Clusterin and Chemotherapy Sensitivity Under Normoxic and Graded Hypoxic Conditions in Colorectal Cancer

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• 作者：David Kevans (1) (2)
  Sheeona Gorman (1) (2)
  Miriam Tosetto (1) (2)
  Kieran Sheahan (1) (2)
  Diarmuid O’Donoghue (1) (2)
  Hugh Mulcahy (1) (2)
  Jacintha O’Sullivan (1) (2)
  
• 关键词：Clusterin ; Colorectal cancer ; Treatment sensitivity ; Hypoxia
• 刊名：Journal of Gastrointestinal Cancer
• 出版年：2012
• 出版时间：June 2012
• 年：2012
• 卷：43
• 期：2
• 页码：305-313
• 全文大小：300KB
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• 作者单位：David Kevans (1) (2)
  Sheeona Gorman (1) (2)
  Miriam Tosetto (1) (2)
  Kieran Sheahan (1) (2)
  Diarmuid O’Donoghue (1) (2)
  Hugh Mulcahy (1) (2)
  Jacintha O’Sullivan (1) (2)
  
  1. Centre for Colorectal Disease, St. Vincent’s University Hospital, Elm Park, Dublin 4, Ireland
  2. University College Dublin, Dublin, Ireland
  
• ISSN：1941-6636

文摘

Background and Aims In vitro studies have shown that clusterin modulates treatment sensitivity in a number of human cancers; however, the interaction between clusterin expression and hypoxia in controlling treatment response in CRC has not previously been examined. The aim of this study was to assess the effect of clusterin overexpression in CRC cells on sensitivity to 5-fluorouracil (5-FU), oxaliplatin and FOLFOX treatment under normoxic and graded hypoxic conditions. Methods SW480 colon cancer cells were transfected with full length Clusterin cDNA to generate a clusterin overexpressing cell line. Overexpression was confirmed by western blot analysis. The response of parental and clusterin overexpressing cells to 5-FU, oxaliplatin and FOLFOX was examined using a crystal violet-based proliferation assay under normoxic conditions, 3% and 1% hypoxic conditions. The levels of apoptosis and G2/M arrest in FOLFOX-treated cells were assessed by flow cytometry. Results Under normoxic conditions, clusterin overexpressing cells were more sensitive to FOLFOX treatment (p--.01); under 3% and 1% hypoxic conditions, overexpressing clusterin cells were more sensitive to 5-FU, oxaliplatin and FOLFOX, p values <0.05 for all conditions. Under normoxic conditions, overexpressing clusterin cells showed significantly higher levels of apoptosis when treated with FOLFOX compared to untransfected cells; levels of G2M cells were not significantly different. Under both 3% and 1% hypoxia, the percentage of cells undergoing apoptosis following FOLFOX treatment was significantly higher in overexpressing clusterin cells. Conclusion These in vitro findings suggest that tumours expressing high levels of clusterin, particularly if hypoxic in nature, may benefit from treatments such as FOLFOX.