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1.
Mol Cancer ; 23(1): 152, 2024 Jul 31.
Artículo en Inglés | MEDLINE | ID: mdl-39085861

RESUMEN

Chemotherapy in combination with immunotherapy has gradually shown substantial promise to increase T cell infiltration and antitumor efficacy. However, paclitaxel in combination with immune checkpoint inhibitor targeting PD-1/PD-L1 was only used to treat a small proportion of metastatic triple-negative breast cancer (TNBC), and the clinical outcomes was very limited. In addition, this regimen cannot prevent paclitaxel-induced peripheral neuropathy. Therefore, there was an urgent need for a novel target to enhance the antitumor activity of paclitaxel and alleviate chemotherapy-induced peripheral neuropathy in breast cancer. Here, we found that Dickkopf-1 (DKK1) expression was upregulated in multiply subtypes of human breast cancer specimens after paclitaxel-based chemotherapy. Mechanistic studies revealed that paclitaxel promoted DKK1 expression by inducing EGFR signaling in breast cancer cells, and the upregulation of DKK1 could hinder the therapeutic efficacy of paclitaxel by suppressing the infiltration and activity of CD8+ T cells in tumor microenvironment. Moreover, paclitaxel treatment in tumor-bearing mice also increased DKK1 expression through the activation of EGFR signaling in the primary sensory dorsal root ganglion (DRG) neurons, leading to the development of peripheral neuropathy, which is charactered by myelin damage in the sciatic nerve, neuropathic pain, and loss of cutaneous innervation in hindpaw skin. The addition of an anti-DKK1 antibody not only improved therapeutic efficacy of paclitaxel in two murine subtype models of breast cancer but also alleviated paclitaxel-induced peripheral neuropathy. Taken together, our findings providing a potential chemoimmunotherapy strategy with low neurotoxicity that can benefit multiple subtypes of breast cancer patients.


Asunto(s)
Péptidos y Proteínas de Señalización Intercelular , Paclitaxel , Enfermedades del Sistema Nervioso Periférico , Paclitaxel/efectos adversos , Paclitaxel/farmacología , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Péptidos y Proteínas de Señalización Intercelular/genética , Humanos , Animales , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Femenino , Ratones , Línea Celular Tumoral , Receptores ErbB/metabolismo , Microambiente Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Neoplasias de la Mama/metabolismo , Transducción de Señal/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/patología , Neoplasias de la Mama Triple Negativas/metabolismo
2.
Br J Cancer ; 131(8): 1387-1398, 2024 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-39266624

RESUMEN

BACKGROUND: Temozolomide (TMZ) is the first-line chemotherapeutic drug for gliomas treatment. However, the clinical efficacy of TMZ in glioma patients was very limited. Therefore, it is urgently needed to discover a novel approach to increase the sensitivity of glioma cells to TMZ. METHODS: Western blot, immunohistochemical staining, and qRT-PCR assays were used to explore the mechanisms underlying TMZ promoting DKK1 expression and andrographolide (AND) inhibiting DKK1 expression. HPLC was used to detect the ability of andrographolide (AND) to penetrate the blood-brain barrier. MTT assay, bioluminescence images, magnetic resonance imaging (MRI) and H&E staining were employed to measure the proliferative activity of glioma cells and the growth of intracranial tumors. RESULTS: TMZ can promote DKK1 expression in glioma cells and brain tumors of an orthotopic model of glioma. DKK1 could promote glioma cell proliferation and tumor growth in an orthotopic model of glioma. Mechanistically, TMZ increased EGFR expression and subsequently induced the activation of its downstream MEK-ERK and PI3K-Akt pathways, thereby promoting DKK1 expression in glioma cells. Andrographolide inhibited TMZ-induced DKK1 expression through inactivating MEK-ERK and PI3K-Akt pathways. Andrographolide can cross the blood-brain barrier, the combination of TMZ and andrographolide not only improved the anti-tumor effects of TMZ but also showed a survival benefit in an orthotopic model of glioma. CONCLUSION: Andrographolide can enhance anti-tumor activity of TMZ against glioma by inhibiting DKK1 expression.


Asunto(s)
Antineoplásicos Alquilantes , Neoplasias Encefálicas , Proliferación Celular , Diterpenos , Glioma , Péptidos y Proteínas de Señalización Intercelular , Temozolomida , Diterpenos/farmacología , Diterpenos/uso terapéutico , Temozolomida/farmacología , Glioma/tratamiento farmacológico , Glioma/patología , Glioma/genética , Glioma/metabolismo , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Humanos , Animales , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/genética , Línea Celular Tumoral , Ratones , Antineoplásicos Alquilantes/farmacología , Antineoplásicos Alquilantes/uso terapéutico , Proliferación Celular/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Ratones Desnudos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Sinergismo Farmacológico , Receptores ErbB/genética , Receptores ErbB/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos
3.
Org Biomol Chem ; 22(13): 2677, 2024 Mar 27.
Artículo en Inglés | MEDLINE | ID: mdl-38477554

RESUMEN

Expression of Concern for 'Conjugation of substituted naphthalimides to polyamines as cytotoxic agents targeting the Akt/mTOR signal pathway' by Zhi-Yong Tian et al., Org. Biomol. Chem., 2009, 7, 4651-4660, https://doi.org/10.1039/B912685F.

