title: ABT-737 reverses the acquired radioresistance of breast cancer cells by targeting Bcl-2 and Bcl-xL.
abstract: BACKGROUND
  Acquired radioresistance of cancer cells remains a fundamental barrier to attaining the maximal efficacy of radiotherapy for the treatment of breast cancer. Anti-apoptotic proteins, such as Bcl-2 and Bcl-xL, play an important role in the radioresistance of cancer cells. In the present study, we aimed to determine if ABT-737, a BH3-only mimic, could reverse the acquired radioresistance of the breast cancer cell line MDA-MB-231R by targeting Bcl-2 and Bcl-xL.
  
  
  METHODS
  The radiosensitivity of MDA-MB-231 and MDA-MB-231R cells was compared using colony formation assays. Reverse-transcription PCR and western blot were performed to detect the expression of Bcl-2 and Bcl-xL in the cancer cell lines. Annexin V flow cytometric analysis and caspase-3 colorimetric assay were used to evaluate apoptosis of the cancer cells. Cell viability was measured using the Cell Counting Kit-8. The animals used in this study were 4 to 6-week-old athymic female BALB/c nu/nu mice.
  
  
  RESULTS
  The MDA-MB-231R cells were more radioresistant than the MDA-MB-231 cells, and Bcl-2 and Bcl-xL were overexpressed in the MDA-MB-231R cells. While ABT-737 was able to restore the radiosensitivity of the MDA-MB-231R cells in vitro and in vivo experiment, it was not able to enhance the radiosensitivity of the MDA-MB-231 cells. In addition, ABT-737 increased radiation-induced apoptosis in the MDA-MB-231R cells. Bcl-2 and Bcl-xL were down regulated in the MDA-MB-231R cells following treatment with ABT-737.
  
  
  CONCLUSIONS
  Targeting of the anti-apoptotic proteins Bcl-2 and Bcl-xL with ABT-737 may reverse the acquired radioresistance of MDA-MB-231R cells in vitro and in vivo. These findings suggest an attractive strategy for overcoming the acquired radioresistance of breast cancer cells.
authors.affiliation: Department of Breast and Thyroid Surgery, Provincial Hospital Affiliated to Shandong University, 324 Jingwu-Weiqi Road, Jinan, 250021, People's Republic of China.
authors.forename: Ji-Yu
authors.initials: JY
authors.lastname: Li
authors.forename: Yu-Yang
authors.initials: YY
authors.lastname: Li
authors.forename: Wei
authors.initials: W
authors.lastname: Jin
authors.forename: Qing
authors.initials: Q
authors.lastname: Yang
authors.forename: Zhi-Ming
authors.initials: ZM
authors.lastname: Shao
authors.forename: Xing-Song
authors.initials: XS
authors.lastname: Tian
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D001713:Biphenyl Compounds / Q000008:administration & dosage*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000532:radiotherapy; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D051379:Mice; D009596:Nitrophenols / Q000008:administration & dosage*; D010879:Piperazines / Q000008:administration & dosage; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011836:Radiation Tolerance / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage; D013449:Sulfonamides / Q000008:administration & dosage*; D051020:bcl-X Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: C501332:ABT-737; C494811:BCL2L1 protein, human; D001713:Biphenyl Compounds; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D011838:Radiation-Sensitizing Agents; D013449:Sulfonamides; D051020:bcl-X Protein