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Carcinogenesis Advance Access published online on October 10, 2003
Carcinogenesis, doi:10.1093/carcin/bgg188
© 2003 by Oxford University Press
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© 2003 Oxford University Press

MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION

Dual-efficacy of silibinin in protecting or enhancing ultraviolet B radiation-caused apoptosis in human immortalized keratinocyte HaCaT cells

Sivanandhan Dhanalakshmi 1, G. U. Mallikarjuna 1, Rana P. Singh 1, and Rajesh Agarwal 2*

1 Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Health Sciences Center, Denver, CO 80262, USA
2 Department of Pharmaceutical Sciences, School of Pharmacy and University of Colorado Cancer Center, University of Colorado Health Sciences Center, Denver, CO 80262, USA

* Corresponding author. E-mail: Rajesh.Agarwal{at}UCHSC.edu.

Received 11 August 2003 ; revised 16 September 2003 ; accepted 25 September 2003

Abstract

An increasing incidence of human skin cancer and other adverse effects of solar ultraviolet (UV) radiation enhance the need for novel chemoprevention strategies. Here, we studied the effect of silibinin on UVB-induced apoptosis in HaCaT cells. Silibinin strongly prevented lower doses (15 and 30 mJ/cm2) of UVB-induced apoptosis, as observed by a reversal in UVB-caused PARP cleavage, caspase 9 activation and apoptotic cells. UVB-induced PARP cleavage was also abolished by all caspase inhibitor suggesting that it is a caspase-dependent effect. In other studies, silibinin restored UVB-caused depletion in an inhibitor of apoptosis protein, survivin, concomitant with an up-regulation in transcription factor NF-{kappa}B DNA binding activity, without any noticeable effect on UVB-caused AP1 activation. Further, silibinin treatment up-regulated UVB-induced Erk1/2 phosphorylation suggesting its possible role as survival event in protective effect of silibinin. In other studies, silibinin caused a moderate increase in phospho-Bcl-2 without any noticeable changes in total Bcl-2 levels, and down-regulated bax levels moderately. Silibinin also caused a strong decrease in Bad heterodimerization with bclx(L), which was consistent with an increased translocation of bclx(L) to the mitochondria from the cytosol. Consistent with its protective effect on UVB-caused apoptosis, silibinin also increased S phase arrest possibly providing prolonged time for efficient DNA repair. Interestingly, protective effects of silibinin in HaCaT cells were lost at higher dose of UVB (120 mJ/cm2), and instead it further enhanced UVB-caused apoptosis together with a strong decrease in UVB-caused AP1 activation. Together, these results clearly demonstrate the dual-efficacy of silibinin in protecting or enhancing UVB-caused apoptosis in the same cellular system, and suggest that silibinin possibly works as an UVB-damage sensor to exert its biological action.

Silibinin, UVB, HaCaT, apoptosis, cell cycle
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