4.
Cell Commun Signal ; 20(1): 175, 2022 Nov 08.
Artículo en Inglés | MEDLINE | ID: mdl-36348350

RESUMEN

BACKGROUND: Spermine is frequently elevated in tumor tissues and body fluids of cancer patients and is critical for cancer cell proliferation, migration and invasion. However, the immune functions of spermine in hepatocellular carcinoma progression remains unknown. In the present study, we aimed to elucidate immunosuppressive role of spermine in hepatocellular carcinoma and to explore the underlying mechanism. METHODS: Whole-blood spermine concentration was measured using HPLC. Human primary HCC tissues were collected to examine the expression of CaSR, p-Akt, ß-catenin, STT3A, PD-L1, and CD8. Mouse model of tumorigenesis and lung metastasis were established to evaluate the effects of spermine on hepatocellular carcinoma. Western blotting, immunofluorescence, real time PCR, digital Ca2+ imaging, and chromatin immunoprecipitation assay were used to investigate the underlying mechanisms by which spermine regulates PD-L1 expression and glycosylation in hepatocellular carcinoma cells. RESULTS: Blood spermine concentration in the HCC patient group was significantly higher than that in the normal population group. Spermine could facilitate tumor progression through inducing PD-L1 expression and decreasing the CD8+ T cell infiltration in HCC. Mechanistically, spermine activates calcium-sensing receptor (CaSR) to trigger Ca2+ entry and thereby promote Akt-dependent ß-catenin stabilization and nuclear translocation. Nuclear ß-catenin induced by spermine then activates transcriptional expression of PD-L1 and N-glycosyltransferase STT3A, while STT3A in turn increases the stability of PD-L1 through inducing PD-L1 protein N-glycosylation in HCC cells. CONCLUSIONS: This study reveals the crucial function of spermine in establishing immune privilege by increasing the expression and N-glycosylation of PD-L1, providing a potential strategy for the treatment of hepatocellular carcinoma. Video Abstract.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Ratones , Animales , Humanos , Carcinoma Hepatocelular/patología , Antígeno B7-H1/metabolismo , beta Catenina , Neoplasias Hepáticas/patología , Espermina/farmacología , Proteínas Proto-Oncogénicas c-akt , Línea Celular Tumoral , Microambiente Tumoral
5.
Cancer Sci ; 112(2): 679-690, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33164305

RESUMEN

High-mobility group protein A2 (HMGA2) is highly expressed in hepatocellular carcinoma (HCC) cells and contributes to tumor metastasis and poor patient survival. However, the molecular mechanism through which HMGA2 is transcriptionally regulated in HCC cells remains largely unclear. Here, we showed that the expression HMGA2 was upregulated in HCC, and that elevated HMGA2 could promote tumor metastasis. Incubation of HCC cells with epidermal growth factor (EGF) could promote the expression of HMGA2 mRNA and protein. Mechanistic studies suggested that EGF can phosphorylate p300 at Ser1834 residue through the PI3K/Akt signaling pathway in HCC cells. Knockdown of p300 can reverse EGF-induced HMGA2 expression and histone H3-K9 acetylation, whereas a phosphorylation-mimic p300 S1834D mutant can stimulate HMGA2 expression as well as H3-K9 acetylation in HCC cells. Furthermore, we identified that p300-mediated H3-K9 acetylation participates in EGF-induced HMGA2 expression in HCC. In addition, the levels of H3-K9 acetylation positively correlated with the expression levels of HMGA2 in a chemically induced HCC model in rats and human HCC specimens.


Asunto(s)
Carcinoma Hepatocelular/patología , Regulación Neoplásica de la Expresión Génica/fisiología , Proteína HMGA2/biosíntesis , Histonas/metabolismo , Neoplasias Hepáticas/patología , Acetilación , Animales , Carcinoma Hepatocelular/metabolismo , Receptores ErbB/metabolismo , Humanos , Neoplasias Hepáticas/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Ratas , Ratas Sprague-Dawley , Transcripción Genética , Factores de Transcripción p300-CBP/metabolismo
6.
Cancer Cell Int ; 19: 168, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31285694

