ABSTRACT
Prolyl-tRNA synthetase 1 (PARS1) has attracted much interest in controlling pathologic accumulation of collagen containing high amounts of proline in fibrotic diseases. However, there are concerns about its catalytic inhibition for potential adverse effects on global protein synthesis. We developed a novel compound, DWN12088, whose safety was validated by clinical phase 1 studies, and therapeutic efficacy was shown in idiopathic pulmonary fibrosis model. Structural and kinetic analyses revealed that DWN12088 binds to catalytic site of each protomer of PARS1 dimer in an asymmetric mode with different affinity, resulting in decreased responsiveness at higher doses, thereby expanding safety window. The mutations disrupting PARS1 homodimerization restored the sensitivity to DWN12088, validating negative communication between PARS1 promoters for the DWN12088 binding. Thus, this work suggests that DWN12088, an asymmetric catalytic inhibitor of PARS1 as a novel therapeutic agent against fibrosis with enhanced safety.
Subject(s)
Amino Acyl-tRNA Synthetases , Humans , Amino Acyl-tRNA Synthetases/chemistry , Amino Acyl-tRNA Synthetases/genetics , Amino Acyl-tRNA Synthetases/metabolism , Fibrosis , Proline/genetics , Proline/metabolism , Protein BiosynthesisABSTRACT
Epidermal growth factor receptor mutation-positive non-small cell lung cancer is cared for mainly by target therapeutics in the clinical treatment at present. We investigated the antitumor effect of HangAmDan-B1 (HAD-B1) combined with afatinib on H1975 (L858R/T790M double mutation) lung cancer cells. The combined treatment of HAD-B1 with afatinib inhibited the proliferation of H1975 cells in a dose-dependent manner compared with the treatment of afatinib or HAD-B1 alone. The combined treatment group significantly induced early apoptosis and cell cycle arrest of the cells compared with afatinib- or HAD-B1-treated control group. Profile analysis of cell cycle proteins in H1975 cells treated with the combination of HAD-B1 and afatinib using InnoPharmaScreen antibody microarray showed downregulation of pERK1/2 and upregulation of p16 in the cells. In vivo tumor growth assay in xenograft animal model of human H1975 lung cancer cells revealed that the mean tumor volume in the group treated with the combination of HAD-B1 and afatinib showed a significant reduction compared with the control groups.
Subject(s)
Afatinib/pharmacology , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Lung Neoplasms/drug therapy , Protein Kinase Inhibitors/pharmacology , Animals , Apoptosis/drug effects , Cell Cycle Checkpoints/drug effects , Cell Line, Tumor , Drug Resistance, Neoplasm/drug effects , ErbB Receptors/metabolism , Humans , Lung Neoplasms/metabolism , Mice , Mutation/drug effects , Signal Transduction/drug effects , Xenograft Model Antitumor Assays/methodsABSTRACT
The goal of this study is to determine the anti-cancer mechanism of Cordycepin in A549 Cisplatin-Resistance (CR) lung cancer cells. Cordycepin inhibited the viability of A549CR cells in a dose-dependent manner. The cell inhibition was due to induction of apoptosis in the cells treated with Cordycepin by activation of caspase -3, -8 and -9 activities. The cell cycle analysis showed that accumulation of Sub G1 was observed in Cordycepin-treated with A549CR lung cancer cells. Based on the data of expression profile analysis of cell signaling proteins using IPS-FPAA, H-Ras was down-regulated in Cordycepin-treated A549CR cells. Collectively, anti-proliferative function of Cordycepin was due to stimulation of the cell apoptosis and the cell cycle arrest via caspases activation and down-regulation of H-Ras.