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


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).


CONCLUSIONS
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.
Sowery
Richard D
RD
The Prostate Centre at Vancouver General Hospital, Vancouver, BC, Canada.
Hadaschik
Boris A
BA
So
Alan I
AI
Zoubeidi
Amina
A
Fazli
Ladan
L
Hurtado-Coll
Antonio
A
Gleave
Martin E
ME
D000728:Androgens / Q000378:metabolism; D045744:Cell Line, Tumor; D051152:Clusterin / Q000378:metabolism*; D015331:Cohort Studies; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D020360:Neoadjuvant Therapy; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000627:therapeutic use*; D011468:Prostatectomy / Q000379:methods; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000601:surgery; D043823:Taxoids / Q000627:therapeutic use*; D013873:Thionucleotides / Q000008:administration & dosage / Q000627:therapeutic use*
D000728:Androgens; D051152:Clusterin; C503781:OGX-011; D016376:Oligonucleotides, Antisense; D043823:Taxoids; D013873:Thionucleotides; D000077143:Docetaxel