ABSTRACT
At a time when the population shows increasing longevity, entities such as cancer and chronic kidney disease (CKD) are more frequently connected. In the United States, approximately 6% of the patients on hemodialysis have cancer. The challenge to manage oncologic patients with CKD in a hemodialytic program represents a great shortage of available information on the choice of the best drug, timing, dosage adjustments, dialysis method, and treatment safety. We present the case of a patient with prostate cancer and terminal CKD in hemodialysis, and the treatment sequence after the development of resistance to hormonal blockade therapy, which included docetaxel, enzalutamide, and radium-223.
Subject(s)
Humans , Male , Middle Aged , Adenocarcinoma/complications , Antineoplastic Agents/administration & dosage , Dialysis , Prostatic Neoplasms/complications , Renal Insufficiency, Chronic/drug therapy , Phenylthiohydantoin/administration & dosage , Prostatic Neoplasms, Castration-Resistant/complications , Radium/administration & dosage , Renal Insufficiency, Chronic/complications , Taxoids/administration & dosageABSTRACT
Objective@#To establish enzalutamide-resistant human prostate cancer cell lines and screen out the lncRNA and mRNA expression profiles associated with enzalutamide resistance.@*METHODS@#Human prostate cancer cell lines LNCAP and C4-2B were cultured with 10 μmol/L enzalutamide for 6 months in vitro for the establishment of enzalutamide-resistant subclones LNCAP-ENZA and C4-2B-ENZA. The IC50 value and enzalutamide resistance index of each cell line were examined by MTT assay, the expressions of enzalutamide-related genes FL-AR, AR-V7 and HnRNPA1 were determined by Western blot, and the lncRNA and mRNA differential expressions of C4-2B and C4-2B-ENZA were detected by high-throughout lncRNA microarray.@*RESULTS@#Compared with LNCAP and C4-2B, the IC50 values of enzalutamide-resistant subclones LNCAP-ENZA (60.83 μmol/L) and C4-2B-ENZA (88.32 μmol/L) were increased significantly (P < 0.05) and the enzalutamide-resistance indexes of the LNCAP-ENZA and C4-2B-ENZA cells were 4.94 and 4.67, respectively. The expressions of AR-V7 and HnRNPA1 were markedly up-regulated in the LNCAP-ENZA and C4-2B-ENZA cells as compared with those in the LNCAP and C4-2B cells, but that of FL-AR showed no significant change. A total of 1 440 lncRNAs and 1 236 mRNAs were identified as differentially expressed in the C4-2B-ENZA cells.@*CONCLUSIONS@#Enzalutamide -resistant human prostate cancer cell subclones LNCAP-ENZA and C4-2B-ENZA were successfully established and enzalutamide resistance-associated lncRNA and mRNA were identified, which may provide some molecular evidence for the management of enzalutamide-resistant human prostate cancer.
Subject(s)
Humans , Male , Cell Line, Tumor , Drug Resistance, Neoplasm , Phenylthiohydantoin , Pharmacology , Prostatic Neoplasms , Drug Therapy , Genetics , Pathology , RNA, Long Noncoding , Metabolism , RNA, Messenger , Metabolism , RNA, Neoplasm , Metabolism , Receptors, AndrogenABSTRACT
Androgen receptor (AR) is a ligand-activated transcription factor that plays a pivotal role in the development and progression of many severe diseases such as prostate cancer, muscle atrophy, and osteoporosis. Binding of ligands to AR triggers the conformational changes in AR that may affect the recruitment of coactivators and downstream response of AR signaling pathway. Therefore, AR ligands have great potential to treat these diseases. In this study, we searched for novel AR ligands by performing a docking-based virtual screening (VS) on the basis of the crystal structure of the AR ligand binding domain (LBD) in complex with its agonist. A total of 58 structurally diverse compounds were selected and subjected to LBD affinity assay, with five of them (HBP1-3, HBP1-17, HBP1-38, HBP1-51, and HBP1-58) exhibiting strong binding to AR-LBD. The IC values of HBP1-51 and HBP1-58 are 3.96 µM and 4.92 µM, respectively, which are even lower than that of enzalutamide (Enz, IC = 13.87 µM), a marketed second-generation AR antagonist. Further bioactivity assays suggest that HBP1-51 is an AR agonist, whereas HBP1-58 is an AR antagonist. In addition, molecular dynamics (MD) simulations and principal components analysis (PCA) were carried out to reveal the binding principle of the newly-identified AR ligands toward AR. Our modeling results indicate that the conformational changes of helix 12 induced by the bindings of antagonist and agonist are visibly different. In summary, the current study provides a highly efficient way to discover novel AR ligands, which could serve as the starting point for development of new therapeutics for AR-related diseases.
Subject(s)
Humans , Male , Androgen Receptor Antagonists , Pharmacology , Androgens , Metabolism , Pharmacology , Biological Assay , Cell Line, Tumor , Drug Discovery , Methods , Ligands , Molecular Docking Simulation , Molecular Dynamics Simulation , Phenylthiohydantoin , Pharmacology , Principal Component Analysis , Prostatic Neoplasms , Drug Therapy , Protein Binding , Physiology , Protein Conformation , Receptors, Androgen , MetabolismABSTRACT
En el presente trabajo se describe un procedimiento para la separación de 20 PTH-aminoácidos por cromatografía líquida de alta eficiencia en fase inversa, utilizando una columna de tipo C-8, de 50 mm de largo, que permite una gran economía de disolventes y de tiempo. La separación se completa en 14 minutos y utiliza un gradiente de iso-propanol en acetato de amonio 0,025 M a pH 5,3