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1.
Am J Physiol Gastrointest Liver Physiol ; 326(6): G631-G642, 2024 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-38593468

RESUMEN

Lysophosphatidic acid (LPA) is a bioactive lipid molecule that regulates a wide array of cellular functions, including proliferation, differentiation, and survival, via activation of cognate receptors. The LPA5 receptor is highly expressed in the intestinal epithelium, but its function in restoring intestinal epithelial integrity following injury has not been examined. Here, we use a radiation-induced injury model to study the role of LPA5 in regulating intestinal epithelial regeneration. Control mice (Lpar5f/f) and mice with an inducible, epithelial cell-specific deletion of Lpar5 in the small intestine (Lpar5IECKO) were subjected to 10 Gy total body X-ray irradiation and analyzed during recovery. Repair of the intestinal mucosa was delayed in Lpar5IECKO mice with reduced epithelial proliferation and increased crypt cell apoptosis. These effects were accompanied by reduced numbers of OLFM4+ intestinal stem cells (ISCs). The effects of LPA5 on ISCs were corroborated by studies using organoids derived from Lgr5-lineage tracking reporter mice with deletion of Lpar5 in Lgr5+-stem cells (Lgr5Cont or Lgr5ΔLpar5). Irradiation of organoids resulted in fewer numbers of Lgr5ΔLpar5 organoids retaining Lgr5+-derived progenitor cells compared with Lgr5Cont organoids. Finally, we observed that impaired regeneration in Lpar5IECKO mice was associated with reduced numbers of Paneth cells and decreased expression of Yes-associated protein (YAP), a critical factor for intestinal epithelial repair. Our study highlights a novel role for LPA5 in regeneration of the intestinal epithelium following irradiation and its effect on the maintenance of Paneth cells that support the stem cell niche.NEW & NOTEWORTHY We used mice lacking expression of the lysophosphatidic acid receptor 5 (LPA5) in intestinal epithelial cells and intestinal organoids to show that the LPA5 receptor protects intestinal stem cells and progenitors from radiation-induced injury. We show that LPA5 induces YAP signaling and regulates Paneth cells.


Asunto(s)
Mucosa Intestinal , Receptores del Ácido Lisofosfatídico , Regeneración , Transducción de Señal , Animales , Ratones , Apoptosis/efectos de la radiación , Proliferación Celular/efectos de la radiación , Mucosa Intestinal/metabolismo , Mucosa Intestinal/efectos de la radiación , Intestino Delgado/efectos de la radiación , Intestino Delgado/metabolismo , Lisofosfolípidos/metabolismo , Ratones Noqueados , Organoides/metabolismo , Organoides/efectos de la radiación , Traumatismos Experimentales por Radiación/metabolismo , Traumatismos Experimentales por Radiación/patología , Receptores del Ácido Lisofosfatídico/metabolismo , Receptores del Ácido Lisofosfatídico/genética , Regeneración/efectos de la radiación , Células Madre/efectos de la radiación , Células Madre/metabolismo , Proteínas Señalizadoras YAP/metabolismo
2.
Bioorg Med Chem ; 28(2): 115240, 2020 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-31843463

RESUMEN

CXCR4 is involved in various diseases such as inflammation, tumor growth, and cancer metastasis through the interaction with its natural endogenous ligand, chemokine CXCL12. In an effort to develop imaging probes for CXCR4, we developed a novel small molecule CXCR4-targeted PET agent (compound 5) by combining our established benzenesulfonamide scaffold with a labeling component by virtue of click chemistry. 5 shows nanomolar affinity (IC50 = 6.9 nM) against a known CXCR4 antagonist (TN14003) and inhibits more than 65% chemotaxis at 10 nM in vitro assays. Radiofluorinated compound 5 ([18F]5) demonstrates a competitive cellular uptake against CXCL12 in a dose-dependent manner. Further, microPET images of [18F]5 exhibits preferential accumulation of radioactivity in the lesions of λ-carrageenan-induced paw edema, human head and neck cancer orthotopic xenograft, and metastatic lung cancer of each mouse model.


