Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 8 de 8
Filter
Add more filters










Database
Publication year range
1.
J Med Chem ; 65(16): 11010-11033, 2022 08 25.
Article in English | MEDLINE | ID: mdl-35695407

ABSTRACT

MicroRNAs (miRNAs) are key players in human hepatocellular carcinoma (HCC) tumorigenesis. Therefore, small molecules targeting components of miRNA biogenesis may provide new therapeutic means for HCC treatment. By a high-throughput screening and structural simplification, we identified a small molecule, CIB-3b, which suppresses the growth and metastasis of HCC in vitro and in vivo by modulating expression profiles of miRNAome and proteome in HCC cells. Mechanistically, CIB-3b physically binds to transactivation response (TAR) RNA-binding protein 2 (TRBP) and disrupts the TRBP-Dicer interaction, thereby altering the activity of Dicer and mature miRNA production. Structure-activity relationship study via the synthesis of 45 CIB-3b derivatives showed that some compounds exhibited a similar inhibitory effect on miRNA biogenesis to CIB-3b. These results support TRBP as a potential therapeutic target in HCC and warrant further development of CIB-3b along with its analogues as a novel therapeutic strategy for the treatment of HCC.


Subject(s)
Carcinoma, Hepatocellular , DEAD-box RNA Helicases , Liver Neoplasms , MicroRNAs , Nuclear Receptor Coactivators , Ribonuclease III , Carcinoma, Hepatocellular/drug therapy , Cell Line , DEAD-box RNA Helicases/antagonists & inhibitors , Humans , Liver Neoplasms/drug therapy , MicroRNAs/metabolism , Nuclear Receptor Coactivators/antagonists & inhibitors , RNA-Binding Proteins/metabolism , Ribonuclease III/antagonists & inhibitors
2.
J Med Chem ; 65(1): 460-484, 2022 01 13.
Article in English | MEDLINE | ID: mdl-34931827

ABSTRACT

Cancer cell proliferation in some organs often depends on conversion of pyruvate to oxaloacetate via pyruvate carboxylase (PC) for replenishing the tricarboxylic acid cycle to support biomass production. In this study, PC was identified as the cellular target of erianin using the photoaffinity labeling-click chemistry-based probe strategy. Erianin potently inhibited the enzymatic activity of PC, which mediated the anticancer effect of erianin in human hepatocellular carcinoma (HCC). Erianin modulated cancer-related gene expression and induced changes in metabolic intermediates. Moreover, erianin promotes mitochondrial oxidative stress and inhibits glycolysis, leading to insufficient energy required for cell proliferation. Analysis of 14 natural analogs of erianin showed that some compounds exhibited potent inhibitory effects on PC. These results suggest that PC is a cellular target of erianin and reveal the unrecognized function of PC in HCC tumorigenesis; erianin along with its analogs warrants further development as a novel therapeutic strategy for the treatment of HCC.


Subject(s)
Antineoplastic Agents/pharmacology , Bibenzyls/pharmacology , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/metabolism , Liver Neoplasms/drug therapy , Liver Neoplasms/metabolism , Pyruvate Carboxylase/antagonists & inhibitors , Antineoplastic Agents/chemistry , Bibenzyls/chemistry , Cell Proliferation/drug effects , Click Chemistry , Gene Expression Regulation, Neoplastic/drug effects , Humans , Oxidative Stress/drug effects , Phenol/pharmacology , Structure-Activity Relationship
3.
J Med Chem ; 64(11): 7404-7421, 2021 06 10.
Article in English | MEDLINE | ID: mdl-34038111

ABSTRACT

Imbalance miRNAs contribute to tumor formation; therefore, the development of small-molecule compounds that regulate miRNA biogenesis is an important strategy in oncotherapy. Here, (-)-Gomisin M1 (GM) was found to modulate miRNA biogenesis to inhibit the proliferation, migration, and invasion of hepatocellular carcinoma (HCC) cells. GM modulated expression profiles of miRNA and protein in HCC cells and suppressed tumor growth in a mouse model. Mechanistically, GM affected miRNA maturation by targeting TAR RNA-binding protein 2 (TRBP), with an efficacy higher than that of enoxacin, and promoted the binding of TRBP with Dicer. Structural simplification and a preliminary structure-activity relationship study via the synthesis of 20 GM derivatives showed that compound 9 exhibited more potent inhibitory activity in HCC cell proliferation and affinity for TRBP than did GM. These results suggest that TRBP may be a novel potential therapeutic target in HCC and compound 9 may be a potential drug candidate for the treatment of HCC.


