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1.
Cancer Sci ; 112(5): 1963-1974, 2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-33544933

RESUMEN

The emergence of acquired resistance is a major concern associated with molecularly targeted kinase inhibitors. The C797S mutation in the epidermal growth factor receptor (EGFR) confers resistance to osimertinib, a third-generation EGFR-tyrosine kinase inhibitor (EGFR-TKI). We report that the derivatization of the marine alkaloid topoisomerase inhibitor lamellarin N provides a structurally new class of EGFR-TKIs. One of these, lamellarin 14, is effective against the C797S mutant EGFR. Bioinformatic analyses revealed that the derivatization transformed the topoisomerase inhibitor-like biological activity of lamellarin N into kinase inhibitor-like activity. Ba/F3 and PC-9 cells expressing the EGFR in-frame deletion within exon 19 (del ex19)/T790M/C797S triple-mutant were sensitive to lamellarin 14 in a dose range similar to the effective dose for cells expressing EGFR del ex19 or del ex19/T790M. Lamellarin 14 decreased the autophosphorylation of EGFR and the downstream signaling in the triple-mutant EGFR PC-9 cells. Furthermore, intraperitoneal administration of 10 mg/kg lamellarin 14 for 17 days suppressed tumor growth of the triple-mutant EGFR PC-9 cells in a mouse xenograft model using BALB/c nu/nu mice. Thus, lamellarin 14 serves as a novel structural backbone for an EGFR-TKI that prevents the development of cross-resistance against known drugs in this class.


Asunto(s)
Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Acrilamidas/farmacología , Compuestos de Anilina/farmacología , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Ensayos de Selección de Medicamentos Antitumorales/métodos , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , Fluoroacetatos , Expresión Génica , Compuestos Heterocíclicos de 4 o más Anillos/química , Xenoinjertos , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Terapia Molecular Dirigida , Moluscos/química , Mutagénesis Sitio-Dirigida , Mutación , Inhibidores de Proteínas Quinasas/química
2.
Bioorg Med Chem ; 34: 116039, 2021 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-33556869

RESUMEN

Azalamellarin N, a synthetic lactam congener of the marine natural product lamellarin N, and its A-ring-modified analogues were synthesized and evaluated as potent and non-covalent inhibitors of the drug-resistant epidermal growth factor receptor T790M/L858R mutant. An in vitro tyrosine kinase assay indicated that the inhibitory activities of the synthetic azalamellarin analogues were higher than those of the corresponding lamellarins. The azalamellarin analogue bearing two 3-(dimethylamino)propoxy groups at C20- and C21-positions exhibited the highest activity and selectivity against the mutant kinase [IC50 (T790M/L858R) = 1.7 nM; IC50 (WT) = 4.6 nM]. The inhibitory activity was attributed to the hydrogen bonding interaction between the lactam NH group of the B-ring and carbonyl group of a methionine residue.


Asunto(s)
Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Compuestos Heterocíclicos de 4 o más Anillos/síntesis química , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Afatinib/farmacología , Línea Celular Tumoral , Gefitinib/farmacología , Humanos , Modelos Moleculares , Estructura Molecular , Mutación , Conformación Proteica
3.
Biochem Biophys Res Commun ; 532(3): 440-445, 2020 11 12.
Artículo en Inglés | MEDLINE | ID: mdl-32891433

RESUMEN

Aberrant activation of the canonical Wnt/ß-catenin signaling pathway triggers tumorigenesis in various tissues. This study identified an atrarate compound, IMU14, derived from filamentous fungi as an inhibitor of Wnt/ß-catenin signaling in phenotypic chemical inhibitor screening of the zebrafish eyeless phenotype. Its derivatization resulted in synthesis of IMU1003 with enhanced Wnt inhibitory activity. IMU1003 inhibited ß-catenin/TCF-dependent transcriptional activation and decreased nuclear ß-catenin level. In addition, IMU1003 selectively decreased viability and target gene products of the Wnt/ß-catenin signaling pathway in human non-colorectal cancer cell lines harboring intact APC and ß-catenin. Therefore, atrarate derivatives inhibit Wnt/ß-catenin signaling and show anticancer potential, and we developed a new class of chemical backbones for Wnt/ß-catenin signaling inhibitors.