Asunto(s)
Carcinoma de Células Escamosas/diagnóstico por imagen , Neoplasias de Cabeza y Cuello/diagnóstico por imagen , Tomografía de Emisión de Positrones , Radiofármacos/farmacología , Receptores CXCR4/antagonistas & inhibidores , Sulfonamidas/farmacología , Animales , Carragenina/administración & dosificación , Relación Dosis-Respuesta a Droga , Edema/inducido químicamente , Edema/tratamiento farmacológico , Edema/metabolismo , Femenino , Humanos , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Inyecciones Subcutáneas , Ligandos , Masculino , Ratones , Ratones Desnudos , Estructura Molecular , Radiofármacos/síntesis química , Radiofármacos/química , Receptores CXCR4/metabolismo , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/química , Distribución Tisular , Bencenosulfonamidas
3.
Bioorg Med Chem Lett ; 29(2): 220-224, 2019 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-30514601

RESUMEN

CXCR4 and its cognate ligand CXCL12 has been linked to various pathways such as cancer metastasis, inflammation, HIV-1 proliferation, and auto-immune diseases. Small molecules have shown potential as CXCR4 inhibitors and modulators, and therefore can mitigate diseases related to the CXCR4-CXCL12 pathway. We have designed and synthesized a series of 2,5-diamino and 2,5-dianilinomethyl pyridine derivatives as potential CXCR4 antagonists. Thirteen compounds have an effective concentration (EC) of 100 nM or less in a binding affinity assay and nine of these have at least 75% inhibition of invasion in Matrigel binding assay. Compounds 3l, 7f, 7j, and 7p show a minimal reduction in inflammation when carrageenan paw edema test is conducted. Overall, these compounds show potential as CXCR4 antagonist.


Asunto(s)
Edema/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Piridinas/farmacología , Receptores CXCR4/antagonistas & inhibidores , Animales , Carragenina , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Edema/inducido químicamente , Humanos , Inflamación/inducido químicamente , Ratones , Estructura Molecular , Piridinas/síntesis química , Piridinas/química , Receptores CXCR4/metabolismo , Relación Estructura-Actividad
4.
Biochem Biophys Res Commun ; 503(2): 1087-1091, 2018 09 05.
Artículo en Inglés | MEDLINE | ID: mdl-29936177

RESUMEN

Triple negative breast cancer (TNBC) is among the most aggressive breast cancer subtypes with poor prognosis. The purpose of this study is to better understand the molecular basis of TNBC as well as develop new therapeutic strategies. Our results demonstrate that HDAC9 is overexpressed in TNBC compared to non-TNBC cell lines and tissues and is inversely proportional with miR-206 expression levels. We show that HDAC9 selective inhibition blocked the invasion of TNBC cells in vitro and repressed the angiogenesis shown via in vivo Matrigel plug assays. Subsequent HDAC9 siRNA knockdown was then shown to restore miR-206 while also decreasing VEGF and MAPK3 levels. Furthermore, the inhibition of miR-206 neutralized the action of HDAC9 siRNA on decreasing VEGF and MAPK3 levels. This study highlights HDAC9 as a mediator of cell invasion and angiogenesis in TNBC cells through VEGF and MAPK3 by modulating miR-206 expression and suggests that selective inhibition of HDAC9 may be an efficient route for TNBC therapy.


Asunto(s)
Regulación Neoplásica de la Expresión Génica , Histona Desacetilasas/genética , MicroARNs/genética , Neovascularización Patológica/genética , Proteínas Represoras/genética , Neoplasias de la Mama Triple Negativas/genética , Línea Celular Tumoral , Femenino , Humanos , Invasividad Neoplásica/genética , Invasividad Neoplásica/patología , Neovascularización Patológica/patología , Neoplasias de la Mama Triple Negativas/patología
7.
Biochem Biophys Res Commun ; 477(3): 461-6, 2016 08 26.
Artículo en Inglés | MEDLINE | ID: mdl-27318091

