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Iminoenamine based novel androgen receptor antagonist exhibited anti-prostate cancer activity in androgen independent prostate cancer cells through inhibition of AKT pathway
Kalapattukuppuswamy Kuppuswamy B. Balasubramanian
Published in Elsevier Ireland Ltd
2017
PMID: 28757136
Volume: 275
   
Pages: 22 - 34
Abstract
Treatment by androgen receptor (AR) antagonists is one of the regimens for prostate cancer. The prolonged treatment with AR antagonist leads to the expression of point mutation in the ligand binding domain of the AR. This point mutation causes resistance to AR antagonist by converting them into an agonist. The T887A mutated AR was frequently expressed in androgen independent prostate cancer (AIPC) patients. Through literature survey and molecular modelling, we have identified a novel AR antagonist having a bulky β-iminoenamine BF2 complex scaffold. The tested and standard ligands were screened in AR positive (LNCaP, MCF-7 and MDA-MB-453), AR negative (PC3), and non-cancerous (3T3) cell lines through anti-proliferation assay. The ligand, ARA3 was the most potent molecule among all the tested ligands and was 7.6 folds selective for AR positive cell lines. The mechanism of anti-prostate cancer activity of ARA3 was confirmed by western blot, qPCR, and apoptotic assays in LNCaP (T887A positive AR) cells. Structural activity relationship was derived by correlating the in-vitro and in-silico data. Consequently, we have identified the essential functional groups that could prevent the resistance concerning mutant AR. The ARA3 induces the apoptosis in AIPC cells by preventing the AR mediated activation of AKT pathway. The bicalutamide did not induce the apoptosis because it failed to prevent the AR mediated activation of AKT. © 2017 Elsevier B.V.
About the journal
JournalData powered by TypesetChemico-Biological Interactions
PublisherData powered by TypesetElsevier Ireland Ltd
ISSN00092797
Open AccessNo
Concepts (82)
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    ANDROGEN
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    ANDROGEN RECEPTOR
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    ANDROGEN RECEPTOR ANTAGONIST
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    Bicalutamide
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    Enamine
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    ENZALUTAMIDE
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    FLUTAMIDE
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    IMINOENAMINE
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    Messenger rna
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    Protein kinase b
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    Unclassified drug
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    AKT1 PROTEIN, HUMAN
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    Amine
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    ANDROGEN RECEPTOR
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    ANDROGEN RECEPTOR ANTAGONIST
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    Antineoplastic agent
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    AR PROTEIN, HUMAN
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    Caspase 3
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    Imine
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    PROTEIN BAX
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    Protein bcl 2
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    Antineoplastic activity
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    Antiproliferative activity
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    APOPTOSIS ASSAY
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    Article
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    CELL ACTIVATION
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    Cell activity
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    CELL PROLIFERATION ASSAY
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    Cell structure
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    Computer model
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    Controlled study
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    Drug mechanism
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    Drug screening
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    Drug structure
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    Enzyme inhibition
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    Gene control
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    Gene expression regulation
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    In vitro study
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    INTRACELLULAR SIGNALING
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    LNCAP CELL LINE
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    Mcf-7 cell line
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    MDA MB 453 CELL LINE
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    MDA-MB CELL LINE
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    Molecular model
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    Polymerase chain reaction
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    Prostate cancer
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    PROSTATE CANCER CELL LINE
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    Protein expression
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    Quantitative analysis
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    Structure activity relation
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    Western blotting
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    Antagonists and inhibitors
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    Apoptosis
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    Binding site
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    Cell proliferation
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    Chemistry
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    Drug effects
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    Enzymology
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    Fluorescence microscopy
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    Genetics
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    Human
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    Male
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    Metabolism
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    Molecular docking
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    Mutation
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    Pathophysiology
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    PROSTATE TUMOR
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    Tumor cell line
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    Amines
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    ANDROGEN RECEPTOR ANTAGONISTS
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    Antineoplastic agents
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    BCL-2-ASSOCIATED X PROTEIN
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    Binding sites
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    Cell line, tumor
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    Humans
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    Imines
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    Microscopy, fluorescence
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    Molecular docking simulation
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    PROSTATIC NEOPLASMS
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    Proto-oncogene proteins c-akt
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    Proto-oncogene proteins c-bcl-2
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    RECEPTORS, ANDROGEN