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¹ The Prostate Centre, Vancouver General Hospital; ² Division of Urology, University of British Columbia, Vancouver, British Columbia, Canada; ³ Department of Urology, Hyogo Medical Center for Adults, Akashi, Japan; ⁴ Department of Urology, University of Washington, Seattle, Washington; and ⁵ Division of Oncology, Department of Internal Medicine, University Hospital, Zurich, Switzerland

Requests for reprints: Martin E. Gleave, Division of Urology, University of British Columbia, D-9, 2733 Heather Street, Vancouver, British Columbia, Canada V5Z 3J5. Phone: 604-875-5003; Fax: 604-875-5604. E-mail: m.gleave{at}ubc.ca

Bcl-2 and Bcl-xL are associated with treatment resistance and progression in many cancers, including prostate cancer. The objective of this study was to determine whether a novel bispecific antisense oligonucleotide targeting both Bcl-2 and Bcl-xL induces apoptosis and enhances chemosensitivity in androgen-independent PC3 prostate cancer cells. An antisense oligonucleotide with complete sequence identity to Bcl-2 and three-base mismatches to Bcl-xL selected from five antisense oligonucleotides targeting various regions with high homology between Bcl-2 and Bcl-xL was found to be the most potent inhibitor of both Bcl-2 and Bcl-xL expression in PC3 cells. This selected Bcl-2/Bcl-xL bispecific antisense oligonucleotide reduced mRNA and protein levels in a dose-dependent manner, reducing Bcl-2 and Bcl-xL protein levels to 12% and 19%, respectively. Interestingly, Mcl-1 was down-regulated as well, although levels of Bax, Bad, or Bak were not altered after treatment with this bispecific antisense oligonucleotide. Indirect down-regulation of inhibitor of apoptosis (IAP) family, including XIAP, cIAP-1 and cIAP-2, via second mitochondria-derived activator of caspases was also observed after bispecific antisense oligonucleotide treatment. Executioner caspase-3, caspase-6, and caspase-7 were shown to be involved in apoptosis induced by bispecific antisense oligonucleotide. This Bcl-2/Bcl-xL bispecific antisense oligonucleotide also enhanced paclitaxel chemosensitivity in PC3 cells, reducing the IC₅₀ of paclitaxel by >90%. These findings illustrate that combined suppression of antiapoptotic Bcl-2 family members using this antisense oligonucleotide could be an attractive strategy for inhibiting cancer progression through alteration of the apoptotic rheostat in androgen-independent prostate cancer.

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Received 3/ 3/05; revised 7/ 1/05; accepted 8/30/05.

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