title: Silymarin and its active component silibinin act as novel therapeutic alternatives for salivary gland cancer by targeting the ERK1/2-Bim signaling cascade.
abstract: OBJECTIVE
  Approximately 20% of all salivary gland cancer patients who are treated with current treatment modalities will ultimately develop metastases. Its most common form, mucoepidermoid carcinoma (MEC) is a highly aggressive tumor with an overall 5-year survival rate of ~30%. Until now, several chemotherapeutic drugs have been tested for the treatment of salivary gland tumors, but the results have been disappointing and the drugs often cause unwanted side effects. Therefore, several recent studies have focused on the potential of alternative and/or complementary therapeutic options, including the use of silymarin.
  
  
  METHODS
  The effects of silymarin and its active component silibinin on salivary gland cancer-derived MC3 and HN22 cells and their underlying molecular mechanisms were examined using trypan blue exclusion, 4'-6-diamidino-2-phenylindole (DAPI) staining, Live/Dead, Annexin V/PI staining, mitochondrial membrane potential (ΔΨm) measurement, quantitative RT-PCR, soft agar colony formation and Western blotting analyses.
  
  
  RESULTS
  We found that silymarin and silibinin dramatically increased the expression of the pro-apoptotic protein Bim in a concentration- and time-dependent manner and, concomitantly, induced apoptosis in MC3 and HN22 cells. We also found that ERK1/2 signaling inhibition successfully sensitized these cells to the apoptotic effects of silymarin and silibinin, which indicates that the ERK1/2 signaling pathway may act as an upstream regulator that modulates the silymarin/silibinin-induced Bim signaling pathway.
  
  
  CONCLUSIONS
  Taken together, we conclude that ERK1/2 signaling pathway inhibition by silymarin and silibinin increases the expression of the pro-apoptotic Bcl-2 family member Bim which, subsequently, induces mitochondria-mediated apoptosis in salivary gland cancer-derived cells.
authors.affiliation: Division of high-risk pathogen research, Korea Centers for Disease Control and Prevention, Osong, 28160, Republic of Korea.
authors.forename: Eun-Sun
authors.initials: ES
authors.lastname: Choi
authors.affiliation: Department of Oral Pathology, School of Dentistry and Institute of Biodegradable material, Institute of Oral Bioscience, Chonbuk National University, Brain Korea 21 Project, Jeonju, 54986, Republic of Korea.
authors.forename: Sejun
authors.initials: S
authors.lastname: Oh
authors.affiliation: Department of Oral Pathology, School of Dentistry and Institute of Biodegradable material, Institute of Oral Bioscience, Chonbuk National University, Brain Korea 21 Project, Jeonju, 54986, Republic of Korea.
authors.forename: Boonsil
authors.initials: B
authors.lastname: Jang
authors.affiliation: Department of Oral Pathology, School of Dentistry and Institute of Biodegradable material, Institute of Oral Bioscience, Chonbuk National University, Brain Korea 21 Project, Jeonju, 54986, Republic of Korea.
authors.forename: Hyun-Ju
authors.initials: HJ
authors.lastname: Yu
authors.affiliation: Department of Oral Pathology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul, 03080, Republic of Korea.
authors.forename: Ji-Ae
authors.initials: JA
authors.lastname: Shin
authors.affiliation: Department of Oral Pathology, School of Dentistry and Institute of Biodegradable material, Institute of Oral Bioscience, Chonbuk National University, Brain Korea 21 Project, Jeonju, 54986, Republic of Korea.
authors.forename: Nam-Pyo
authors.initials: NP
authors.lastname: Cho
authors.affiliation: Department of Oral Pathology, School of Dentistry and Institute of Biodegradable material, Institute of Oral Bioscience, Chonbuk National University, Brain Korea 21 Project, Jeonju, 54986, Republic of Korea.
authors.forename: In-Hyoung
authors.initials: IH
authors.lastname: Yang
authors.affiliation: Department of Oral Pathology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul, 03080, Republic of Korea.
authors.forename: Dong-Hoon
authors.initials: DH
authors.lastname: Won
authors.affiliation: Department of Oral Pathology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul, 03080, Republic of Korea.
authors.forename: Hye-Jeong
authors.initials: HJ
authors.lastname: Kwon
authors.affiliation: Department of Oral Pathology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul, 03080, Republic of Korea.
authors.forename: Seong Doo
authors.initials: SD
authors.lastname: Hong
authors.affiliation: Department of Oral Pathology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul, 03080, Republic of Korea. efiwdsc@snu.ac.kr.
authors.forename: Sung-Dae
authors.initials: SD
authors.lastname: Cho
mesh_terms: D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D000072224:Bcl-2-Like Protein 11 / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D012468:Salivary Gland Neoplasms / Q000473:pathology*; D000077385:Silybin; D012838:Silymarin / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; D000072224:Bcl-2-Like Protein 11; D012838:Silymarin; D000077385:Silybin
keywords: Apoptosis; ERK/Bim signaling; Salivary gland tumor; Silibinin; Silymarin