RESUMEN

Triple negative breast tumors don't respond to Tamoxifen and Herceptin, two of the most effective medications for treating breast cancer. Additionally, triple negative breast cancer (TNBC) intrinsically resists or will eventually acquire resistance to chemotherapy. The purpose of this study is to understand better the molecular basis of TNBC as well as develop new therapeutic strategies against it. Here, we analyzed miRNA-206 expression levels in breast cancer cell lines and tissues. In addition, we investigated whether miR-206 mimics inhibited TNBC tumor invasion and angiogenesis. The results showed that miR-206 was downregulated in TNBC compared to non-TNBC cell lines and tissues. Additionally, the decreased levels of miR-206 were inversely consistent with expression levels of VEGF. Furthermore, the forced expression of miR-206 in the mimic-transfected TNBC cells downregulated VEGF, MAPK3, and SOX9 expression levels. The miR-206 mimics inhibited TNBC breast cell invasion and angiogenesis. These findings demonstrate for the first time the involvement of miRNA-206 in TNBC invasion and angiogenesis and suggest that miR-206 may be an efficient agent for therapy of TNBC.


Asunto(s)
MicroARNs/genética , Invasividad Neoplásica , Neovascularización Patológica , Neoplasias de la Mama Triple Negativas/patología , Línea Celular Tumoral , Femenino , Humanos , Proteína Quinasa 3 Activada por Mitógenos/genética , Factor de Transcripción SOX9/genética , Neoplasias de la Mama Triple Negativas/genética , Factor A de Crecimiento Endotelial Vascular/metabolismo
8.
Bioorg Med Chem ; 24(21): 5052-5060, 2016 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-27576294

RESUMEN

Targeting the interaction between G-Protein Coupled Receptor, CXCR4, and its natural ligand CXCL12 is a leading strategy to mitigate cancer metastasis and reduce inflammation. Several pyridine-based compounds modeled after known small molecule CXCR4 antagonists, AMD3100 and WZ811, were synthesized. Nine hit compounds were identified. These compounds showed lower binding concentrations than AMD3100 (1000nM) and six of the nine compounds had an effective concentration (EC) less than or equal to WZ811 (10nM). Two of the hit compounds (2g and 2w) inhibited invasion of metastatic cells at a higher rate than AMD3100 (62%). Compounds 2g and 2w also inhibit inflammation in the same range as WZ811 in the paw edema test at 40% reduction in inflammation. These preliminary results are the promising foundation of a new class of pyridine-based CXCR4 antagonists.


Asunto(s)
Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/farmacología , Edema/tratamiento farmacológico , Piridinas/farmacología , Receptores CXCR4/antagonistas & inhibidores , Animales , Antiinflamatorios no Esteroideos/química , Carragenina , Modelos Animales de Enfermedad , Edema/inducido químicamente , Humanos , Ratones , Ratones Endogámicos C57BL , Simulación del Acoplamiento Molecular , Piridinas/síntesis química , Piridinas/química , Receptores CXCR4/metabolismo
9.
Breast Cancer Res Treat ; 146(3): 535-42, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-25030358

RESUMEN

Metastasis remains a main cause of mortality from breast cancer and an unresolved issue. The purpose of this study is to investigate the role of miR-302a in the development of breast cancer metastasis mediated by CXCR4, a critical regulator of metastasis, and to identify miR-302a as an effective therapeutic agent for therapy and prevention of breast cancer metastasis. Our studies show that miR-302a expression levels were downregulated in metastatic breast cancer cells and tumor tissues. Additionally, the expression levels of miR-302a were inversely correlated with CXCR4 levels. More promisingly, miR-302a inhibited the invasion and metastasis of breast cancer cells in vitro and in vivo and reduced the expression of CXCR4. Our findings demonstrated that the repression of miR-302a levels contributes to breast cancer metastasis and restoration of miR-302a baseline expression inhibits the invasion and metastasis of breast cancer cells. These data suggest that miR-302a mimics are potential therapeutic agents for breast cancer metastasis.


