Denver that the compound silibinin, derived from milk thistle, helps prevent the growth and development of lung tumors in mice.

Dr Agarwal's team injected 75 mice with urethane to induce lung tumors, and injected a control group with saline. The animals injected with urethane were provided with normal diets for two weeks, after which they were given diets containing 0.033 percent, 0.1 percent, 0.33 percent, 1 percent, or no silibinin. Ten mice from each group were examined 20 weeks following injection, when lung tumors in this model are in their early stage, while the remainder were examined after 29 weeks.

It was found that mice injected with urethane who received any of the silibinin-containing diets had fewer and smaller tumors than those who received unsupplemented diets at both stages of examination. At 20 weeks, the mean number of larger tumors was reduced by 93 percent among those who received 1 percent silibinin compared to injected mice given the control diet. A significant reduction in tumor size was also observed among the mice examined after 29 weeks, with a 50-83 percent reduction compared to untreated mice. Additionally, silibinin was associated with a reduction in tumor microvessel density of 89 percent compared to the tumors of mice who did not receive the compound, indicating an inhibitory effect on angiogenesis.

"Although the mechanisms by which silibinin interferes with lung tumor growth in preclinical models remains to be explored," the authors note, "these results raise the possibility that silibinin may have chemopreventive activity against lung tumor growth and progression in humans."
 

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And... published a week before

1: Carcinogenesis. 2006 Jun 15; [Epub ahead of print] Related Articles, Links


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.

Tyagi A, Singh RP, Agarwal C, Agarwal R.

Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Health Sciences Center, Denver, CO 80262, USA.

Silibinin, a natural flavonolignan, induces apoptosis in human bladder transitional-cell papilloma RT4 cells both in vitro and in vivo; however, mechanisms of such efficacy are not completely identified. Here, we studied the mechanisms involved in silibinin-induced apoptosis of RT4 cells having intact p53. Silibinin increased p53 protein level together with its increased phosphorylation at serine 15, activated caspase cascade, and caused Bid cleavage for apoptosis. Silibinin-caused p53 activation was mediated via ATM-Chk2 pathway, which in turn induced caspase-2-mediated apoptosis. Pifithrin-alpha, a p53 inhibitor, reversed silibinin-induced caspase activation including caspase-2; however, caspase-2 inhibitor also reversed p53 phosphorylation suggesting a bidirectional regulation between them. Further, silibinin-caused a rapid translocation of p53 and Bid into mitochondria leading to increased permeabilization of mitochondrial membrane and cytochrome C release into the cytosol. JNK1/2 activation was observed as a connecting link for p53-mediated caspase-2 activation. Interestingly, silibinin-induced apoptosis was mediated, in part, via Cip1/p21 cleavage by caspase which was reversed by Cip1/p21 siRNA. Together, these results suggested the novel mechanisms for apoptosis induction by silibinin involving p53-caspase-2 activation, and caspase-mediated cleavage of Cip1/p21.

Thus the unkown mechanism of tumor growth progression inhibition is likely via activation of the p53 tumor suppresor gene resulting in activation of the caspase cascade inducing apoptosis in the tumor cells.

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