期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 14, 期 6, 页码 11942-11962出版社
MDPI
DOI: 10.3390/ijms140611942
关键词
androgen receptor; cAMP-dependent protein kinase A; regulatory subunit type I alpha; prostate cancer; antisense molecules; dual targeting; LNCaP xenografts; castration resistance
资金
- COMET Center ONCOTYROL
- Austrian Federal Ministries BMVIT/BMWFJ (via FFG)
- Tiroler Zukunftsstiftung/Standortagentur Tirol (SAT) (I.E.E., Oncotyrol 3.4)
- Austrian Cancer Society/Tirol
- Association for International Cancer Research, U.K.
- European Union
Progression to castration resistance is a major problem in the treatment of advanced prostate cancer and is likely to be driven by activation of several molecular pathways, including androgen receptor (AR) and cyclic AMP-dependent protein kinase A (PKA). In this study, we examined the therapeutic efficacy of a combined inhibition of the AR and the regulatory subunit type I alpha (RI alpha) of protein kinase A with second generation antisense oligonucleotides (ODNs) in androgen-sensitive LNCaP and castration-resistant LNCaPabl tumors in vivo. We found that targeting the AR alone inhibited LNCaP, as well as LNCaPabl tumors. Combined inhibition resulted in an improved response over single targeting and even a complete tumor remission in LNCaPabl. Western blot analysis revealed that both ODNs were effective in reducing their target proteins when administered alone or in combination. In addition, treatment with the ODNs was associated with an induction of apoptosis. Our data suggest that dual targeting of the AR and PKARI alpha is more effective in inhibiting LNCaP and LNCaPabl tumor growth than single treatment and may give a treatment benefit, especially in castration-resistant prostate cancers.
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