Asunto(s)
Neoplasias de la Mama/genética , MicroARNs/genética , Metástasis de la Neoplasia/genética , Receptores CXCR4/biosíntesis , Regiones no Traducidas 3' , Adulto , Anciano , Animales , Neoplasias de la Mama/patología , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Ratones , MicroARNs/biosíntesis , MicroARNs/metabolismo , Persona de Mediana Edad , Metástasis de la Neoplasia/patología , Receptores CXCR4/genética , Transducción de Señal/genética
10.
Heterocycl Comm ; 20(3): 149-153, 2014 May.
Artículo en Inglés | MEDLINE | ID: mdl-25620839

RESUMEN

A series of pyridine derivatives were synthesized as potential inhibitors of chemokine receptor type 4. This chemokine receptor has been linked to various disease pathways including HIV-1 proliferation, autoimmune disorders, inflammatory diseases, and cancer metastasis. The compounds were tested for activity using an affinity binding assay and an assay that tests the ability to inhibit cell invasion. Two hit compounds (2b and 2j) have been identified for further evaluation that inhibit cell invasion by at least 50% and have an effective concentration of less than 100 nM in the binding affinity assay. The structures of the synthesized compounds were confirmed by spectral data.

11.
Medicine (Baltimore) ; 103(10): e37226, 2024 Mar 08.
Artículo en Inglés | MEDLINE | ID: mdl-38457544

RESUMEN

BACKGROUND: The efficacy and safety of Xiaoyao Pill combined with Western medicine in the treatment of schizophrenia are still inconclusive. This meta-analysis summarized relevant studies to compare the efficacy and safety of Xiaoyao Pill combined with Western medicine and Western medicine alone in the treatment of schizophrenia, aiming to provide guidance for clinical treatment. METHODS: In this meta-analysis, we searched PubMed, Embase, Cochrane Library, CNKI, Wanfang, CQVIP, and CBM databases from the establishment of the databases to August 2023. The study proposed to include studies that reported combination of Xiaoyao Pill with Western medicine and Western medicine alone in the treatment of schizophrenia, excluding published literature, unpublished literature, literature with incomplete or inadequate information, animal experiments, literature reviews and systematic studies. Data were analyzed using Review manager 5.3. RESULTS: About 9 studies (6 RCTs and 3 case-control studies) were included in this meta-analysis. The sample size ranged from 60 to 128, with a total of 779 patients, including 395 in the combined treatment group and 384 in the control group. Pooled results showed that the total effective rate of combined treatment group was significantly higher than that of Western medicine alone (OR = 4.21, 95% CI: 1.50-11.83, P = .006). Positive and Negative Syndrome Scale (PANSS) (-) (MD = -2.30, 95% CI: -3.72 ~ -0.89, P = .001) and PANSS (+) (MD = -2.60, 95% CI: -3.34 ~ -1.86, P < .00001) of combined treatment group were all significantly lower than that of Western medicine alone. Additionally, PRL levels of combined treatment group was significantly lower than that of Western medicine alone (MD = -28.78, 95% CI: -42.20 ~ -15.35, P < .0001). However, there was no significant difference in BPRS and total PANSS between combined treatment group and Western medicine alone group. Notably, pooled results showed that there was no significant difference in incidence of adverse events between combined treatment group and Western medicine alone group. CONCLUSION: The effective rate of Xiaoyao Pill combined with Western medicine in the treatment of schizophrenia is higher than that of Western medicine alone, which can effectively relieve the positive and negative symptoms of schizophrenia, and can significantly reduce the level of PRL. In the treatment of schizophrenia, clinicians can give priority to Xiaoyao Pill combined with Western medicine therapy.


Asunto(s)
Medicamentos Herbarios Chinos , Esquizofrenia , Humanos , Esquizofrenia/tratamiento farmacológico , Medicamentos Herbarios Chinos/efectos adversos , Estudios de Casos y Controles
12.
Pharm Res ; 30(4): 1008-16, 2013 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-23184229

