Knock-down of Bcl-2 by antisense oligodeoxynucleotides induces radiosensitization and inhibition of angiogenesis in human PC-3 prostate tumor xenografts

Satoshi Anai, Steven Goodison, Kathleen Shiverick, Yoshihiko Hirao, Bob D. Brown, Charles J. Rosser

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

Expression of the proto-oncogene Bcl-2 is associated with tumor progression. Bcl-2's broad expression in tumors, coupled with its role in resistance to chemotherapy and radiation therapy-induced apoptosis, makes it a rational target for anticancer therapy. Antisense Bcl-2 oligodeoxy-nucleotide (ODN) reagents have been shown to be effective in reducing Bcl-2 expression in a number of systems. We investigated whether treating human prostate cancer cells with antisense Bcl-2 ODN (G3139, oblimersen sodium, Genasense) before irradiation would render them more susceptible to radiation effects. Two prostate cancer cell lines expressing Bcl-2 at different levels (PC-3-Bcl-2 and PC-3-Neo) were subjected to antisense Bcl-2 ODN, reverse control (CTL), or mock treatment. Antisense Bcl-2 ODN alone produced no cytotoxic effects and was associated with G1 cell cycle arrest. The combination of antisense Bcl-2 ODN with irradiation sensitized both cell lines to the killing effects of radiation. Both PC-3-Bcl-2 and PC-3-Neo xenografts in mice treated with the combination of antisense Bcl-2 ODN and irradiation were more than three times smaller by volume compared with xenografts in mice treated with reverse CTL alone, antisense Bcl-2 ODN alone, irradiation alone, or reverse CTL plus radiotherapy (P = 0.0001). Specifically, PC-3-Bcl-2 xenograft tumors treated with antisense Bcl-2 ODN and irradiation had increased rates of apoptosis and decreased rates of angiogenesis and proliferation. PC-3-Neo xenograft tumors had decreased proliferation only. This is the first study which shows that therapy directed at Bcl-2 affects tumor vasculature. Together, these findings warrant further study of this novel combination of Bcl-2 reduction and radiation therapy, as well as Bcl-2 reduction and angiogenic therapy.

Original languageEnglish (US)
Pages (from-to)101-111
Number of pages11
JournalMolecular Cancer Therapeutics
Volume6
Issue number1
DOIs
StatePublished - Jan 1 2007
Externally publishedYes

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Heterografts
Prostate
Nucleotides
Neoplasms
Radiotherapy
Radiation Effects
Prostatic Neoplasms
Apoptosis
G1 Phase Cell Cycle Checkpoints
Cell Line
Proto-Oncogenes
oblimersen
Therapeutics
Drug Therapy

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Knock-down of Bcl-2 by antisense oligodeoxynucleotides induces radiosensitization and inhibition of angiogenesis in human PC-3 prostate tumor xenografts. / Anai, Satoshi; Goodison, Steven; Shiverick, Kathleen; Hirao, Yoshihiko; Brown, Bob D.; Rosser, Charles J.

In: Molecular Cancer Therapeutics, Vol. 6, No. 1, 01.01.2007, p. 101-111.

Research output: Contribution to journalArticle

Anai, Satoshi ; Goodison, Steven ; Shiverick, Kathleen ; Hirao, Yoshihiko ; Brown, Bob D. ; Rosser, Charles J. / Knock-down of Bcl-2 by antisense oligodeoxynucleotides induces radiosensitization and inhibition of angiogenesis in human PC-3 prostate tumor xenografts. In: Molecular Cancer Therapeutics. 2007 ; Vol. 6, No. 1. pp. 101-111.
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