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: Cynthia Tilley, Gagan Deep, Chapla Agarwal, Michael F Wempe, David Biedermann, Kateřina Valentová, Vladimir Kren, Rajesh Agarwal
• Journal: Molecular carcinogenesis (Mol Carcinog) Vol. 55 Issue 1 Pg. 3-14 (Jan 2016) ISSN: 1098-2744 [Electronic] United States
• PMID: 25492239 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 Wiley Periodicals, Inc.

Chemical References

• Antineoplastic Agents
• Antioxidants
• NF-kappa B
• Silymarin
• Transcription Factor AP-1
• Transcription Factors
• Silybin

Topics

• Allografts
• Animals
• Antineoplastic Agents (chemistry, pharmacology)
• Antioxidants (chemistry, pharmacology)
• Apoptosis (drug effects)
• Carcinoma, Basal Cell (drug therapy, metabolism, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Disease Models, Animal
• Enzyme Activation (drug effects)
• Humans
• Mice
• Mice, Knockout
• NF-kappa B (metabolism)
• Signal Transduction (drug effects)
• Silybin
• Silymarin (chemistry, pharmacology)
• Skin Neoplasms (drug therapy, metabolism, pathology)
• Transcription Factor AP-1 (metabolism)
• Transcription Factors (metabolism)
• Tumor Stem Cell Assay