Asunto(s)
Hidroxibenzoatos/farmacología , Vía de Señalización Wnt/efectos de los fármacos , beta Catenina/metabolismo , Animales , Animales Modificados Genéticamente , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Expresión Génica/efectos de los fármacos , Células HEK293 , Humanos , Mutación , Vía de Señalización Wnt/genética , Pez Cebra/embriología , Pez Cebra/genética
4.
Biochem Biophys Res Commun ; 506(1): 183-188, 2018 11 17.
Artículo en Inglés | MEDLINE | ID: mdl-30342850

RESUMEN

The Wnt/ß-catenin signaling pathway controls cell proliferation and differentiation, and therefore, when this pathway is excessively activated, it causes tumorigenesis. Our chemical suppressor screening in zebrafish embryos identified antifungal azoles including clotrimazole, miconazole, and itraconazole, as Wnt/ß-catenin signaling inhibitors. Here we show the mechanism underlying the Wnt/ß-catenin pathway inhibition by antifungal azoles. Clotrimazole reduced ß-catenin revels in a proteasome-independent fashion. By gene knockdown of two translational regulators, heme-regulated translational inhibitor and double-stranded RNA-induced protein kinase, we show that they mediate the clotrimazole-induced inhibition of the Wnt/ß-catenin pathway. Thus, clotrimazole inhibits the Wnt/ß-catenin pathway by decreasing ß-catenin protein levels through translational regulation. Antifungal azoles represent genuine candidate compounds for anticancer drugs or chemopreventive agents that reduce adenomatous polyps.


Asunto(s)
Clotrimazol/farmacología , Vía de Señalización Wnt/efectos de los fármacos , eIF-2 Quinasa/metabolismo , Animales , Antifúngicos , Azoles/farmacología , Activación Enzimática/efectos de los fármacos , Técnicas de Silenciamiento del Gen , Humanos , Biosíntesis de Proteínas/efectos de los fármacos , Biosíntesis de Proteínas/genética , beta Catenina/efectos de los fármacos , beta Catenina/metabolismo
5.
Bioorg Med Chem ; 25(24): 6563-6580, 2017 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-29133033

RESUMEN

A series of A-ring-modified lamellarin N analogues were designed, synthesized, and evaluated as potential noncovalent inhibitors of the EGFR T790M/L858R mutant, a causal factor in the drug-resistant non-small cell lung cancer. Several water-soluble ammonium- or guanidinium-tethered analogues exhibited good kinase inhibitory activities. The most promising analogue, 14f, displayed an excellent inhibitory profile against the T790M/L858R mutant [IC50 (WT) = 31.8 nM; IC50 (T790M/L858R) = 8.9 nM]. The effects of A-ring-substituents on activity were rationalized by docking studies.


Asunto(s)
Diseño de Fármacos , Receptores ErbB/antagonistas & inhibidores , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Relación Dosis-Respuesta a Droga , Receptores ErbB/genética , Receptores ErbB/metabolismo , Compuestos Heterocíclicos de 4 o más Anillos/síntesis química , Compuestos Heterocíclicos de 4 o más Anillos/química , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Mutación , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Relación Estructura-Actividad
6.
Biochem Biophys Res Commun ; 430(4): 1240-5, 2013 Jan 25.
Artículo en Inglés | MEDLINE | ID: mdl-23266613

RESUMEN

Anchorage-independent growth is evidence of the malignant transformation of cells. We previously reported the characterization of anicequol, a novel inhibitor of the anchorage-independent growth of tumor cells, and here we show that the effects of 25-hydroxycholesterol (25-HC) on colon cancer cells were very similar to those of anicequol. By analyzing the effects of inhibitors and performing RNA interference experiments, we found that p38 mitogen-activated protein kinase (p38MAPK) was involved in anicequol- and 25-HC-induced anoikis in DLD-1 cells. In addition, Rho-associated, coiled-coil containing protein kinase (ROCK) was also associated with anoikis induced by anicequol or 25-HC. Taken together, our findings suggest that activation of the p38MAPK and ROCK pathways might provide a new therapeutic strategy against cancer, and raise the possibility that tumor metastasis is influenced by 25-HC under physiological conditions.


