title: Silibinin Treatment Inhibits the Growth of Hedgehog Inhibitor-Resistant Basal Cell Carcinoma Cells via Targeting EGFR-MAPK-Akt and Hedgehog Signaling.
abstract: Basal cell carcinoma (BCC) is the most common skin malignancy. Deregulated hedgehog signaling plays a central role in BCC development; therefore, hedgehog inhibitors have been approved to treat locally advanced or metastatic BCC. However, the development of resistance to hedgehog inhibitors is the major challenge in effective treatment of this disease. Herein, we evaluated the efficacy of a natural agent silibinin to overcome resistance with hedgehog inhibitors (Sant-1 and GDC-0449) in BCC cells. Silibinin (25-100 μm) treatment for 48 h strongly inhibited growth and induced death in ASZ001, Sant-1-resistant (ASZ001-Sant-1) and GDC-0449-resistant (ASZ001-GDC-0449) BCC cells. Furthermore, colony-forming ability of ASZ001, ASZ001-Sant-1 and ASZ001-GDC-0449 cells was completely inhibited by silibinin treatment. Molecular analysis showed that silibinin treatment decreased the level of phosphorylated EGFR (Tyrosine 1173) and total EGFR in ASZ001-Sant-1 cells, key signaling molecules responsible for BCC resistance toward hedgehog inhibitors. Further, silibinin treatment decreased the phosphorylated Akt (Serine 473), phosphorylated ERK1/2 (Threonine 202/Tyrosine 204), cyclin D1 and Gli-1 level but increased the SUFU expression in ASZ001-Sant-1-resistant cells. Silibinin treatment of ASZ001-Sant-1-resistant cells also decreased bcl-2 but increased cleaved caspase 3 and PARP cleavage, suggesting induction of apoptosis. Together, these results support silibinin use to target hedgehog inhibitor-resistant BCC cells.
authors.affiliation: Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO.|School of Life Sciences, Jawaharlal Nehru University, New Delhi, India.
authors.forename: Arpit
authors.initials: A
authors.lastname: Dheeraj
authors.affiliation: Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO.
authors.forename: Cynthia M
authors.initials: CM
authors.lastname: Rigby
authors.affiliation: Department of Clinical Pharmacy, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO.
authors.forename: Cindy L
authors.initials: CL
authors.lastname: O'Bryant
authors.affiliation: Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO.|University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, CO.
authors.forename: Chapla
authors.initials: C
authors.lastname: Agarwal
authors.affiliation: School of Life Sciences, Jawaharlal Nehru University, New Delhi, India.
authors.forename: Rana P
authors.initials: RP
authors.lastname: Singh
authors.affiliation: Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO.|Department of Cancer Biology and Comprehensive Cancer Center, Wake Forest Baptist Medical Center, Winston-Salem, NC.
authors.forename: Gagan
authors.initials: G
authors.lastname: Deep
authors.affiliation: Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO.|University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, CO.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Agarwal
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D002280:Basal Cell Carcinoma / Q000378:metabolism / Q000473:pathology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000378:metabolism*; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D000077385:Silybin / Q000494:pharmacology*; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology*
chemical_list: D000970:Antineoplastic Agents; D053823:Hedgehog Proteins; D000077385:Silybin; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases