Clusterin knockdown using the antisense oligonucleotide OGX-011 re-sensitizes docetaxel-refractory prostate cancer PC-3 cells to chemotherapy

BJU Int. 2008 Aug;102(3):389-97. doi: 10.1111/j.1464-410X.2008.07618.x. Epub 2008 Mar 11.


Objectives: To characterize changes in secretory clusterin (sCLU) expression in prostate cancer cells after treatment with docetaxel and to determine whether sCLU knockdown can re-introduce chemosensitivity in a docetaxel-resistant, androgen-independent human prostate cancer model.

Patients and methods: A tissue microarray was constructed for 84 radical prostatectomy (RP) specimens from a multicentre Phase II trial of neoadjuvant combined androgen ablation and docetaxel (CUOG-P01a) and assessed for changes in the expression of the cytoprotective chaperone sCLU. The human prostate cancer cell line PC-3 was repeatedly exposed to docetaxel chemotherapy in vitro, and a docetaxel-resistant cell subline (PC-3dR) was developed and analysed.

Results: sCLU levels were significantly higher in RP specimens treated with neoadjuvant combined androgen ablation and docetaxel than in untreated specimens. Similarly, sCLU expression increased 2.5-fold in the newly developed docetaxel-refractory PC-3dR cell line compared with parental PC-3 cells. There was a dose-dependent and sequence-specific decrease in sCLU levels in PC-3dR cells using OGX-011, an antisense oligonucleotide against human sCLU. OGX-011 and small-interference RNA both chemosensitized PC-3dR cells to docetaxel and mitoxantrone in vitro and apoptotic rates in PC-3dR cells were significantly increased when OGX-011 was combined with docetaxel. In vivo, growth of PC-3dR xenografts in nude mice was synergistically inhibited by OGX-011 combined with paclitaxel or mitoxantrone (by 76% and 44% compared with their mismatch controls, respectively).

Conclusion: The present findings indicate that targeted knockdown of sCLU enhances the effects of cytotoxic chemotherapy in docetaxel-refractory cells, and provide preclinical proof of principle for clinical trials testing OGX-011 in second-line chemotherapy regimens for patients with docetaxel-refractory prostate cancer.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androgens / metabolism
  • Cell Line, Tumor
  • Clusterin / metabolism*
  • Cohort Studies
  • Docetaxel
  • Dose-Response Relationship, Drug
  • Humans
  • Immunohistochemistry
  • Male
  • Neoadjuvant Therapy
  • Neoplasms, Hormone-Dependent / drug therapy*
  • Neoplasms, Hormone-Dependent / pathology
  • Neoplasms, Hormone-Dependent / surgery
  • Oligonucleotides, Antisense / administration & dosage
  • Oligonucleotides, Antisense / therapeutic use*
  • Prostatectomy / methods
  • Prostatic Neoplasms / drug therapy
  • Prostatic Neoplasms / metabolism*
  • Prostatic Neoplasms / surgery
  • Taxoids / therapeutic use*
  • Thionucleotides / administration & dosage
  • Thionucleotides / therapeutic use*


  • Androgens
  • Clusterin
  • OGX-011
  • Oligonucleotides, Antisense
  • Taxoids
  • Thionucleotides
  • Docetaxel