Asunto(s)
Anoicis/efectos de los fármacos , Neoplasias del Colon/enzimología , Ergosterol/análogos & derivados , Hidroxicolesteroles/farmacología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Quinasas Asociadas a rho/metabolismo , Línea Celular Tumoral , Ergosterol/farmacología , Humanos , Interferencia de ARN , Proteínas Quinasas p38 Activadas por Mitógenos/genética , Quinasas Asociadas a rho/genética
7.
iScience ; 25(3): 103912, 2022 Mar 18.
Artículo en Inglés | MEDLINE | ID: mdl-35530256

RESUMEN

Ivermectin (IVM), an avermectin-derivative anthelmintic, specifically binds to glutamate-gated chloride ion channels (GluCls), causing paralysis in invertebrates. IVM also exhibits other biological activities such as Wnt/ß-catenin pathway inhibition in vertebrates that do not possess GluCls. This study showed that affinity purification using immobilized IVM B1a isolated TELO2, a cofactor of phosphatidylinositol 3-kinase-related kinases (PIKKs), as a specific IVM B1a-binding protein. TELO2 knockdown reduced cytoplasmic ß-catenin and the transcriptional activation of ß-catenin/TCF. IVM B1a bound to TELO2 through the C-terminal α-helix, in which mutations conferred IVM resistance. IVM reduced the TELO2 and PIKK protein levels and the AKT and S6 kinase phosphorylation levels. The inhibition of mTOR kinase reduced the cytoplasmic ß-catenin level. Therefore, IVM binds to TELO2, inhibiting PIKKs and reducing the cytoplasmic ß-catenin level. In conclusion, our data indicate TELO2 as a druggable target for human diseases involving abnormalities of the Wnt/ß-catenin pathway and PIKKs, including mTOR.

8.
Biochem Biophys Res Commun ; 409(3): 418-23, 2011 Jun 10.
Artículo en Inglés | MEDLINE | ID: mdl-21586273

RESUMEN

Candida albicans is the most common and virulent fungus causing candidiasis in various parts of the body and can be lethal to immunocompromised patients. All currently known antifungal therapies are drugs which cause serious side effects in the host. An inhibitor specific for fungus survival is an ideal therapeutic. C. albicans MPS1 (monopolar spindle 1) has been reported as a kinase essential to its survival. Because CaMps1p shares limited sequence homology with the human ortholog (hMps1p), we screened for a chemical inhibitor in anticipation of finding one with Candida specific cytotoxicity. In vitro screening using a recombinant catalytic domain of CaMps1p identified LY83583 (6-anilino-5,8-quinolinedione), known as a guanylate cyclase inhibitor, to be blocking CaMps1p kinase activity. In addition to its in vitro kinase inhibition, LY83583 reduced the growth rate of C. albicans. Finally, we compared the inhibitory activity on CaMps1p and hMps1p among inhibitors against those kinases. LY83583 showed specific inhibition for CaMps1p with no effect on hMps1p activity. Conversely, the CaMps1p activity was not affected by known hMps1p inhibitors. These findings suggest that CaMps1p may well be an ideal target molecule for antifungal therapy.


Asunto(s)
Aminoquinolinas/farmacología , Antifúngicos/farmacología , Candida albicans/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Aminoquinolinas/aislamiento & purificación , Antifúngicos/aislamiento & purificación , Candida albicans/enzimología , Proteínas de Ciclo Celular/antagonistas & inhibidores , Evaluación Preclínica de Medicamentos , Humanos , Inhibidores de Proteínas Quinasas/aislamiento & purificación , Proteínas Serina-Treonina Quinasas/química , Proteínas Tirosina Quinasas
9.
Biol Pharm Bull ; 33(2): 168-73, 2010.
Artículo en Inglés | MEDLINE | ID: mdl-20118535

RESUMEN

The resorcylic acid lactone hypothemycin has been shown to inactivate protein kinases by binding to a cysteine conserved in 46 protein kinases, including mitogen-activated protein kinase kinase (MEK), extracellular signal-regulated kinase (ERK) and platelet-derived growth factor receptor (PDGFR). We assessed the selectivity of hypothemycin in cellular contexts. Hypothemycin normalized the morphology and inhibited anchorage-independent growth of Ki-ras transformed normal rat kidney (NRK) cells with selectivity and potency comparable to or greater than that of the MEK inhibitor U0126. In Ki-ras-transformed and phorbol 12-myristate 13-acetate (PMA)-treated NRK cells, hypothemycin blocked ERK activation but showed a minimal effect on autophosphorylation of protein kinase D1 (PKD1), another kinase containing the conserved cysteine. Hypothemycin potently inhibited PDGFR autophosphorylation and activation of the MEK-ERK pathway in platelet-derived growth factor (PDGF)-treated NRK cells. However, the phosphoinositide-3-kinase (PI3K) pathway was only modestly attenuated. Hypothemycin also inhibited growth factor- and anchorage-independent growth of human cancer cell lines with a constitutively active MEK-ERK pathway. Although hypothemycin has the potential to inactivate various protein kinases, the results indicate that in intracellular environments, hypothemycin can inhibit the MEK-ERK axis with sufficient selectivity to normalize transformed phenotypes of cells dependent on this pathway.


