title: Enhanced inhibition of prostate tumor growth by dual targeting the androgen receptor and the regulatory subunit type iα of protein kinase a in vivo.
abstract: 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.
authors.affiliation: Division of Experimental Urology, Innsbruck Medical University, 6020 Innsbruck, Anichstraße 35, Austria. iris.eder@i-med.ac.at.
authors.forename: Iris E
authors.initials: IE
authors.lastname: Eder
authors.forename: Martina
authors.initials: M
authors.lastname: Egger
authors.forename: Hannes
authors.initials: H
authors.lastname: Neuwirt
authors.forename: Christof
authors.initials: C
authors.lastname: Seifarth
authors.forename: Danilo
authors.initials: D
authors.lastname: Maddalo
authors.forename: Andreas
authors.initials: A
authors.lastname: Desiniotis
authors.forename: Georg
authors.initials: G
authors.lastname: Schäfer
authors.forename: Martin
authors.initials: M
authors.lastname: Puhr
authors.forename: Jasmin
authors.initials: J
authors.lastname: Bektic
authors.forename: Andrew C B
authors.initials: AC
authors.lastname: Cato
authors.forename: Helmut
authors.initials: H
authors.lastname: Klocker
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002369:Castration; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000473:pathology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011944:Receptors, Androgen / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: C410798:AR protein, human; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; D016376:Oligonucleotides, Antisense; D047428:Protein Kinase Inhibitors; D011944:Receptors, Androgen