RESUMEN

BACKGROUND: DKK1 has been reported to act as a tumor suppressor in breast cancer. However, the mechanism of DKK1 inhibits breast cancer migration and invasion was still unclear. METHODS: Western blot and real time PCR was used to detect the expression of DKK1, ß-catenin and MMP7 in breast cancer cells. Wound scratch assay and transwell assay was employed to examine migration and invasion of breast cancer cell. RESULTS: DKK1 overexpression dramatically inhibits breast cancer cell migration and invasion. Knockdown of DKK1 promotes migration and invasion of breast cancer cells. DKK1 suppressed breast cancer cell migration and invasion through suppression of ß-catenin and MMP7 expression. XAV-939, an inhibitor of ß-catenin accumulation could reverse DKK1 silencing-induced MMP7 expression in breast cancer cells. Meanwhile, XAV-939 also could reverse the increase in the cell number invaded through Matrigel when DKK1 was knockdown. Furthermore, depletion of MMP7 also could reverse DKK1 knockdown-induced increase in the cell number invaded through Matrigel. CONCLUSIONS: DKK1 inhibits migration and invasion of breast cancer cell through suppression of ß-catenin/MMP7 pathway, our findings offered a potential alternative for breast cancer prevention and treatment.

7.
Cell Biol Int ; 43(8): 931-939, 2019 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-31124219

RESUMEN

Phosphoinositide 3-kinase (PI3K) signaling is frequently deregulated in breast cancer and plays a critical role in tumor progression. However, resistance to PI3K inhibitors in breast cancer has emerged, which is due to the enhanced ß-catenin nuclear accumulation. Until now, the mechanisms underlying PI3K inhibition-induced ß-catenin nuclear accumulation remains largely unknown. In the present study, we found inhibition of PI3K with LY294002 promoted ß-catenin nuclear accumulation in MCF-7 and MDA-MB-231 breast cancer cells. Combining PI3K inhibitor LY294002 with XAV-939, an inhibitor against ß-catenin nuclear accumulation, produced an additive anti-proliferation effect against breast cancer cells. Subsequent experiments suggested ß-catenin nuclear accumulation induced by PI3K inhibition depended on the feedback activation of epidermal growth factor receptor (EGFR) signaling pathway in breast cancer cells. Inhibition of EGFR phosphorylation with Gefitinib enhanced anti-proliferation effect of PI3K inhibitor LY294002 in MCF-7 and MDA-MB-231 cells. Taken together, our findings may elucidate a possible mechanism explaining the poor outcome of PI3K inhibitors in breast cancer treatment.


Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Proliferación Celular/efectos de los fármacos , Cromonas/farmacología , Gefitinib/farmacología , Compuestos Heterocíclicos con 3 Anillos/farmacología , Morfolinas/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica , Resistencia a Antineoplásicos , Receptores ErbB/antagonistas & inhibidores , Femenino , Humanos , Células MCF-7 , Inhibidores de las Quinasa Fosfoinosítidos-3 , beta Catenina/antagonistas & inhibidores
8.
Cell Commun Signal ; 16(1): 82, 2018 11 16.
Artículo en Inglés | MEDLINE | ID: mdl-30445978

RESUMEN

BACKGROUND: Knockdown of Akt1 promotes Epithelial-to-Mesenchymal Transition in breast cancer cells. However, the mechanisms are not completely understood. METHODS: Western blotting, immunofluorescence, luciferase assay, real time PCR, ELISA and Matrigel invasion assay were used to investigate how Akt1 inhibition promotes breast cancer cell invasion in vitro. Mouse model of lung metastasis was used to measure in vivo efficacy of Akt inhibitor MK2206 and its combination with Gefitinib. RESULTS: Knockdown of Akt1 stimulated ß-catenin nuclear accumulation, resulting in breast cancer cell invasion. ß-catenin nuclear accumulation induced by Akt1 inhibition depended on the prolonged activation of EGFR signaling pathway in breast cancer cells. Mechanistic experiments documented that knockdown of Akt1 inactivates PIKfyve via dephosphorylating of PIKfyve at Ser318 site, resulting in a decreased degradation of EGFR signaling pathway. Inhibition of Akt1 using MK2206 could induce an increase in the expression of EGFR and ß-catenin in breast cancer cells. In addition, MK2206 at a low dosage enhance breast cancer metastasis in a mouse model of lung metastasis, while an inhibitor of EGFR tyrosine kinase Gefitinib could potentially suppress breast cancer metastasis induced by Akt1 inhibition. CONCLUSION: EGFR-mediated ß-catenin nuclear accumulation is critical for Akt1 inhibition-induced breast cancer metastasis.


