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1.
Med Res Rev ; 43(5): 1263-1321, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-36951271

RESUMEN

Gastrointestinal (GI) tumors (cancers of the esophagus, gastric, liver, pancreas, colon, and rectum) contribute to a large number of deaths worldwide. STAT3 is an oncogenic transcription factor that promotes the transcription of genes associated with proliferation, antiapoptosis, survival, and metastasis. STAT3 is overactivated in many human malignancies including GI tumors which accelerates tumor progression, metastasis, and drug resistance. Research in recent years demonstrated that noncoding RNAs (ncRNAs) play a major role in the regulation of many signaling pathways including the STAT3 pathway. The major types of endogenous ncRNAs that are being extensively studied in oncology are microRNAs, long noncoding RNAs, and circular RNAs. These ncRNAs can either be tumor-promoters or tumor-suppressors and each one of them imparts their activity via different mechanisms. The STAT3 pathway is also tightly modulated by ncRNAs. In this article, we have elaborated on the tumor-promoting role of STAT3 signaling in GI tumors. Subsequently, we have comprehensively discussed the oncogenic as well as tumor suppressor functions and mechanism of action of ncRNAs that are known to modulate STAT3 signaling in GI cancers.


Asunto(s)
Neoplasias Gastrointestinales , MicroARNs , ARN Largo no Codificante , Humanos , MicroARNs/genética , ARN Largo no Codificante/genética , Neoplasias Gastrointestinales/genética , Transducción de Señal , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo
2.
Drug Dev Res ; 84(8): 1724-1738, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37756467

RESUMEN

Signal transducer and activator of transcription 3 (STAT3) and STAT5 are the transcription factors that have been studied extensively in relevance to the development of cancers in humans. Suppression of either STAT3 or STAT5-mediated signaling events has been demonstrated to be effective in inducing cytotoxicity in cancer cells. Herein, new hybrids of triazolyl-indolo-quinoxaline are synthesized and examined for their effect on the activation of STAT3 and STAT5 pathways in gastric cancer (GC) cells. Among the newly synthesized compounds, 2,3-difluoro-6-((1-(3-fluorophenyl)-1H-1,2,3-triazol-5-yl)methyl)-6H-indolo[2,3-b]quinoxaline (DTI) displayed selective cytotoxicity against GC cells over their normal counterpart. Flow cytometric analysis, annexin-V-fluorescein isothiocyanate staining, terminal deoxynucleotidyl transferase dUTP nick end labeling assay, live and dead assay, and caspase activation experiments suggested DTI as a potent inducer of apoptosis. The mechanistic approach revealed that DTI imparts cytotoxicity via downregulating the phosphorylation of STAT3Y705 and STAT5Y694/699 . DTI significantly reduced the nuclear pool of STAT3/STAT5 and reduced the DNA interaction ability of STAT3/STAT5 as evidenced by immunofluorescence and electrophoretic mobility shift assay. Further investigation revealed that inhibitory effects towards STAT proteins were mediated through the suppression of upstream kinases such as JAK1, JAK2, and Src. Treatment of GC cells with pervanadate counteracted the DTI-driven STAT3/STAT5 inhibition suggesting the involvement of tyrosine phosphatase. Upon DTI exposure, there was a significant upregulation in the mRNA and protein expression of PTPεC, which is a negative regulator of the JAK-STAT pathway. Knockdown of PTPεC suppressed the DTI-induced STATs inhibition in GC cells. Taken together, triazolyl-indolo-quinoxaline is presented as a new inhibitor of the STAT3/STAT5 pathway in GC cells.


Asunto(s)
Transducción de Señal , Neoplasias Gástricas , Humanos , Factor de Transcripción STAT5/metabolismo , Factor de Transcripción STAT5/farmacología , Factor de Transcripción STAT3/metabolismo , Proteínas de Unión al ADN/metabolismo , Transactivadores , Regulación hacia Arriba , Quinoxalinas/farmacología , Quinasas Janus/metabolismo , Quinasas Janus/farmacología , Factores de Transcripción STAT/metabolismo , Factores de Transcripción STAT/farmacología , Fosforilación , Apoptosis
3.
Cells ; 10(1)2020 12 22.
Artículo en Inglés | MEDLINE | ID: mdl-33374892

