title: Silibinin sensitizes chemo-resistant breast cancer cells to chemotherapy.
abstract: BACKGROUND
  Multiple drug resistance is the major obstacle to conventional chemotherapy. Silibinin, a nontoxic naturally occurring compound, has anticancer activity and can increase the cytotoxic effects of chemotherapy in various cancer models.
  
  
  OBJECTIVE
  To evaluate the effects of silibinin on enhancing the sensitivity of chemo-resistant human breast cell lines to doxorubicin (DOX) and paclitaxel (PAC).
  
  
  METHODS
  The cells were treated with silibinin (at 50 to 600 μM concentrations) and/or chemo drugs for 24 and 48 h, then cell viability and changes in oncogenic proteins were determined by MTT assay and Western blotting/RT-PCR, respectively. Flow cytometry was used to study apoptosis in the cells receiving different treatments. The antitumorigenic effects of silibinin (at 200 to 400 μM concentration) were evaluated by mammosphere assay.
  
  
  RESULTS
  Silibinin exerted significant growth inhibitory effects with IC50ranging from 200 to 570 μM in different cell lines. Treatment of DOX-resistant MDA-MB-435 cells with silibinin at 200 μM reduced DOX IC50from 71 to 10 μg/mL and significantly suppressed the key oncogenic pathways including STAT3, AKT, and ERK in these cells. Interestingly treatment of DOX-resistant MDA-MB-435 cells with silibinin at 400 μM concentration for 48 h induced a 50% decrease in the numbers of colonies as compared with DMSO-treated cells. Treatment of PAC-resistant MCF-7 cells with silibinin at 400 μM concentration generated synergistic effects when it was used in combination with PAC at 250 nM concentration (CI = 0.81).
  
  
  CONCLUSIONS
  Silibinin sensitizes chemo-resistant cells to chemotherapeutic agents and can be useful in treating breast cancers.
authors.affiliation: a Biotechnology Research Center , Tabriz University of Medical Sciences , Tabriz , Iran.|b Faculty of Pharmacy , Tabriz University of Medical Sciences , Tabriz , Iran.|c Department of Laboratory Medicine and Pathology, Faculty of Medicine and Dentistry , University of Alberta , Edmonton , Alberta , Canada.
authors.forename: Ommoleila
authors.initials: O
authors.lastname: Molavi
authors.affiliation: b Faculty of Pharmacy , Tabriz University of Medical Sciences , Tabriz , Iran.
authors.forename: Farzaneh
authors.initials: F
authors.lastname: Narimani
authors.affiliation: b Faculty of Pharmacy , Tabriz University of Medical Sciences , Tabriz , Iran.
authors.forename: Farshid
authors.initials: F
authors.lastname: Asiaee
authors.affiliation: b Faculty of Pharmacy , Tabriz University of Medical Sciences , Tabriz , Iran.
authors.forename: Simin
authors.initials: S
authors.lastname: Sharifi
authors.affiliation: b Faculty of Pharmacy , Tabriz University of Medical Sciences , Tabriz , Iran.
authors.forename: Vahideh
authors.initials: V
authors.lastname: Tarhriz
authors.affiliation: b Faculty of Pharmacy , Tabriz University of Medical Sciences , Tabriz , Iran.
authors.forename: Ali
authors.initials: A
authors.lastname: Shayanfar
authors.affiliation: b Faculty of Pharmacy , Tabriz University of Medical Sciences , Tabriz , Iran.
authors.forename: Mohammadsaied
authors.initials: M
authors.lastname: Hejazi
authors.affiliation: c Department of Laboratory Medicine and Pathology, Faculty of Medicine and Dentistry , University of Alberta , Edmonton , Alberta , Canada.
authors.forename: Raymond
authors.initials: R
authors.lastname: Lai
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D017239:Paclitaxel / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000502:physiology; D000077385:Silybin; D012838:Silymarin / Q000494:pharmacology*
chemical_list: D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D012838:Silymarin; D000077385:Silybin; D004317:Doxorubicin; D017239:Paclitaxel
keywords: Resistance; STAT3 pathway; apoptosis; doxorubicin; paclitaxel