RESUMEN

PURPOSE: Solid tumors can be resistant or develop resistance to radiotherapy. The purpose of this study is to explore whether microRNA-302 is involved in radioresistance and can be exploited as a sensitizer to enhance sensitivity of breast cancer cells to radiation therapy. METHODS: MiR-302 expression levels in radioresistant cell lines were analyzed in comparison with their parent cell lines. Furthermore, we investigated whether enforced expression of miR-302 sensitized radioresistant breast cancer cells to ionizing radiation in vitro and in vivo. RESULTS: MiR-302 was downregulated in irradiated breast cancer cells. Additionally, the expression levels of miR-302a were inversely correlated with those of AKT1 and RAD52, two critical regulators of radioresistance. More promisingly, miR-302a sensitized radioresistant breast cancer cells to radiation therapy in vitro and in vivo and reduced the expression of AKT1 and RAD52. CONCLUSION: Our findings demonstrated that decreased expression of miR-302 confers radioresistance and restoration of miR-302 baseline expression sensitizes breast cancer cells to radiotherapy. These data suggest that miR-302 is a potential sensitizer to radiotherapy.


Asunto(s)
Neoplasias de la Mama/genética , Neoplasias de la Mama/radioterapia , Mama/efectos de la radiación , Regulación Neoplásica de la Expresión Génica , MicroARNs/genética , Mama/metabolismo , Mama/patología , Neoplasias de la Mama/patología , Línea Celular Tumoral , Femenino , Humanos , Proteínas Proto-Oncogénicas c-akt/genética , Proteína Recombinante y Reparadora de ADN Rad52/genética , Tolerancia a Radiación
13.
Cells ; 11(14)2022 07 20.
Artículo en Inglés | MEDLINE | ID: mdl-35883686

RESUMEN

Renewal of the intestinal epithelium is orchestrated by regenerative epithelial proliferation within crypts. Recent studies have shown that lysophosphatidic acid (LPA) can maintain intestinal epithelial renewal in vitro and conditional deletion of Lpar5 (Lpar5iKO) in mice ablates the intestinal epithelium and increases morbidity. In contrast, constitutive Lpar5 deletion (Lpar5cKO) does not cause a defect in intestinal crypt regeneration. In this study, we investigated whether another LPA receptor (LPAR) compensates for constitutive loss of LPA5 function to allow regeneration of intestinal epithelium. In Lpar5cKO intestinal epithelial cells (IECs), Lpar2 was upregulated and blocking LPA2 function reduced proliferation and increased apoptosis of Lpar5cKO IECs. Similar to Lpar5cKO mice, the absence of Lpar2 (Lpar2-/-) resulted in upregulation of Lpar5 in IECs, indicating that LPA2 and LPA5 reciprocally compensate for the loss of each other. Blocking LPA2 in Lpar5cKO enteroids reduced phosphorylation of Akt, indicating that LPA2 maintains the growth of Lpar5cKO enteroids through activation of the PI3K-Akt pathway. The present study provides evidence that loss of an LPAR can be compensated by another LPAR. This ability to compensate needs to be considered in studies aimed to define receptor functions or test the efficacy of a LPAR-targeting drug using genetically engineered animal models.


Asunto(s)
Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Animales , Células Epiteliales , Lisofosfolípidos , Ratones , Organoides , Regulación hacia Arriba
14.
Cell Mol Gastroenterol Hepatol ; 14(1): 129-150, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35390517

RESUMEN

BACKGROUND & AIMS: Regeneration of the epithelium by stem cells in the intestine is supported by intrinsic and extrinsic factors. Lysophosphatidic acid (LPA), a bioactive lipid mediator, regulates many cellular functions, including cell proliferation, survival, and cytokine secretion. Here, we identify LPA5 receptor as a potent regulator of the survival of stem cells and transit-amplifying cells in the intestine. METHODS: We have used genetic mouse models of conditional deletion of Lpar5, Lpar5f/f;Rosa-CreERT (Lpar5KO), and intestinal epithelial cell-specific Lpar5f/f;AhCre (Lpar5IECKO) mice. Mice were treated with tamoxifen or ß-naphthoflavone to delete Lpar5 expression. Enteroids derived from these mice were used to determine the effect of Lpar5 loss on the apoptosis and proliferation of crypt epithelial cells. RESULTS: Conditional loss of Lpar5 induced ablation of the intestinal mucosa, which increased morbidity of Lpar5KO mice. Epithelial regeneration was compromised with increased apoptosis and decreased proliferation of crypt epithelial cells by Lpar5 loss. Interestingly, intestinal epithelial cell-specific Lpar5 loss did not cause similar phenotypic defects in vivo. Lpar5 loss reduced intestinal stem cell marker gene expression and reduced lineage tracing from Lgr5+ ISCs. Lpar5 loss induced CXCL10 expression which exerts cytotoxic effects on intestinal stem cells and progenitors in the intestinal crypts. By co-culturing Lpar5KO enteroids with wild-type or Lpar5KO splenocytes, we demonstrated that lymphocytes protect the intestinal crypts via a LPA5-dependent suppression of CXCL10. CONCLUSIONS: LPA5 is essential for the regeneration of intestinal epithelium. Our findings reveal a new finding that LPA5 regulates survival of stem cells and transit-amplifying cells in the intestine.