Asunto(s)
Neoplasias de la Mama/patología , Núcleo Celular/metabolismo , Receptores ErbB/metabolismo , Técnicas de Silenciamiento del Gen , Proteínas Proto-Oncogénicas c-akt/deficiencia , Proteínas Proto-Oncogénicas c-akt/genética , beta Catenina/metabolismo , Transporte Activo de Núcleo Celular/efectos de los fármacos , Transporte Activo de Núcleo Celular/genética , Núcleo Celular/efectos de los fármacos , Receptores ErbB/antagonistas & inhibidores , Gefitinib/farmacología , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/genética , Células MCF-7 , Metástasis de la Neoplasia , Fosfatidilinositol 3-Quinasas/metabolismo
10.
Bioorg Med Chem ; 24(4): 672-80, 2016 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-26752094

RESUMEN

A novel series of 7-aminoalkyl-substituted flavonoid derivatives 5a-5r were designed, synthesized and evaluated as potential cholinesterase inhibitors. The results showed that most of the synthesized compounds exhibited potent acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities at the micromolar range. Compound 2-(naphthalen-1-yl)-7-(8-(pyrrolidin-1-yl)octyloxy)-4H-chromen-4-one (5q) showed the best inhibitory activity (IC50, 0.64µM for AChE and 0.42µM for BChE) which were better than our previously reported compounds and the commercially available cholinergic agent Rivastigmine. The results from a Lineweaver-Burk plot indicated a mixed-type inhibition for compound 5q with AChE and BChE. Furthermore, molecular modeling study showed that 5q targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. Besides, these compounds (5a-5r) did not affect PC12 and HepG2 cell viability at the concentration of 10µM. Consequently, these flavonoid derivatives should be further investigated as multipotent agents for the treatment of Alzheimer's disease.


Asunto(s)
Inhibidores de la Colinesterasa/farmacología , Colinesterasas/metabolismo , Diseño de Fármacos , Flavonoides/farmacología , Animales , Butirilcolinesterasa/metabolismo , Dominio Catalítico/efectos de los fármacos , Supervivencia Celular , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Relación Dosis-Respuesta a Droga , Activación Enzimática/efectos de los fármacos , Flavonoides/síntesis química , Flavonoides/química , Células Hep G2 , Humanos , Modelos Moleculares , Estructura Molecular , Células PC12 , Ratas , Relación Estructura-Actividad
11.
Mol Cancer ; 12: 157, 2013 Dec 10.
Artículo en Inglés | MEDLINE | ID: mdl-24325363

RESUMEN

BACKGROUND: Recently several reports have indicated that elevated expression of DKK1 is tightly associated with the progression of hepatocellular carcinoma (HCC). However, the biological function of DKK1 in HCC has not yet been well documented. METHODS: In this study, the role of DKK1 in tumor cell proliferation, migration and invasion was investigated using MTT, colony formation, wound scratch, transwell assays, and also human HCC samples. RESULTS: Both gain- and loss-of-function studies showed that DKK1 did not influence the tumor cell proliferation and colony formation, while dramatically promoted HCC cell migration and invasion. Subsequent investigations revealed that ß-catenin was an important target of DKK1. The blocking of ß-catenin by pharmacological inhibitor antagonized the function of DKK1, whereas introduction of ß-catenin by transfection with plasmids or treatment with GSK3ß inhibitor phenocopied the pro-migration and pro-invasion effects of DKK1. We further disclosed that DKK1 exerted its pro-invasion function, at least in part, by promoting ß-catenin expression, in turn, upregulating the expression of matrix metalloproteinase 7 (MMP7), which was independent of the canonical Wnt signaling pathway. Moreover, introduction of MMP7 significantly enhanced the ability of HCC cells to invade extracellular matrix gel in vitro. Consistently, in human HCC tissues, DKK1 level was positively correlated with ß-catenin expression, as well as tumor metastasis. CONCLUSION: Taken together, these results demonstrated that DKK1 is overexpressed in HCC; moreover, ectopic expression DKK1 promotes HCC cell migration and invasion at least partly through ß-catenin/MMP7 signaling axis, suggesting that DKK1 may be a promising target for HCC therapy.


Asunto(s)
Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Metaloproteinasa 7 de la Matriz/metabolismo , beta Catenina/metabolismo , Carcinoma Hepatocelular/genética , Línea Celular , Movimiento Celular , Regulación Neoplásica de la Expresión Génica , Células Hep G2 , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Neoplasias Hepáticas/genética , Metaloproteinasa 7 de la Matriz/genética , Invasividad Neoplásica , Transducción de Señal , beta Catenina/genética
12.
Anticancer Drugs ; 24(1): 32-42, 2013 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-23032518