Asunto(s)
Quinasas MAP Reguladas por Señal Extracelular/antagonistas & inhibidores , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/fisiología , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Quinasas de Proteína Quinasa Activadas por Mitógenos/fisiología , Animales , Butadienos/farmacología , Línea Celular Tumoral , Transformación Celular Neoplásica/efectos de los fármacos , Quinasas MAP Reguladas por Señal Extracelular/fisiología , Fibroblastos/efectos de los fármacos , Fibroblastos/enzimología , Flavonoides/farmacología , Inhibidores de Crecimiento/farmacología , Humanos , Riñón/citología , Riñón/efectos de los fármacos , Riñón/enzimología , Nitrilos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Ratas , Zearalenona/análogos & derivados , Zearalenona/farmacología
10.
Eukaryot Cell ; 7(10): 1640-8, 2008 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-18708562

RESUMEN

Protein phosphatases are critical for the regulation of many cellular processes. Null mutants of 21 putative protein phosphatases of Candida albicans were constructed by consecutive allele replacement using the URA3 and ARG4 marker genes. A simple silkworm model of C. albicans infection was used to screen the panel of mutants. Four null mutant (cmp1Delta, yvh1Delta, sit4Delta, and ptc1Delta) strains showed attenuated virulence in the silkworm model relative to that of control and parental strains. Three of the mutants, the cmp1Delta, yvh1Delta, and sit4Delta mutants, had previously been identified as affecting virulence in a conventional mouse model, indicating the validity of the silkworm model screen. Disruption of the putative protein phosphatase gene PTC1 of C. albicans, which has 52% identity to the Saccharomyces cerevisiae type 2C protein phosphatase PTC1, significantly reduced virulence in the silkworm model. The mutant was also avirulent in a mouse model of disseminated candidiasis. Reintroducing either of the C. albicans PTC1 alleles into the disruptant strain, using a cassette containing either allele under the control of a constitutive ACT1 promoter, restored virulence in both infection models. Characterization of ptc1Delta revealed other phenotypic traits, including reduced hyphal growth in vitro and in vivo, and reduced extracellular proteolytic activity. We conclude that PTC1 may contribute to pathogenicity in C. albicans.


Asunto(s)
Bombyx , Candida albicans/enzimología , Candida albicans/patogenicidad , Candidiasis/microbiología , Proteínas Fúngicas/metabolismo , Modelos Animales , Proteína Fosfatasa 1/metabolismo , Animales , Candida albicans/genética , Proteínas Fúngicas/genética , Humanos , Hifa/genética , Hifa/metabolismo , Ratones , Ratones Endogámicos ICR , Modelos Genéticos , Proteína Fosfatasa 1/genética , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Virulencia
11.
Bioorg Med Chem ; 16(11): 6042-53, 2008 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-18474428

RESUMEN

We designed chiral 2-nitroimidazole derivatives containing a 2-aminomethylene-4-cyclopentene-1,3-dione moiety as antiangiogenic hypoxic cell radiosensitizers. Based on results of molecular orbital calculations, the 2-aminomethylene-4-cyclopentene-1,3-dione moiety is expected to show high electrophilicity comparable to that of the 2-methylene-4-cyclopentene-1,3-dione moiety included in TX-1123 and tyrphostin AG17. We evaluated the antiangiogenic and radiosensitizing effects of the new compounds, along with other biological properties including their activities as hypoxic cytotoxicities and protein tyrosine kinase (PTK) inhibitory activities. Among the compounds tested, 5 (TX-2036) proved to be the strongest antiangiogenic hypoxic cell radiosensitizer. All the other chiral 2-nitroimidazole derivatives having 2-aminomethylene-4-cyclopentene-1,3-dione moiety tested were also antiangiogenic hypoxic cell radiosensitizers. The PTK inhibitory activity of 5 (TX-2036) showed this to be a promising and potent EGFR kinase inhibitor, having an IC(50) value of lower than 2microM. This compound also was an Flt-1 kinase inhibitor having an IC(50) value of lower than 20microM. Our results show that these chiral 2-nitroimidazole derivatives that contain the 2-aminomethylene-4-cyclopentene-1,3-dione moiety as a potent antiangiogenic pharmacophoric descriptor are promising lead candidates for the development of antiangiogenic hypoxic cell radiosensitizers.