Subject(s)
Polycyclic Compounds/chemistry , RNA-Binding Proteins/metabolism , Animals , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/pathology , Cell Cycle Checkpoints/drug effects , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , DEAD-box RNA Helicases/chemistry , DEAD-box RNA Helicases/metabolism , Enoxacin/chemistry , Enoxacin/metabolism , Enoxacin/pharmacology , Enoxacin/therapeutic use , Gene Expression Regulation, Neoplastic/drug effects , Humans , Liver Neoplasms/drug therapy , Liver Neoplasms/genetics , Liver Neoplasms/pathology , Mice , Mice, Nude , MicroRNAs/metabolism , Polycyclic Compounds/metabolism , Polycyclic Compounds/pharmacology , Polycyclic Compounds/therapeutic use , Proteome/drug effects , Proteome/metabolism , RNA-Binding Proteins/antagonists & inhibitors , Ribonuclease III/chemistry , Ribonuclease III/metabolism , Structure-Activity Relationship , Transcriptome/drug effects , Transplantation, Heterologous
4.
Toxicol Appl Pharmacol ; 404: 115203, 2020 10 01.
Article in English | MEDLINE | ID: mdl-32822738

ABSTRACT

Indoleamine 2,3 dioxygenase (IDO) is upregulated in many tumor types, including breast cancer, and plays a reputable role in promoting tumor immune tolerance. The importance of the immunosuppressive mechanism of IDO by suppressing T-cell function has garnered profound interest in the development of clinical IDO inhibitors. Herein, we established a screening method with cervical HeLa cells to induce IDO expression using interferon-γ (IFN-γ). After screening our chemical library, we found that salinomycin potently inhibited IFN-γ-stimulated kynurenine synthesis with IC50 values of 3.36-4.66 µM in both human cervical and breast cancer cells. Salinomycin lowered the IDO1 and IDO2 expression with no impact on the expression of tryptophan-2,3-dioxygenase. Interestingly, salinomycin potently repressed the IDO1 enzymatic activity by directly targeting the proteins in cells. Molecular docking revealed an alignment that favors nucleophilic attack of salinomycin in the catalytic domain of IDO1. Activation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway by IFN-γ was significantly suppressed by salinomycin, via inhibiting the Jak1, Jak2, and STAT1/3 phosphorylation. Moreover, it inhibited IFN-γ-induced activation of the nuclear factor (NF)-κB pathway by inhibiting IκB degradation and NF-κB phosphorylation without affecting BIN1 expression. Furthermore, salinomycin significantly restored the proliferation of T cells co-cultured with IFN-γ-treated breast cancer cells and potentiated antitumor activity of cisplatin in vivo. These findings suggest that salinomycin suppresses kynurenine synthesis by inhibiting the catalytic activity of IDO1 and its expression by inhibiting the JAK/STAT and NF-κB pathways. Salinomycin warrants further investigation as a novel dual-functional IDO inhibitor for cancer immunotherapy.


Subject(s)
Breast Neoplasms/immunology , Gene Expression Regulation, Neoplastic/drug effects , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Pyrans/pharmacology , T-Lymphocytes/drug effects , Animals , Anti-Bacterial Agents/pharmacology , Cell Line, Tumor , Cell Survival/drug effects , Female , Humans , Immunosuppression Therapy , Indoleamine-Pyrrole 2,3,-Dioxygenase/genetics , Mice , Mice, Inbred C57BL , Models, Molecular , Neoplasms, Experimental , Protein Conformation
5.
Toxicol Appl Pharmacol ; 371: 41-54, 2019 05 15.
Article in English | MEDLINE | ID: mdl-30946863

ABSTRACT

Erianin, a component extracted from the traditional Chinese herbal medicine Dendrobium, has shown significant anti-tumour activity in various cancers but not in bladder cancer. In this study, we assessed the effects of Erianin on bladder cancer growth and elucidated the related mechanisms. First, Erianin was synthesized with high yields, and markedly suppressed EJ and T24 cell proliferation. It induced G2/M-phase arrest in vitro. Furthermore, Erianin triggered apoptosis via caspase cascades activation and the mitochondrial-mediated apoptotic pathway. Bim up-regulation and Bcl-2 down-regulation as the symbol of apoptosis which were found to play the dominant role in the effects of Erianin. We further showed that JNK pathway activation is necessary for the Erianin-mediated anti-proliferation and apoptotic response. Finally, Erianin exhibited anti-tumour activity and induced apoptosis in tumour tissue in vivo. Collectively, these results suggest that Erianin induced cell cycle G2/M-phase arrest and apoptosis via the JNK signalling pathway in bladder cancer, indicating the potential usefulness of Erianin for the therapy of bladder cancer.


Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Bibenzyls/pharmacology , Cell Proliferation/drug effects , Dendrobium , JNK Mitogen-Activated Protein Kinases/metabolism , Mitochondria/drug effects , Urinary Bladder Neoplasms/drug therapy , Animals , Antineoplastic Agents/isolation & purification , Bcl-2-Like Protein 11/genetics , Bcl-2-Like Protein 11/metabolism , Bibenzyls/isolation & purification , Cell Line, Tumor , Dendrobium/chemistry , G2 Phase Cell Cycle Checkpoints/drug effects , Humans , Mice, Nude , Mitochondria/enzymology , Mitochondria/pathology , Phenol , Proto-Oncogene Proteins c-bcl-2/genetics , Proto-Oncogene Proteins c-bcl-2/metabolism , Signal Transduction , Tumor Burden/drug effects , Urinary Bladder Neoplasms/enzymology , Urinary Bladder Neoplasms/genetics , Urinary Bladder Neoplasms/pathology , Xenograft Model Antitumor Assays
6.
Biotechnol Lett ; 40(1): 23-30, 2018 Jan.
Article in English | MEDLINE | ID: mdl-28948407

ABSTRACT

OBJECTIVE: To synthesize and determine the antitumor activity of 10-chlorocanthin-6-one in ovarian cancer HO8910PM cells. RESULTS: Among the synthesized canthin-6-one analogs, 10-chlorocanthin-6-one was the most cytotoxic (IC50 = 4.9 µM), as demonstrated by a dose-dependent cytotoxicity assay. Moreover, 10-chlorocanthin-6-one induced apoptosis through the activation of poly(ADP-ribose) polymerase and caspase-3 cleavage, upregulation of Bcl-2, and downregulation of Bim, x-linked inhibitor of apoptosis protein (XIAP), and survivin in HO8910PM cells. Furthermore, Bim RNA, upregulated in a concentration-dependent manner, and knockdown of Bim via short-hairpin RNAs attenuated the inhibitory effects of 10-chlorocanthin-6-one on HO8910PM cell growth. CONCLUSIONS: 10-Chlorocanthin-6-one inhibits cell proliferation and induces apoptosis in H08910PM cells. The underlying molecular mechanisms of 10-chlorocanthin-6-one include activation of the Bim-mediated mitochondrial apoptotic pathway via upregulation of Bim and downregulation of Bcl-2, XIAP, and survivin. These data suggest that Bim is a potential target of 10-chlorocanthin-6-one, further demonstrating its potential use in the prevention and treatment of ovarian cancer.


Subject(s)
Alkaloids/chemical synthesis , Alkaloids/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Carbolines/chemical synthesis , Carbolines/pharmacology , Cell Proliferation/drug effects , Cell Survival/drug effects , Ovarian Neoplasms/drug therapy , Apoptosis/drug effects , Cell Line, Tumor , Drug Evaluation, Preclinical/methods , Female , Gene Expression Profiling , Gene Expression Regulation/drug effects , Humans , Inhibitory Concentration 50
7.
Biotechnol Lett ; 40(1): 31, 2018 01.
Article in English | MEDLINE | ID: mdl-29288350

ABSTRACT

The addresses given for the authors of this paper were incorrect. The correct assignments of the authors are given in this erratum.

8.
Zhongguo Zhong Yao Za Zhi ; 36(24): 3535-8, 2011 Dec.
Article in Chinese | MEDLINE | ID: mdl-22368873

ABSTRACT

OBJECTIVE: To investigate the apoptosis of bladder cancer cell 5637 induced by pseudolaric acid B in vitro and its mechanism. METHOD: The cell proliferation was detected by MTT assay;the cell cycle was measured by flow cytometry; the cell apoptosis was observed by flow cytometry with Annexin V-FITC/PI double staining; the expressions of survivin protein and caspase-3 protein were detected by Western blot assay. RESULT: It showed that pseudolaric acid B remarkably induced apoptosis of 5637 cell line. Moreover, pseudolaric acid B suppressed survivin and up-regulated caspase-3 expression. CONCLUSION: Pseudolaric acid B inhibits the proliferation and induces the apoptosis of 5637 cells. The molecular mechanism of pseudolaric acid B inducing the apoptosis of 5637 cells may be associated with its action of down-regulating the expression of survivin, and up-regulating the expression of caspase-3.


Subject(s)
Apoptosis/drug effects , Diterpenes/pharmacology , Drugs, Chinese Herbal/pharmacology , Urinary Bladder Neoplasms/drug therapy , Caspase 3/analysis , Cell Cycle/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , Inhibitor of Apoptosis Proteins/analysis , Survivin , Urinary Bladder Neoplasms/pathology
SELECTION OF CITATIONS
SEARCH DETAIL
...