RESUMEN

Polyamines as a vector to ferry toxic agents have attracted attention, and naphthalimide-polyamine conjugates show potent activity and tumor cell selectivity. The present study was carried out to evaluate the antitumor effects and preliminary systemic toxicity of ANISpm, a novel 3-amino-naphthalimide-spermine conjugate. The polyamine transport system recognition of ANISpm, supported by α-difluoromethylornithine (DFMO)/spermidine (Spd) experiments, is in accordance with its potent cell selectivity between human hepatoma HepG2 cells and normal QSG7701 hepatocyte. The antiproliferative effect is because of ANISpm-induced cell apoptosis, a common characteristic of both naphthalimide and polyamine analogs. Various apoptotic assessment assays have shown that ANISpm can induce apoptosis through the PI3K/Akt signal pathway. The apoptotic signaling cascade involves Akt inactivation, which results in a series of cellular events. The downstream pathway includes Bad dephosphorylation, dissociation of 14-3-3 and Bad, and binding to Bcl-xL, which triggers the disruption of the mitochondrial membrane, release of cytochrome c, and caspases' cascade activation. Furthermore, the Akt/mTOR signal pathway is also involved in ANISpm-mediated cell-cycle arrest. Additive DFMO or Spd, which only enhances or attenuates ANISpm-mediated cell apoptosis, respectively, does not alter the signal pathway. In addition, preliminary toxicology evaluation showed that ANISpm had no obvious system toxicity at a dose of 2.5 mg/kg, which exerted potent antitumor activity in vivo, especially hematotoxicity. Thus, ANISpm merits further investigation as a potential chemotherapeutic agent against hepatocellular carcinoma.


Asunto(s)
Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Naftalimidas/farmacología , Espermina/análogos & derivados , Animales , Apoptosis/efectos de los fármacos , Células CHO , Carcinoma Hepatocelular/patología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Cricetinae , Cricetulus , Relación Dosis-Respuesta a Droga , Células Hep G2 , Hepatocitos/metabolismo , Humanos , Neoplasias Hepáticas/patología , Masculino , Ratones , Naftalimidas/síntesis química , Naftalimidas/toxicidad , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Espermina/síntesis química , Espermina/farmacología , Espermina/toxicidad , Serina-Treonina Quinasas TOR/metabolismo , Pruebas de Toxicidad , Proteína Letal Asociada a bcl/metabolismo
13.
Bioorg Med Chem Lett ; 23(8): 2288-92, 2013 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-23489627

RESUMEN

Up to now, bismuth(III) complexes with thiosemicarbazones have been comparatively rare. Here, a main group seven-coordinated bismuth(III) complex [Bi(L)(NO3)2(CH3CH2OH)] (1) (HL = 2-acetylpyridine N(4)-phenylthiosemicarbazone) has been synthesized and characterized by elemental analysis, IR, (1)H NMR and single-crystal X-ray diffraction studies. The cytotoxicity data suggest that 1 exhibits higher in vitro antiproliferative activity in four human cancer cells tested. Its possible apoptotic mechanism has been evaluated in HepG2 cells. Compound 1 promotes a dose-dependent apoptosis in HepG2 cells and the apoptosis is associated with an increase in intracellular reactive oxygen species (ROS) production and reduction of mitochondrial membrane potential (MMP).


Asunto(s)
Bismuto/química , Complejos de Coordinación/química , Piridinas/síntesis química , Tiosemicarbazonas/síntesis química , Complejos de Coordinación/síntesis química , Complejos de Coordinación/farmacología , Cristalografía por Rayos X , Ensayos de Selección de Medicamentos Antitumorales , Células HCT116 , Células HeLa , Células Hep G2 , Humanos , Células K562 , Estructura Molecular , Piridinas/química , Tiosemicarbazonas/química , Tiosemicarbazonas/farmacología
14.
Acta Pharmacol Sin ; 34(11): 1403-10, 2013 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-23974517

RESUMEN

AIM: To investigate the effects and the molecular mechanisms of fucoxanthin, a major carotenoid found in edible seaweed, on HeLa cells. METHODS: The cytotoxicity of fucoxanthin was evaluated using MTT assay. Cell cycle and apoptosis were evaluated using flow cytometric analysis. Autophagy was detected with acridine orange staining and transient transfection of the GFP-LC3 plasmid into the cells. Protein expression was detected with Western blotting. RESULTS: Treatment of HeLa cells with fucoxanthin (10-80 µmol/L) for 48 h caused dose-dependent cytotoxicity with an IC50 value of 55.1±7.6 µmol/L. Fucoxanthin (10, 20, and 40 µmol/L) dose-dependently induced G0/G1 arrest, but did not change the apoptosis of HeLa cells. The same concentrations of fucoxanthin dose-dependently increased the protein expression of LC3 II (the autophagosome marker) and Beclin 1 (the initiation factor for autophagosome formation) in HeLa cells. Moreover, fucoxanthin dose-dependently decreased the levels of phosphorylated Akt and its downstream proteins p53, p70S6K, and mTOR, and increases the expression of PTEN in HeLa cells. Pretreatment of HeLa cells with 3-methyladenine (5 mmol/L) blocked the cytotoxic effect of fucoxanthin as well as fucoxanthin-induced autophagy. CONCLUSION: Fucoxanthin exerts autophagy-dependent cytotoxic effect in HeLa cells via inhibition of Akt/mTOR signaling pathway.