Asunto(s)
Lisofosfolípidos , Células Madre , Animales , Intestinos , Lisofosfolípidos/metabolismo , Ratones , Transducción de Señal , Células Madre/metabolismo
15.
Pharm Res ; 28(12): 3091-100, 2011 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-21853360

RESUMEN

PURPOSE: To explore whether miR-19 is involved in the regulation of multidrug resistance (MDR), one of the main causes of breast cancer mortality, and modulates sensitivity of tumor cells to chemotherapeutic agents. METHODS: We analyzed miRNA expression levels in three MDR cell lines in comparison with their parent cell line, MCF-7, using a miRNA microarray. We investigated whether inhibitor of miR-19 sensitized MDR cells to chemotherapeutic agents in vitro and in vivo. RESULTS: MiR-19 was overexpressed in all three MDR cell lines compared to their parental cell line, MCF-7. Expression levels of miR-19 in MDR cells were inversely consistent with those of PTEN. Inhibitor of miR-19a restored sensitivity of MDR cells to cytotoxic agents; administration of LNA-antimiR-19a, a chemo-modified miR-19a inhibitor, sensitized MDR cells to chemotherapeutic agents in vivo. CONCLUSION: Our findings demonstrate, for the first time, involvement of miR-19 in multidrug resistance through modulation of PTEN and suggest that miR-19 may be a potential target for preventing and reversing MDR in tumor cells.


Asunto(s)
Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Resistencia a Antineoplásicos , MicroARNs/genética , Fosfohidrolasa PTEN/genética , Mama/efectos de los fármacos , Mama/metabolismo , Línea Celular Tumoral , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , MicroARNs/antagonistas & inhibidores
16.
Cancer Chemother Pharmacol ; 85(2): 413-423, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31907648

RESUMEN

PURPOSE: Although histone deacetylase (HDAC) inhibitors have been shown to effectively induce the inhibition of proliferation and migration in breast cancer, the mechanism of HDAC9's contribution to chemoresistance remains poorly understood. The aim of this study was to investigate the role of miR-30c-regulated HDAC9 in chemoresistance of breast cancer and to determine the potential of selective inhibition of HDAC9 in sensitizing resistant breast cancer cells to chemotherapy. METHODS: Expression levels of HDAC9 and miR-30c were measured in breast cancer cells and tissues using quantitative PCR analysis. The effect of selective inhibition of HDAC9 on sensitizing MDR cells to chemotherapy was assessed. MiR-30c/HDAC9 pathways' potential to mediate chemoresistance was analyzed. RESULTS: Our studies show that HDAC9 was significantly up-regulated in chemoresistant breast cancer cell lines compared to a chemosensitive cell line and was inversely correlated with the levels of miR-30c. MiR-30c mimics and HDAC9 inhibitors reversed the chemoresistance of multidrug-resistant breast cancer cells. CONCLUSIONS: These results indicate that the mechanism of chemoresistance reversal with selective HDAC inhibition was partially realized by regulating miR-30c via directly targeting HDAC9. Our findings suggest that the miR-30c/HDAC9 signaling axis could be a novel and potential therapeutic target in chemoresistant breast cancer.