RESUMEN

There is an urge for traditional herbal remedies as an alternative to modern medicine in treating several ailments. Alangium salviifolium is one such plant, used traditionally to treat several diseases. In several reports, there are findings related to the use of this plant extract that demonstrate its therapeutic value. However, very few attempts have been made to identify the extensive metabolite composition of this plant. Here, we performed metabolite profiling and identification from the bark of A. salviifolium by extracting the sample in organic and aqueous solvents. The organic and aqueous extracts were fraction-collected using the Agilent 1260 Analytical Scale Fraction Collection System. Each of the fractions was analyzed on Liquid Chromatogaphy/Quadrupole Time-of-Flight LC/Q-TOF and Gas Chromatography/Quadrupole Time-of-Flight GC/instruments. The Liquid Chromatography/Mass Spectrometry (LC/MS) analyses were performed using Hydrophilic Ineraction Liquid Chromatography (HILIC), as well as reversed-phase chromatography using three separate, orthogonal reverse phase columns. Samples were analyzed using an Agilent Jet Stream (AJS) source in both positive and negative ionization modes. The compounds found were flavonoids, fatty acids, sugars, and terpenes. Eighty-one secondary metabolites were identified as having therapeutic potential. The data produced was against the METLIN database using accurate mass and/or MS/MS library matching. Compounds from Alangium that could not be identified by database or library matching were subsequently searched against the ChemSpider) database of over 30 million structures using MSMS data and Agilent MSC software.In order to identify compounds generated by GC/MS, the data were searched against the AgilentFiehn GCMS Metabolomics Library as well as the Wiley/NIST libraries.


Asunto(s)
Alangiaceae , Metaboloma , Corteza de la Planta , Extractos Vegetales/química , Alangiaceae/química , Alangiaceae/metabolismo , Cromatografía Líquida de Alta Presión/métodos , Corteza de la Planta/química , Corteza de la Planta/metabolismo , Espectrometría de Masas en Tándem/métodos
4.
Curr Org Synth ; 17(3): 243-250, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32096746

RESUMEN

Design of chemically novel, biologically potent small heterocyclic molecules with anticancer activities, which targets the enzyme heparanase has gained prominent clinical interest. We have synthesized a novel class of carboxamide derivatives by coupling various substituted aromatic acid hydrazides and triazoleamine with pyrrolidine carboxylic acid by using coupling agents. The synthesized compounds are characterized by spectroscopic techniques such as FT-IR, HRMS and NMR. These compounds are investigated for cytotoxicity on different cancer cell lines and heparanase inhibitory activity. Most of them showed moderate heparanase inhibitory activity and good cytotoxicity.


Asunto(s)
Antineoplásicos/farmacología , Inhibidores Enzimáticos/farmacología , Glucuronidasa/antagonistas & inhibidores , Hidrazinas/farmacología , Pirrolidinonas/farmacología , Triazoles/farmacología , Animales , Antineoplásicos/síntesis química , Línea Celular Tumoral , Inhibidores Enzimáticos/síntesis química , Humanos , Hidrazinas/síntesis química , Ratones , Pirrolidinonas/síntesis química , Triazoles/síntesis química
5.
Front Pharmacol ; 9: 309, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29755344

RESUMEN

Cancer is a major cause of death worldwide, with an increasing number of cases being reported annually. The elevated rate of mortality necessitates a global challenge to explore newer sources of anticancer drugs. Recent advancements in cancer treatment involve the discovery and development of new and improved chemotherapeutics derived from natural or synthetic sources. Natural sources offer the potential of finding new structural classes with unique bioactivities for cancer therapy. Endophytic fungi represent a rich source of bioactive metabolites that can be manipulated to produce desirable novel analogs for chemotherapy. This review offers a current and integrative account of clinically used anticancer drugs such as taxol, podophyllotoxin, camptothecin, and vinca alkaloids in terms of their mechanism of action, isolation from endophytic fungi and their characterization, yield obtained, and fungal strain improvement strategies. It also covers recent literature on endophytic fungal metabolites from terrestrial, mangrove, and marine sources as potential anticancer agents and emphasizes the findings for cytotoxic bioactive compounds tested against specific cancer cell lines.

6.
Med Chem ; 11(5): 462-72, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25494807

RESUMEN

2,4-Disubstituted thiophene derivatives were synthesized and assessed for antiinflammatory and anti-cancer activities by targeting two important enzymes of the arachidonic acid metabolism. Both lipoxygenase and cyclooxygenase enzymes play vital role in chronic inflammation and carcinogenesis. Previous studies have proved that COX-2 and 5-LOX are highly activated in various types of cancers; hence inhibition of these clinically important enzymes constitutes the essential criterion for the suppression of tumor progression and metastasis. Among the tested derivatives, 2d and 2g compounds emerged as potent inhibitors of lipoxygenase and cyclooxygenase enzymes. The potent inhibitor of cyclooxygenase was further tested for in vitro cytotoxicity on cervical cancer (HeLa) cells and in vivo tumor model studies using EAT bearing mice where 2-(3,4,5- trimethoxyphenyl)-4-(N-methylindol-3-yl) thiophene (2g) showed eloquent activity. Further, in silico modeling results confirmed the active catalytic ligand binding pockets, which is evident from higher atomic contact energy values of 2d and 2g than compared to standard drug. Thus, 2g may find better application in management of inflammation and in proapoptotic therapeutic engineering.