Asunto(s)
Inhibidores de la Angiogénesis/síntesis química , Hipoxia de la Célula/efectos de los fármacos , Ciclopentanos/síntesis química , Diseño de Fármacos , Nitroimidazoles/química , Fármacos Sensibilizantes a Radiaciones/síntesis química , Inhibidores de la Angiogénesis/toxicidad , Animales , Antineoplásicos/síntesis química , Antineoplásicos/toxicidad , Línea Celular , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Embrión de Pollo , Ciclopentanos/toxicidad , Ratones , Modelos Moleculares , Nitroimidazoles/toxicidad , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/toxicidad , Fármacos Sensibilizantes a Radiaciones/toxicidad , Ratas , Estereoisomerismo
14.
Anticancer Res ; 38(6): 3471-3476, 2018 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-29848699

RESUMEN

BACKGROUND: Transcriptional co-activators YES-associated protein (YAP) and transcriptional coactivator with PDZ-motif (TAZ) stimulate the expression of cell cycle-related genes to permit for tumour cell growth. MLN8237 is a potent aurora-A kinase inhibitor; however, patients responding to MLN8237 are limited. Therefore, rational combination therapy could enhance their response. MATERIALS AND METHODS: YAP and TAZ were depleted using siRNA and then treated with MLN8237 in YAP/TAZ-dependent OVCAR-8 and MDA-MB-231 cell lines. MLN8237 was combined with fluvastatin, an agent constraining nuclear localisation of YAP/TAZ for potential combination therapy in vitro. RESULTS: Depletion of either YAP or TAZ sensitised these cell lines to MLN8237, resulting in apoptosis and reduction in aurora-A. MLN8237 reduced YAP/TAZ expression. A combination of MLN8237 with fluvastatin effectively reduced the cell viability of OVCAR-8 and MDA-MB-231 cell lines. CONCLUSION: A combination of MLN8237 and small-molecule agents inactivating YAP/TAZ, such as statins, could be a novel therapeutic strategy for YAP/TAZ-dependent cancer.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Aurora Quinasa A/antagonistas & inhibidores , Azepinas/farmacología , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Fosfoproteínas/metabolismo , Pirimidinas/farmacología , Proteínas Adaptadoras Transductoras de Señales/genética , Apoptosis/efectos de los fármacos , Apoptosis/genética , Aurora Quinasa A/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Sinergismo Farmacológico , Ácidos Grasos Monoinsaturados/farmacología , Fluvastatina , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Indoles/farmacología , Péptidos y Proteínas de Señalización Intracelular/genética , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patología , Fosfoproteínas/genética , Interferencia de ARN , Transactivadores , Factores de Transcripción , Proteínas Coactivadoras Transcripcionales con Motivo de Unión a PDZ , Proteínas Señalizadoras YAP
15.
FEBS Open Bio ; 8(6): 1001-1012, 2018 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-29928579

RESUMEN

The main reasons for failure of cancer chemotherapy are intrinsic and acquired drug resistance. The Hippo pathway effector Yes-associated protein (YAP) is associated with resistance to both cytotoxic and molecular targeted drugs. Several lines of evidence indicate that YAP activates transcriptional programmes to promote cell cycle progression and DNA damage responses. Therefore, we hypothesised that YAP is involved in the sensitivity of cancer cells to small-molecule agents targeting cell cycle-related proteins. Here, we report that the inactivation of YAP sensitises the OVCAR-8 ovarian cancer cell line to AZD1775, a small-molecule WEE1 kinase inhibitor. The accumulation of DNA damage and mitotic failures induced by AZD1775-based therapy were further enhanced by YAP depletion. YAP depletion reduced the expression of the Fanconi anaemia (FA) pathway components required for DNA repair and their transcriptional regulator E2F1. These results suggest that YAP activates the DNA damage response pathway, exemplified by the FA pathway and E2F1. Furthermore, we aimed to apply this finding to combination chemotherapy against ovarian cancers. The regimen containing dasatinib, which inhibits the nuclear localisation of YAP, improved the response to AZD1775-based therapy in the OVCAR-8 ovarian cancer cell line. We propose that dasatinib acts as a chemosensitiser for a subset of molecular targeted drugs, including AZD1775, by targeting YAP.