Asunto(s)
Antineoplásicos/farmacología , Autofagia/efectos de los fármacos , Neoplasias del Cuello Uterino/tratamiento farmacológico , Xantófilas/farmacología , Antineoplásicos/administración & dosificación , Apoptosis/efectos de los fármacos , Proteínas Reguladoras de la Apoptosis/genética , Beclina-1 , Western Blotting , Ciclo Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Femenino , Citometría de Flujo , Células HeLa , Humanos , Concentración 50 Inhibidora , Proteínas de la Membrana/genética , Proteínas Asociadas a Microtúbulos/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo , Neoplasias del Cuello Uterino/patología , Xantófilas/administración & dosificación
15.
Yao Xue Xue Bao ; 48(5): 675-9, 2013 May.
Artículo en Zh | MEDLINE | ID: mdl-23888689

RESUMEN

Treatment with the combination of Chinese herbs and cytotoxic chemotherapies showed a higher survival rate in clinical trials. In this report, the results demonstrated that the tanshinone II A, a key component of Salvia miltiorrhiza bunge, when it is combined with the cytotoxic drug cisplatin showed synergistic antitumor effects on human prostate cancer PC3 cells and LNCaP cells in vitro. Antiproliferative effects were detected with MTT assay. Cell cycle distribution and apoptosis were detected by flow cytometer. Protein expression was detected by Western blotting. The intracellular concentration of cisplatin was detected by high performance liquid chromatography. The results demonstrated that tanshinone II A significantly enhanced the antiproliferative effects of cisplatin on human prostate cancer PC3 cells and LNCaP cells with the increase of the intracellular concentration of cisplatin. These effects were correlated with cell cycle arrested at S phase and cell apoptosis. The apoptosis might be achieved through death receptor pathway and mitochondrial pathway. Furthermore, the Bcl-2 family members were also involved in this apoptotic process. Collectively, these results indicated that the combination of tanshinone II A and cisplatin had a better treatment effect in vitro not only on androgen-dependent LNCaP cells but also on androgen-independent PC3 cells.


Asunto(s)
Abietanos/farmacología , Apoptosis/efectos de los fármacos , Cisplatino/farmacología , Neoplasias de la Próstata/patología , Abietanos/aislamiento & purificación , Andrógenos/metabolismo , Antineoplásicos/farmacología , Antineoplásicos Fitogénicos/aislamiento & purificación , Antineoplásicos Fitogénicos/farmacología , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Sinergismo Farmacológico , Medicamentos Herbarios Chinos/aislamiento & purificación , Medicamentos Herbarios Chinos/farmacología , Humanos , Masculino , Raíces de Plantas/química , Plantas Medicinales/química , Neoplasias de la Próstata/metabolismo , Salvia miltiorrhiza/química
16.
Yao Xue Xue Bao ; 48(6): 855-9, 2013 Jun.
Artículo en Zh | MEDLINE | ID: mdl-23984518

RESUMEN

This study is to investigate the antitumor activity of ophiopogonin B (OP-B). MTT assay, flow cytometric analysis, acridine orange staining, Lyso-Tracker Red staining and HeLa-GFP-LC3 transfect cells assay were used to detect the proliferation activity, apoptosis and autophagy of HeLa cells. The results showed that OP-B exerted potent antiproliferative activity on HeLa cells, the cell growth inhibition effect of OP-B was not due to apoptosis and OP-B could induce autophagy of HeLa cells. OP-B also induced the protein expression up-regulation of Beclin-1 and promoted LC3 I transformation LC3 II, which were representative proteins of autophagy. Furthermore, 3-MA, an inhibitor of autophagy, not only inhibited OP-B-mediated autophagy but also almost completely reversed the antiproliferative effect of OP-B, suggesting that the growth inhibition effect of OP-B was autophagy dependent. Western blotting demonstrated that OP-B inhibited the phosphorylation of Akt and its' downstream vital protein, such as mTOR and p70S6K. In addition, OP-B also induced the protein expression up-regulation of PTEN, which is a negative regulation protein for Akt/mTOR signaling pathway. However, OP-B did not affect the protein expression of total Akt. Collectively, the antitumor effects of OP-B were autophagy-dependent via repression Akt/mTOR signaling pathway. Therefore, OP-B is a prospective inhibitor of Akt/mTOR and may be used as an alternative compound to treat cervical carcinoma.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Autofagia/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Saponinas/farmacología , Espirostanos/farmacología , Adenina/análogos & derivados , Adenina/farmacología , Apoptosis/efectos de los fármacos , Proteínas Reguladoras de la Apoptosis/metabolismo , Beclina-1 , Relación Dosis-Respuesta a Droga , Células HeLa , Humanos , Proteínas de la Membrana/metabolismo , Proteínas Asociadas a Microtúbulos/metabolismo , Ophiopogon/química , Fosfohidrolasa PTEN/metabolismo , Fosforilación , Plantas Medicinales/química , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Quinasas S6 Ribosómicas 70-kDa/metabolismo , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo , Regulación hacia Arriba
17.
Biochem Pharmacol ; 208: 115378, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36513141

