Antisense MDM2 enhances the response of androgen insensitive human prostate cancer cells to androgen deprivation in vitro and in vivo.
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 tumor 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.
Mu
Zhaomei
Z
Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
Hachem
Paul
P
Hensley
Harvey
H
Stoyanova
Radka
R
Kwon
Hae Won
HW
Hanlon
Alexandra L
AL
Agrawal
Sudhir
S
Pollack
Alan
A
D000726:Androgen Antagonists / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology*; D009919:Orchiectomy; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000096:biosynthesis / Q000235:genetics* / Q000494:pharmacology; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D011944:Receptors, Androgen / Q000187:drug effects / Q000378:metabolism; D014410:Tumor Stem Cell Assay; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D000726:Androgen Antagonists; D020319:Oligodeoxyribonucleotides, Antisense; D011944:Receptors, Androgen; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D016283:Proto-Oncogene Proteins p21(ras)