Asunto(s)
Neoplasias de la Mama/genética , Resistencia a Antineoplásicos/genética , Histona Desacetilasas/genética , MicroARNs/genética , Proteínas Represoras/genética , Apoptosis/efectos de los fármacos , Apoptosis/genética , Neoplasias de la Mama/tratamiento farmacológico , Línea Celular Tumoral , Proliferación Celular/genética , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Inhibidores de Histona Desacetilasas/farmacología , Humanos , Células MCF-7 , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/genética
17.
Eur J Med Chem ; 201: 112479, 2020 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-32534343

RESUMEN

The C-X-C chemokine receptor type 4 (CXCR4) is a potential therapeutic target for HIV infection, metastatic cancer, and inflammatory autoimmune diseases. In this study, we screened the ZINC chemical database for novel CXCR4 modulators through a series of in silico guided processes. After evaluating the screened compounds for their binding affinities to CXCR4 and inhibitory activities against the chemoattractant CXCL12, we identified a hit compound (ZINC 72372983) showing 100 nM affinity and 69% chemotaxis inhibition at the same concentration (100 nM). To increase the potency of our hit compound, we explored the protein-ligand interactions at an atomic level using molecular dynamics simulation which enabled us to design and synthesize a novel compound (Z7R) with nanomolar affinity (IC50 = 1.25 nM) and improved chemotaxis inhibition (78.5%). Z7R displays promising anti-inflammatory activity (50%) in a mouse edema model by blocking CXCR4-expressed leukocytes, being supported by our immunohistochemistry study.


Asunto(s)
Antiinflamatorios/uso terapéutico , Inflamación/tratamiento farmacológico , Piperidinas/uso terapéutico , Receptores CXCR4/metabolismo , Animales , Antiinflamatorios/síntesis química , Antiinflamatorios/metabolismo , Línea Celular Tumoral , Diseño de Fármacos , Humanos , Ratones , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Estructura Molecular , Piperidinas/síntesis química , Piperidinas/metabolismo , Unión Proteica , Relación Estructura-Actividad
18.
Eur J Med Chem ; 185: 111823, 2020 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-31698158

RESUMEN

Breast cancer is the most frequently diagnosed malignancy and the second common cause of death in women worldwide. High mortality in breast cancer is frequently associated with metastatic progression rather than the primary tumor itself. It has been recently identified that the CXCR4/CXCL12 axis plays a pivotal role in breast cancer metastasis, especially in directing metastatic cancer cells to CXCL12-riched organs and tissues. Herein, taking the amide-sulfamide as the lead structure, the second-round structural modifications to the sulfamide structure were performed to obtain more active CXCR4 modulators against tumor metastasis. Both in vivo and in vitro experiments illustrated that compound IIIe possessed potent CXCR4 binding affinity, excellent anti-metastatic and anti-angiogenetic activity against breast cancer. More importantly, in a mouse breast cancer lung metastasis model, compound IIIe exerted a significant inhibitory effect on breast cancer metastasis. Taken together, all these positive results demonstrated that developing of CXCR4 modulators is a promising strategy to mediate breast cancer metastasis.


Asunto(s)
Amidas/farmacología , Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Quimiocina CXCL12/antagonistas & inhibidores , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Experimentales/tratamiento farmacológico , Receptores CXCR4/antagonistas & inhibidores , Amidas/administración & dosificación , Amidas/química , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Neoplasias de la Mama/patología , Adhesión Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Quimiocina CXCL12/metabolismo , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Inyecciones Intravenosas , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/secundario , Ratones , Ratones Desnudos , Estructura Molecular , Neoplasias Experimentales/patología , Neoplasias Experimentales/secundario , Receptores CXCR4/metabolismo , Relación Estructura-Actividad , Células Tumorales Cultivadas , Cicatrización de Heridas/efectos de los fármacos
19.
Cancer Res ; 67(15): 7518-24, 2007 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-17671223

