کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
5559259 | 1561567 | 2017 | 35 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Iminoenamine based novel androgen receptor antagonist exhibited anti-prostate cancer activity in androgen independent prostate cancer cells through inhibition of AKT pathway
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کلمات کلیدی
EREEts related geneestrogen receptor response elementEtv1TMPRSS2AIPCLNCaPBicalutamideAREsETsandrogen independent prostate cancerPDBERGPSALBDDRCDHTerythroblast transformation specificAndrogen receptor antagonist - آنتاگونیست گیرنده آندروژنیProstate specific antigen - آنتی ژن اختصاصی پروستاتApoptosis - خزان یاختهایligand binding domain - دامنه اتصال لیگاندDihydrotestosterone - دی هیدروتستوسترونProstate cancer - سرطان پروستاتDose response curve - منحنی پاسخ دزtransmembrane protease serine 2 - پروتئاز ترانس مایع سریین 2Protein Data Bank - پروتئین بانک اطلاعاتیAndrogen Receptor - گیرنده آندروژنی
موضوعات مرتبط
علوم زیستی و بیوفناوری
علوم محیط زیست
بهداشت، سم شناسی و جهش زایی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
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.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Chemico-Biological Interactions - Volume 275, 25 September 2017, Pages 22-34
Journal: Chemico-Biological Interactions - Volume 275, 25 September 2017, Pages 22-34
نویسندگان
S. Divakar, K. Saravanan, P. Karthikeyan, R. Elancheran, S. Kabilan, K.K. Balasubramanian, Rajlakshmi Devi, J. Kotoky, M. Ramanathan,