RESUMEN

Understanding the mechanisms regulating PD-L1 expression in hepatocellular carcinoma (HCC) is important to improve the response rate to PD-1/PD-L1 blockade therapy. Here, we show that DKK1 expression is positively associated with PD-L1 expression and inversely correlated with CD8+ T cell infiltration in human HCC tumor specimens. In a subcutaneous xenograft tumor model, overexpression of DKK1 significantly promotes tumor growth, tumoral PD-L1 expression, but reduces tumoral CD8+ T cell infiltration; whereas knockdown of DKK1 has opposite effects. Moreover, enforced expression of DKK1 dramatically promotes PD-L1 expression, Akt activation, ß-catenin phosphorylation and total protein expression in HCC cells. By contrast, knockdown of DKK1 inhibits all, relative to controls. In addition, CKAP4 depletion, Akt inhibition, or ß-catenin depletion remarkably abrogates DKK1 overexpression-induced transcriptional expression of PD-L1 in HCC cells. Reconstituted expression of the active Akt1 largely increased PD-L1 transcriptional expression in HCC cells. Similarly, expression of WT ß-catenin, but not the phosphorylation-defective ß-catenin S552A mutant, significantly promotes PD-L1 expression. Correlation analysis of human HCC tumor specimens further revealed that DKK1 and PD-L1 expression were positively correlated with p-ß-catenin expression. Together, our findings revealed that DKK1 promotes PD-L1 expression through the activation of Akt/ß-catenin signaling, providing a potential strategy to enhance the clinical efficacy of PD-1/PD-L1 blockade therapy in HCC patients.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , beta Catenina/metabolismo , Carcinoma Hepatocelular/metabolismo , Línea Celular Tumoral , Neoplasias Hepáticas/metabolismo , Receptor de Muerte Celular Programada 1 , Proteínas Proto-Oncogénicas c-akt , Escape del Tumor
18.
Phytomedicine ; 112: 154715, 2023 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-36821999

RESUMEN

BACKGROUND: Hepatocellular carcinoma (HCC) is a leading cause of cancer-associated mortality in the world. However, the anticancer effects of aucubin against HCC have yet to be reported. Cisplatin often decreased CD8+ tumor-infiltrating lymphocytes in the tumor microenvironment through increasing programmed death-ligand 1 (PD-L1) expression, which seriously affected the prognostic effect of cisplatin in the treatment of patients with HCC. Therefore, it is necessary to identify a novel therapeutic avenue to increase the sensitivity of cisplatin against HCC. PURPOSE: This study aims to evaluate the anti-tumor effect of aucubin on HCC, and also to reveal the synergistic effects and mechanism of aucubin and cisplatin against HCC. STUDY DESIGN AND METHODS: An H22 xenograft mouse model was established for the in vivo experiments. Cancer cell proliferation was detected by MTT assay. RT-qPCR was performed to analyze CD274 mRNA expression in vitro. Western blotting was employed to determine the expression levels of the PD-L1, p-Akt, Akt, p-ß-catenin, and ß-catenin in vitro. Immunofluorescence was carried out to examine ß-catenin nuclear accumulation in HCC cells. Immunohistochemistry was used to detect tumoral PD-L1 and CD8α expression in xenograft mouse model. RESULTS: Aucubin inhibits tumor growth in a xenograft HCC mouse model, but did not affect HCC cell viability in vitro. Aucubin treatment significantly inhibited PD-L1 expression through inactivating Akt/ß-catenin signaling pathway in HCC cells. Overexpression of PD-L1 dramatically reversed aucubin-mediated tumoral CD8+ T cell infiltration and alleviated the antitumor activity of aucubin in xenograft mouse model. Moreover, Cisplatin could induce the expression of PD-L1 through the activation of the Akt/ß-catenin signaling pathway in HCC cells, which can be blocked by aucubin in vitro. In xenograft mouse model, cisplatin treatment induced PD-L1 expression and alleviated the infiltration of CD8+ T lymphocytes in the tumor microenvironment. Aucubin not only abrogated cisplatin-induced PD-L1 expression but also enhanced the antitumor efficacy of cisplatin in a mouse xenograft model of HCC. CONCLUSION: Aucubin exerts antitumor activity against HCC and also enhances the antitumor activity of cisplatin by suppressing the Akt/ß-catenin/PD-L1 axis.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Animales , Ratones , Carcinoma Hepatocelular/metabolismo , Cisplatino/farmacología , Cisplatino/uso terapéutico , Antígeno B7-H1/metabolismo , Neoplasias Hepáticas/metabolismo , beta Catenina/metabolismo , Proteínas Proto-Oncogénicas c-akt , Línea Celular Tumoral , Microambiente Tumoral
19.
Apoptosis ; 17(7): 725-34, 2012 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-22395446

