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

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.