RESUMEN

Squamous cell carcinoma of the head and neck (SCCHN) metastasizes to the lymph nodes and lungs. We have generated previously an orthotopic mouse model for head and neck metastasis and did in vivo selection of SCCHN cells through four rounds of serial metastases. A subpopulation of 686LN cells with high metastatic potential (686LN-Ms) was isolated. When the highly metastatic cells were compared with their low metastatic parental cells (686LN-Ps), we found that CXC chemokine receptor-4 (CXCR4) mRNA levels were significantly higher in the 686LN-Ms cells than the 686LN-Ps cells. Interestingly, the metastatic subclones had lost epithelial morphology and acquired mesenchymal features, which were maintained during cell expansion in vitro. This was featured by decreased E-cadherin and involucrin and increased vimentin and integrin beta(1). These results imply that CXCR4 and epithelial-mesenchymal transition markers can be potential biomarkers to identify the subpopulation of cells with high metastatic potential. Using the orthotopic SCCHN animal model, we showed that anti-CXCR4 treatment suppressed primary tumor growth by inhibiting tumor angiogenesis and prevented lung metastasis. Because the reduction of metastasis seen in the treated group could have resulted from 2-fold reduction in primary tumor size compared with that in the control group, we examined the effects of the CXCR4 antagonist in an experimental metastatic animal model in which 686LN-Ms cells were i.v. injected. 686LN-Ms cells failed to metastasize in the CXCR4 antagonist-treated group, whereas they metastasized to the lungs in the control group. Our data indicate that CXCR4 is an important target to inhibit tumor progression in SCCHN.


Asunto(s)
Carcinoma de Células Escamosas/metabolismo , Neoplasias de Cabeza y Cuello/prevención & control , Neoplasias Pulmonares/prevención & control , Oligopéptidos/uso terapéutico , Receptores CXCR4/metabolismo , Animales , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Northern Blotting , Western Blotting , Carcinoma de Células Escamosas/prevención & control , Carcinoma de Células Escamosas/secundario , División Celular/fisiología , Femenino , Neoplasias de Cabeza y Cuello/metabolismo , Neoplasias de Cabeza y Cuello/patología , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundario , Ratones , Ratones Desnudos , Datos de Secuencia Molecular , Neovascularización Patológica/prevención & control , Análisis de Secuencia por Matrices de Oligonucleótidos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores CXCR4/antagonistas & inhibidores , Receptores CXCR4/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción Genética
20.
Eur J Med Chem ; 181: 111562, 2019 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-31377592

RESUMEN

The interaction between G-Protein coupled receptor CXCR4 and its natural ligand CXCL12 has been linked to inflammation experienced by patients with Irritable Bowel Disease (IBD). Blocking this interaction could potentially reduce inflammatory symptoms in IBD patients. In this work, several thiophene-based and furan-based compounds modeled after AMD3100 and WZ811-two known antagonists that interrupt the CXCR4-CXCL12 interaction-were synthesized and analyzed. Fifteen hit compounds were identified; these compounds exhibited effective concentrations (EC) lower than 1000 nM (AMD3100) and inhibited invasion of metastatic cells by at least 45%. Selected compounds (2d, 2j, 8a) that inhibited metastatic invasion at a higher rate than WZ811 (62%) were submitted for a carrageenan inflammation test, where both 8a and 2j reduced inflammation in the same range as WZ811 (40%) but did not reduce inflammation more than 40%. Select compounds were also modeled in silico to show key residue interactions. These preliminary results with furan-based and thiophene-based analogues contribute to the new class on heterocyclic aromatic-based CXCR4 antagonists.


Asunto(s)
Furanos/farmacología , Compuestos Heterocíclicos/farmacología , Inflamación/tratamiento farmacológico , Receptores CXCR4/antagonistas & inhibidores , Tiofenos/farmacología , Animales , Carragenina/administración & dosificación , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Furanos/síntesis química , Furanos/química , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/química , Miembro Posterior/efectos de los fármacos , Humanos , Inflamación/inducido químicamente , Ratones , Ratones Endogámicos C57BL , Simulación del Acoplamiento Molecular , Estructura Molecular , Receptores CXCR4/metabolismo , Relación Estructura-Actividad , Tiofenos/química
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