Asunto(s)
Antineoplásicos/farmacología , Inhibidores de la Ciclooxigenasa/farmacología , Inhibidores de la Lipooxigenasa/farmacología , Tiofenos/síntesis química , Tiofenos/farmacología , Animales , Antiinflamatorios/síntesis química , Antiinflamatorios/química , Antiinflamatorios/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Inhibidores de la Ciclooxigenasa/síntesis química , Inhibidores de la Ciclooxigenasa/química , Ensayos de Selección de Medicamentos Antitumorales , Activación Enzimática/efectos de los fármacos , Células HeLa , Humanos , Concentración 50 Inhibidora , Inhibidores de la Lipooxigenasa/síntesis química , Inhibidores de la Lipooxigenasa/química , Ratones , Modelos Moleculares , Simulación del Acoplamiento Molecular , Tiofenos/química
7.
PLoS One ; 9(9): e107118, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25268519

RESUMEN

The anti-apoptotic protein Bcl-2 is a well-known and attractive therapeutic target for cancer. In the present study the solution-phase T3P-DMSO mediated efficient synthesis of 2-amino-chromene-3-carbonitriles from alcohols, malanonitrile and phenols is reported. These novel 2-amino-chromene-3-carbonitriles showed cytotoxicity in human acute myeloid leukemia (AML) cell lines. Compound 4 g was found to be the most bioactive, decreasing growth and increasing apoptosis of AML cells. Moreover, compound 4 g (at a concentration of 5 µM) increased the G2/M and sub-G1 (apoptosis) phases of AML cells. The AML cells treated with compound 4 g exhibited decreased levels of Bcl-2 and increased levels of caspase-9. In silico molecular interaction analysis showed that compound 4 g shared a similar global binding motif with navitoclax (another small molecule that binds Bcl-2), however compound 4 g occupies a smaller volume within the P2 hot spot of Bcl-2. The intermolecular π-stacking interaction, direct electrostatic interactions, and docking energy predicted for 4 g in complex with Bcl-2 suggest a strong affinity of the complex, rendering 4 g as a promising Bcl-2 inhibitor for evaluation as a new anticancer agent.


Asunto(s)
Antineoplásicos/farmacología , Benzopiranos/farmacología , Nitrilos/farmacología , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Antineoplásicos/síntesis química , Benzopiranos/síntesis química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Concentración 50 Inhibidora , Leucemia Mieloide Aguda/tratamiento farmacológico , Simulación del Acoplamiento Molecular , Terapia Molecular Dirigida , Nitrilos/síntesis química , Proteínas Proto-Oncogénicas c-bcl-2/química
8.
PLoS One ; 9(9): e107182, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25238069

RESUMEN

Thrombocytopenia is a serious issue connected with the pathogenesis of several human diseases including chronic inflammation, arthritis, Alzheimer's disease, cardiovascular diseases (CVDs) and other oxidative stress-associated pathologies. The indiscriminate use of antibiotics and other biological drugs are reported to result in thrombocytopenia, which is often neglected during the treatment regime. In addition, augmented oxidative stress induced by drugs and pathological conditions has also been shown to induce thrombocytopenia, which seems to be the most obvious consequence of elevated rate of platelet apoptosis. Thus, blocking oxidative stress-induced platelet apoptosis would be of prime importance in order to negotiate thrombocytopenia and associated human pathologies. The current study presents the synthesis and platelet protective nature of novel ibuprofen derivatives. The potent anti-oxidant ibuprofen derivative 4f was selected for the study and the platelet protective efficacy and platelet aggregation inhibitory property has been demonstrated. The compound 4f dose dependently mitigates the oxidative stress-induced platelet apoptosis in both platelet rich plasma and washed platelets. The platelet protective nature of compound 4f was determined by assessing various apoptotic markers such as ROS generation, cytosolic Ca2+ levels, PS externalization, cytochrome C translocation, Caspase activation, mitochondrial membrane depolarization, cytotoxicity, LDH leakage and tyrosine phosphorylation of cytosolic proteins. Furthermore, compound 4f dose dependently ameliorated agonist induced platelet aggregation. Therefore, compound 4f can be estimated as a potential candidate in the treatment regime of pathological disorders associated with platelet activation and apoptosis. In addition, compound 4f can be used as an auxiliary therapeutic agent in pathologies associated with thrombocytopenia.


Asunto(s)
Apoptosis/efectos de los fármacos , Plaquetas/efectos de los fármacos , Ibuprofeno/análogos & derivados , Agregación Plaquetaria/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Plaquetas/citología , Plaquetas/metabolismo , Relación Dosis-Respuesta a Droga , Humanos , Ibuprofeno/química , Ibuprofeno/farmacología , Estrés Oxidativo/efectos de los fármacos
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