Antisense MDM2 enhances the response of androgen insensitive human prostate cancer cells to androgen deprivation in vitro and in vivo

Zhaomei Mu, Paul Hachem, Harvey Hensley, Radka Stoyanova, Won Kwon Hae, Alexandra L. Hanlon, Sudhir Agrawal, Alan Pollack

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

BACKGROUND. Antisense MDM2 oligonucleotide (AS-MDM2) sensitizes androgen sensitive LNCaP cells to androgen deprivation (AD) in vitro and in vivo. In this study, we investigated the effects of AS-MDM2 combined with AD on androgen resistant LNCaP (LNCaP-Res) and moderately androgen resistant bcl-2 overexpressing LNCaP (LNCaP-BST) cells. METHODS. The LNCaP-Res cell line was generated by culturing LNCaP cells in medium containing charcoal-stripped serum for more than 1 year. Apoptosis was quantified in vitro by Annexin V staining and caspase 3 + 7 activity. For the in vivo studies, orthotopic tumor growth was monitored by magnetic resonance imaging (MRI). AS-MDM2 and the mismatch control were given by i.p. injection at doses of 25 mg/kg per day, 5 days/week for 15 days. RESULTS. LNCaP-Res cells expressed high levels of androgen receptor (AR) and bcl-2, and displayed no growth inhibition to AD. AS-MDM2 caused significant reductions in MDM2 and AR expression, and increases in p53 and p21 expression in both cell lines. AS-MDM2 + AD resulted in the highest levels of apoptosis in vitro and rumor growth inhibition in vivo in both cell lines; although, these effects were less pronounced in LNCaP-BST cells. CONCLUSIONS. AS-MDM2 + AD enhanced apoptotic cell death in vitro and tumor growth inhibition in vivo in androgen resistant cell lines. The action of AS-MDM2 + AD was influenced somewhat by bcl-2 expression as an isolated change (LNCaP-BST cells), but not when accompanied by other molecular changes associated with androgen insensitivity (LNCaP-Res cells). MDM2 knockdown has promise for the treatment of men with early hormone refractory disease.

Original languageEnglish (US)
Pages (from-to)599-609
Number of pages11
JournalProstate
Volume68
Issue number6
DOIs
StatePublished - May 1 2008
Externally publishedYes

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Keywords

  • Androgen deprivation
  • Antisense
  • MDM2
  • Prostate cancer

ASJC Scopus subject areas

  • Urology

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