Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
5559259 | Chemico-Biological Interactions | 2017 | 35 Pages |
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.
Keywords
EREEts related geneestrogen receptor response elementEtv1TMPRSS2AIPCLNCaPBicalutamideAREsETsandrogen independent prostate cancerPDBERGPSALBDDRCDHTerythroblast transformation specificAndrogen receptor antagonistProstate specific antigenApoptosisligand binding domainDihydrotestosteroneProstate cancerDose response curvetransmembrane protease serine 2Protein Data BankAndrogen Receptor
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Authors
S. Divakar, K. Saravanan, P. Karthikeyan, R. Elancheran, S. Kabilan, K.K. Balasubramanian, Rajlakshmi Devi, J. Kotoky, M. Ramanathan,