title: Silibinin and its 2,3-dehydro-derivative inhibit basal cell carcinoma growth via suppression of mitogenic signaling and transcription factors activation.
abstract: Basal cell carcinoma (BCC) is the most common cancer worldwide, and its current treatment options are insufficient and toxic. Surprisingly, unlike several other malignancies, chemopreventive efforts against BCC are almost lacking. Silibinin, a natural agent from milk thistle seeds, has shown strong efficacy against several cancers including ultraviolet radiation-induced skin (squamous) cancer; however, its potential activity against BCC is not yet examined. Herein, for the first time, we report the efficacy of silibinin and its oxidation product 2,3-dehydrosilibinin (DHS) against BCC both in vitro and in vivo using ASZ (p53 mutated) and BSZ (p53 deleted) cell lines derived from murine BCC tumors. Both silibinin and DHS significantly inhibited cell growth and clonogenicity while inducing apoptosis in a dose- and time-dependent manner, with DHS showing higher activity at lower concentrations. Both agents also inhibited the mitogenic signaling by reducing EGFR, ERK1/2, Akt, and STAT3 phosphorylation and suppressed the activation of transcription factors NF-κB and AP-1. More importantly, in an ectopic allograft model, oral administration of silibinin and DHS (200 mg/kg body weight) strongly inhibited the ASZ tumor growth by 44% and 71% (P < 0.05), respectively, and decreased the expression of proliferation biomarkers (PCNA and cyclin D1) as well as NF-κB p50 and c-Fos in the tumor tissues. Taken together, these results provide the first evidence for the efficacy and usefulness of silibinin and its derivative DHS against BCC, and suggest the need for additional studies with these agents in pre-clinical and clinical BCC chemoprevention and therapy models.
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, Colorado.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Tilley
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, Colorado.|University of Colorado Cancer Center, University of Colorado Denver, Aurora, Colorado.
authors.forename: Gagan
authors.initials: G
authors.lastname: Deep
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, Colorado.|University of Colorado Cancer Center, University of Colorado Denver, Aurora, Colorado.
authors.forename: Chapla
authors.initials: C
authors.lastname: Agarwal
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, Colorado.|University of Colorado Cancer Center, University of Colorado Denver, Aurora, Colorado.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Wempe
authors.affiliation: Institute of Microbiology, Laboratory of Biotransformation, Academy of Sciences of the Czech Republic, Vídeňská, Prague, Czech Republic.
authors.forename: David
authors.initials: D
authors.lastname: Biedermann
authors.affiliation: Institute of Microbiology, Laboratory of Biotransformation, Academy of Sciences of the Czech Republic, Vídeňská, Prague, Czech Republic.
authors.forename: Kateřina
authors.initials: K
authors.lastname: Valentová
authors.affiliation: Institute of Microbiology, Laboratory of Biotransformation, Academy of Sciences of the Czech Republic, Vídeňská, Prague, Czech Republic.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Kren
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, Colorado.|University of Colorado Cancer Center, University of Colorado Denver, Aurora, Colorado.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Agarwal
mesh_terms: D064591:Allografts; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002280:Basal Cell Carcinoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D000077385:Silybin; D012838:Silymarin / Q000737:chemistry / Q000494:pharmacology*; D012878:Skin Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D014410:Tumor Stem Cell Assay
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D016328:NF-kappa B; D012838:Silymarin; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D000077385:Silybin
keywords: EGFR; basal cell carcinoma; chemoprevention; dehydrosilibinin; mitogenic signaling; phytochemicals; silibinin