RESUMEN

Hepatocellular carcinoma (HCC) is one of the main causes of death in cancer. Some naphthalimide derivatives exert high anti-proliferative effects on HCC. In this study, it is confirmed that 3-nitro-naphthalimide and nitrogen mustard conjugate (NNM-25), a novel compound conjugated by NNM-25, displayed more potent therapeutic action on HCC, both in vivo and in vitro, than amonafide, a naphthalimide drug in clinical trials. More importantly, preliminary toxicological evaluation also supported that NNM-25 exhibited less systemic toxicity than amonafide at the therapeutic dose. The antitumor mechanism of conjugates of naphthalimides with nitrogen mustard remains poorly understood up to now. Here, we first reported that apoptosis might be the terminal fate of cancer cells treated with NNM-25. Inhibition of p53 by siRNA resulted in a significant decrease of NNM-25-induced apoptosis, which corroborated that p53 played a vital role in the cell apoptosis triggered by NNM-25. NNM-25 inhibited the PARP-1 activity, AKT phosphorylation, up-regulated the protein expression of p53, Bad, and mTOR as well as down-regulating the protein expression of Bcl-2 and decreasing mitochondrial membrane potential. It also facilitated cytochrome c release from mitochondria to cytoplasm, activated caspase 8, caspase 9, and caspase 3 in HepG2 cells in vitro, as also authenticated in H22 tumor-bearing mice in vivo. Collectively, the conjugation of naphthalimides with nitrogen mustard provides favorable biological activity and thus is a valuable strategy for future drug design in HCC therapy.


Asunto(s)
Apoptosis/efectos de los fármacos , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , Naftalimidas/farmacología , Compuestos de Mostaza Nitrogenada/farmacología , Poli(ADP-Ribosa) Polimerasas/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Animales , Western Blotting , Carcinoma Hepatocelular/enzimología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , ADN de Neoplasias/metabolismo , Fluorescencia , Humanos , Sustancias Intercalantes/farmacología , Neoplasias Hepáticas/enzimología , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Naftalimidas/síntesis química , Naftalimidas/química , Naftalimidas/toxicidad , Proteínas de Neoplasias/metabolismo , Compuestos de Mostaza Nitrogenada/síntesis química , Compuestos de Mostaza Nitrogenada/química , Inhibidores de Poli(ADP-Ribosa) Polimerasas , ARN Interferente Pequeño/metabolismo , Transducción de Señal/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
20.
Inorg Chem ; 51(22): 12521-6, 2012 Nov 19.
Artículo en Inglés | MEDLINE | ID: mdl-23136979

RESUMEN

Up to now, bismuth(III) complexes with thiosemicarbazones have been comparatively rare. Few in vivo biological studies have been carried out in comparison to the plentiful in vitro data. Here, an interesting nine-coordinated bismuth(III) complex, [Bi(H2L)(NO3)2]NO3 [1; H2L = 2,6-diacetylpyridine bis((4)N-methylthiosemicarbazone)], has been synthesized and structurally characterized. The analytical data reveal the formation of 1:1 (metal/ligand) stoichiometry. In vitro biological studies have indicated that the bismuth complex 1 has shown much higher antibacterial and anticancer activities than its parent ligand, especially with MIC = 10.66 µM against Bacillus cereus and Salmonella typhimurium and IC50 = 26.8 µM against K562 leukemia cells, respectively. More importantly, it also evidently inhibits H22 xenograft tumor growth on tumor-bearing mice (10 mg/kg; inhibitory rate = 61.6%). These results indicate that coordination to bismuth(III) might be an interesting strategy in the discovery of new anticancer drug candidates.


Asunto(s)
Antibacterianos/farmacología , Antineoplásicos/farmacología , Bacillus cereus/efectos de los fármacos , Bismuto/química , Complejos de Coordinación/farmacología , Neoplasias Hepáticas Experimentales/tratamiento farmacológico , Salmonella typhimurium/efectos de los fármacos , Tiosemicarbazonas/química , Animales , Antibacterianos/síntesis química , Antibacterianos/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Células K562 , Masculino , Ratones , Ratones Endogámicos , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura Molecular , Relación Estructura-Actividad
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