16.
Biochem Biophys Res Commun ; 364(4): 990-5, 2007 Dec 28.
Artículo en Inglés | MEDLINE | ID: mdl-17967417

RESUMEN

Novel inhibitors of fungal ATP-binding cassette transporters were obtained by screening compounds and crude extracts from marine-derived fungi and bacteria using disk diffusion assays of Saccharomyces cerevisiae strains overexpressing a variety of fungal multi-drug efflux pumps. The cyclodepsipeptides unnarmicin A and unnarmicin C were able to sensitize cells overexpressing azole drug pumps ScPdr5p, CaCdr1p, CgCdr1p, and CgPdh1p to sub-MIC concentrations of fluconazole without affecting the growth of CaCdr2p and CaMdr1p overexpressing cells. Unnarmicin A and unnarmicin C were potent inhibitors of rhodamine 6G efflux of CaCdr1p expressing cells with IC50 values of 3.61 and 5.65 microM, respectively. They inhibited the in vitro CaCdr1p ATPase activity at IC50 values of 0.495 and 0.688 microM, respectively. And most importantly, they were able to sensitize azole-resistant Candida albicans clinical isolates to fluconazole. Unnarmicin A and unnarmicin C are candidate efflux pump inhibitors with the potential to be used as adjuvants for antifungal chemotherapy.


Asunto(s)
Transportadoras de Casetes de Unión a ATP/antagonistas & inhibidores , Candida albicans/metabolismo , Péptidos Cíclicos/administración & dosificación , Saccharomyces cerevisiae/metabolismo , Candida albicans/efectos de los fármacos , Biología Marina , Saccharomyces cerevisiae/efectos de los fármacos
17.
Jpn J Infect Dis ; 60(1): 45-7, 2007 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-17314425

RESUMEN

We constructed a pair of Nocardia-Escherichia coli shuttle vectors, pNV18 and pNV19, by combining the mycobacterial plasmid pAL5000 with the E. coli vector pK18 or pK19. These vectors have a number of useful features, including small size (4.4 kb), a multiple cloning site, and blue/white selection. To our knowledge, pNV18 and pNV19 are the first cloning vectors for practical use in Nocardia spp.


Asunto(s)
Escherichia coli/genética , Vectores Genéticos/genética , Nocardia/genética , Clonación Molecular , Farmacorresistencia Bacteriana , Operón Lac , Mycobacterium/genética , Plásmidos/genética , Tobramicina/farmacología , Transformación Bacteriana/genética
18.
Anticancer Res ; 37(4): 1793-1797, 2017 04.
Artículo en Inglés | MEDLINE | ID: mdl-28373443

RESUMEN

BACKGROUND: Breast tumor heterogeneity leads to phenotypic diversity, such as tumor-initiating and metastatic properties and drug sensitivity. MATERIALS AND METHODS: We found that a self-floating cell (SFC) culture enriches a drug-resistant subpopulation in a HER2-positive breast cancer cell line. SFCs were analyzed for cancer stem cell markers, gene expression profiles, and sensitivity for anticancer drugs. RESULTS: SFCs expressed cancer stem cell markers, such as aldehyde dehydrogenase (ALDH) activity and elevated HER2 autophosphorylation. Gene expression profiles of SFCs showed a dramatic difference compared to those of parental or forced floating cells. SFCs also expressed CD133, a marker of drug resistance, and resisted cytotoxic drugs by drug efflux transporters. In contrast, HER2 kinase inhibitors efficiently reduced SFC viability. CONCLUSION: SFCs enrich drug-resistant subpopulations even in vitro and might reflect the highly plastic nature of breast cancer cells even in vitro.


