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Silibinin inhibits constitutive and TNFα-induced activation of NF-κB and sensitizes human prostate carcinoma DU145 cells to TNFα-induced apoptosis

Abstract

Prostate cancer (PCA) is one of the most common invasive malignancies of men in the US, however, there have been limited successes so far in its therapy. Even most potent agents (e.g. TNFα) are ineffective in killing human PCA cells possibly due to constitutive activation of NF-κB that subsequently activates a large number of anti-apoptotic genes. In such a scenario, strong apoptotic agent TNFα, further induces NF-κB activation rather than inducing apoptosis. In several recent studies, we have demonstrated both cancer preventive and anti-cancer efficacy of silymarin and its constituent silibinin in a variety of experimental tumor models and cell culture systems. Here we examined whether silibinin is effective in inhibiting constitutive NF-κB activation in human PCA cells, which would help in overcoming TNFα-insensitivity. Our studies reveal that silibinin effectively inhibits constitutive activation of NF-κB in advanced human prostate carcinoma DU145 cells. Consistent with this, nuclear levels of p65 and p50 sub-units of NF-κB were also reduced. In the studies assessing molecular mechanism of this effect, silibinin treatment resulted in a significant increase in the level of IκBα with a concomitant decrease in phospho-IκBα. Kinase assays revealed that silibinin dose-dependently decreases IKKα kinase activity. The effect of silibinin on IKKα seemed to be direct as evidenced by the in vitro kinase assay, where immunoprecipitated IKKα was incubated with silibinin. This shows that silibinin does not necessarily need an upstream event to bring about its inhibitory effect on IKKα and downstream effectors. Additional studies showed that silibinin also inhibits TNFα-induced activation of NF-κB via IκBα pathway and subsequently sensitizes DU145 cells to TNFα-induced apoptosis. These results indicate that silibinin could be used to enhance the effectiveness of TNFα-based chemotherapy in advanced PCA.

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Acknowledgements

This work was supported by grants from the US Army Medical Research and Material Command Prostate Cancer Program DAMD17-98-1-8588 and National Institutes of Health (CA83741 and CA64514).

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Correspondence to C Agarwal.

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Dhanalakshmi, S., Singh, R., Agarwal, C. et al. Silibinin inhibits constitutive and TNFα-induced activation of NF-κB and sensitizes human prostate carcinoma DU145 cells to TNFα-induced apoptosis. Oncogene 21, 1759–1767 (2002). https://doi.org/10.1038/sj.onc.1205240

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