Our recent studies showed that antisense
oligodeoxynucleotide targeting antiapoptotic gene,
clusterin, enhanced apoptosis induced by conventional therapeutic modalities using several
prostate cancer models. In this study, to establish a more effective therapeutic strategy against
prostate cancer, we investigated the effect of combined treatment with antisense
clusterin oligodeoxynucleotide and adenoviral-mediated p53 gene transfer (Ad5CMV-p53) in an
androgen-independent human prostate PC3
tumor model. Treatment of PC3 cells with 500 nmol/L antisense
clusterin oligodeoxynucleotide decreased
clusterin mRNA by >80% compared with that with 500 nmol/L mismatch control
oligodeoxynucleotide.
Clusterin mRNA expression in PC3 cells was highly up-regulated by Ad5CMV-p53 treatment; however, antisense
clusterin oligodeoxynucleotide treatment further suppressed
clusterin expression in PC3 cells after Ad5CMV-p53 treatment. Antisense
clusterin oligodeoxynucleotide treatment significantly enhanced the sensitivity of Ad5CMV-p53 in a dose-dependent manner, reducing the IC50 of Ad5CMV-p53 by 75%. Apoptotic cell death was detected after combined treatment but not
after treatment with either agent alone. In vivo administration of antisense
clusterin oligodeoxynucleotide and Ad5CMV-p53 resulted in a significant inhibition of s.c. PC3
tumor growth as well as
lymph node metastases from orthotopic PC3
tumors compared with administration of either agent alone. Furthermore, combined treatment with antisense
clusterin oligodeoxynucleotide, Ad5CMV-p53, and
mitoxantrone completely eradicated s.c. PC3
tumors and
lymph node metastases from orthotopic PC3
tumors in 60% and 100% of mice, respectively. These findings suggest that combined treatment with antisense
clusterin oligodeoxynucleotide and Ad5CMV-p53 could be a novel strategy to inhibit progression of
hormone-refractory
prostate cancer and that further addition of chemotherapeutic agents may help to enhance the efficacy of this combined regimen.