Asunto(s)
Adenocarcinoma Papilar/patología , Adenocarcinoma/patología , Neoplasias de la Mama/patología , Técnicas de Cultivo de Célula/métodos , Células Madre Neoplásicas/patología , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma Papilar/tratamiento farmacológico , Adenocarcinoma Papilar/genética , Adenocarcinoma Papilar/metabolismo , Aldehído Deshidrogenasa/genética , Aldehído Deshidrogenasa/metabolismo , Antineoplásicos/farmacología , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Western Blotting , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Femenino , Citometría de Flujo , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Técnicas In Vitro , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Fenotipo , Células Tumorales Cultivadas
19.
Anticancer Res ; 26(1A): 91-7, 2006.
Artículo en Inglés | MEDLINE | ID: mdl-16475684

RESUMEN

2,4-Diaminopyrimidine derivatives, that were originally developed as antiviral agents, were modified to antitumor agents by: (i) introducing an amino group at C-5 on the pyrimidine ring, (ii) changing the alkyl group and the ring size of the cycloalkyl group on the beta-position of the omega-hydroxyalkylamino group, (iii) replacing the phenylalkyl group on the cycloalkyl group with the 3,4,5-trimethoxyphenylalkyl group, (iv) the esterification of the primary alcohol with diethyl phosphate and (v) introducing the thiomethyl group at C-2 on the pyrimidine ring. Among the 21 compounds prepared, 6, which has cyclobutyl at the beta-position, exhibited potent activity towards P-388 leukemia. In addition, 14, with methoxyl groups on the phenyl ring and 17, with the thiomethyl group on the pyrimidine ring, showed specific inhibition for the EGFR protein kinase. Moreover, 15 and 16, which carry the diethyl phosphoryl group on the primary alcohol, exhibited inhibitory activity towards P-glycoprotein.


Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Antivirales/química , Pirimidinas/química , Pirimidinas/farmacología , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Animales , Antivirales/farmacología , Línea Celular , Línea Celular Tumoral , Perros , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Leucemia P388/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/síntesis química , Relación Estructura-Actividad
20.
Biochim Biophys Acta ; 1697(1-2): 29-38, 2004 Mar 11.
Artículo en Inglés | MEDLINE | ID: mdl-15023348

RESUMEN

We review in this report our strategy and tactics for the design of 2-hydroxyarylidene-4-cyclopentene-1,3-diones as protein tyrosine kinase (PTK) inhibitors having low mitochondrial toxicities and/or hypoxia-targeting function. We based our synthetic design on an innovative pharmacophore, 2-methylene-4-cyclopentene-1,3-dione. We first showed the effectiveness of this pharmacophore in the development of 2-methylene-4-cyclopentene-1,3-dione as PTK inhibitor that have lower mitochondrial toxicity than the potent PTK inhibitor tyrphostin AG17. Our results show that the cyclopentenedione-derived TX-1123 is a more potent antitumor tyrphostin and also shows lower mitochondrial toxicity than the malononitrile-derived AG17. The O-methylation product of TX-1123 (TX-1925) retained its tyrphostin-like properties, including mitochondrial toxicity and antitumor activities. However, the methylation product of AG17 (TX-1927) retained its tyrphostin-like antitumor activities, but lost its mitochondrial toxicity. Our comprehensive evaluation of these agents with respect to PTK inhibition, mitochondrial inhibition, antitumor activity, and hepatotoxicity demonstrates that PTK inhibitors TX-1123 and TX-1925 are more promising candidates for antitumor agents than tyrphostin AG17. Secondly, as a further investigation of the promising power of this 4-cyclopentene-1,3-dione as an innovative pharmacophore, we discuss our strategy of development of hypoxia-targeting PTK inhibitor TX-1123 analogues, 2-nitroimidazole-aminomethylenecyclopentenediones, such as TX-2036, for cancer treatment, especially for pancreatic cancers, which have a high level of hypoxia.


Asunto(s)
Hipoxia de la Célula/efectos de los fármacos , Ciclopentanos/química , Ciclopentanos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Compuestos de Bencilideno/química , Compuestos de Bencilideno/farmacología , Compuestos de Bencilideno/toxicidad , Hipoxia de la Célula/fisiología , Ciclopentanos/toxicidad , Diseño de Fármacos , Inhibidores Enzimáticos/toxicidad , Humanos , Mitocondrias/efectos de los fármacos , Modelos Moleculares , Nitrilos , Relación Estructura-Actividad , Tirfostinos/química , Tirfostinos/farmacología , Tirfostinos/toxicidad
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