Enhanced Inhibition of Prostate Tumor Growth by Dual Targeting the Androgen Receptor and the Regulatory Subunit Type Iα of Protein Kinase A in Vivo

International Journal of Molecular Sciences

Iris E. Eder¹  Martina Egger¹  Hannes Neuwirt²  Christof Seifarth¹  Danilo Maddalo³  Andreas Desiniotis¹  Georg Schr¹  Martin Puhr¹  Jasmin Bektic¹  Andrew C. B. Cato³ 

[1] Division of Experimental Urology, Innsbruck Medical University, 6020 Innsbruck, Anichstraße 35, Austria; E-Mails:;Department of Internal Medicine IV—Nephrology and Hypertension, Innsbruck Medical University, 6020 Innsbruck, Anichstraße 35, Austria; E-Mail:;Karlsruhe Institute of Technology, Institute of Toxicology and Genetics, Toxicology and Genetics, Hermann-von-Helmholtz-Platz 1, 76344 Eggenstein-Leopoldshafen, Germany; E-Mails:

关键词: androgen receptor;    cAMP-dependent protein kinase A;    regulatory subunit type Iα;    prostate cancer;    antisense molecules;    dual targeting;    LNCaP xenografts;    castration resistance;   

DOI  :  10.3390/ijms140611942

来源: mdpi

【 摘 要 】

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 Iα (RIα) 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 PKARIα 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.

【 授权许可】

CC BY   
© 2013 by the authors; licensee MDPI, Basel, Switzerland