Defining the mechanism of action of silibinin as an anti-cancer and cancer chemopreventive agent

Silibinin, a flavolignan isolated from milk thistle extract, has long been used as an anti-hepatotoxic agent. However, its cancer chemopreventive potential became a highlight recently and several studies have already been published showing its promising anti-cancer efficacy in both in vitro and in vivo cancer models. Existing literature indicates that silibinin can provide protection against a variety of cancers by regulating several mitogenic signaling cascades involved in cell proliferation and survival, as well as by inducing growth arrest by modulating key cell cycle molecules. Moreover, in case of skin cancer studies, silibinin offers remarkable protection against the early DNA damages induced by UVB irradiation in normal skin. Thus silibinin seems to regulate all the three stages of cancer development: initiation, promotion and progression. However, the precise molecular mechanisms/targets that silibinin modulates to initiate its protective response is (are) still unclear. My proposed studies focus on achieving two specific aims: (1) how silibinin regulates the G1 associated cell cycle events, i.e. what are the primary targets of silibinin that initiate the G1 arrest, and (2) how it offers protection against UVB-induced early DNA damage i.e. the molecular targets of silibinin in mediating its response against UVB-induced tumor initiation as well as tumor promotion events.;By utilizing advanced human prostate cancer cell lines DU145, the mechanism of silibinin mediated G1 arrest was investigated. Our studies showed that p21/Cip1 and p27/Kip1 are the crucial targets of silibinin in mediating its G1 arrest response. The induction of these proteins occurs primarily at the post-translational level where silibinin-mediated downregulation of the oncoprotein Skp2 plays the major role. Moreover, our studies also revealed that both p21 and p27 proteins play crucial role in determining overall prostate cancer phenotype, in terms of proliferation and tumorigenicity.;Next, the critical targets of silibinin in mediating its early protective response against UVB-induced cytotoxic events were investigated. Studies performed in mouse keratinocytes JB6 cells revealed that p53 and its downstream target GADD45alpha play crucial role in the protective response of silibinin against UVB-induced apoptosis. Moreover, in in vivo studies using p53 knockout SKH1 hairless mice, the indispensable role of p53 in silibinin's protective response against UVB-induced DNA damage as well as UVB-mediated skin carcinogenesis was further elaborated.