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1.
Nutr Cancer ; 73(11-12): 2720-2731, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33305590

RESUMEN

The present study was taken up to evaluate the apoptosis inducing ability of alcoholic extract of whole plant of Anagallis arvensis (AAE) in HL-60 cells. We observed time and concentration dependent decrease in cell viability after treatment with AAE. Fluorescent staining and scanning electron micrographs of treated HL-60 cells demonstrated chromatin condensation, nuclear fragmentation and formation of apoptotic blebs. There was a marked increase in hypodiploid population of cells as observed by cell cycle analysis. Annexin V-FITC/PI also depicted the presence of apoptotic cells. Anti-apoptotic protein Bcl-2 was observed to be decreased by 62% at 20 µg/ml concentration and a significant increase in ROS production up to 6.9-fold was observed in time dependent manner. In addition, alteration in mitochondrial membrane potential was observed, which was followed by cytochrome c release to cytoplasm. Activated levels of mitochondrial downstream pathway protein namely Caspase-3 and 9, were detected in treated HL-60 cells by colorimetric analysis. DNA ladder formation, a biochemical hallmark of apoptosis was also observed in treated HL-60 cells. The results of the present study support the apoptotic potential of AAE and probability of its promising role in development as effective anticancer agent against leukemia cells.


Asunto(s)
Anagallis , Apoptosis , Caspasa 3/genética , Caspasa 3/metabolismo , Células HL-60 , Humanos , Potencial de la Membrana Mitocondrial , Especies Reactivas de Oxígeno/metabolismo
2.
Biomed Pharmacother ; 95: 856-864, 2017 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-28903181

RESUMEN

Cisplatin is a potent and widely used chemotherapeutic agent to treat a variety of tumors. However, its clinical use is associated with undesirable side effects and acquired resistance to cisplatin. In this study, cisplatin loaded hyaluronic acid (HA) functionalized poly (lactic-co-glycolic acid)-poly (ethylene glycol) nanoparticles (CP-HA-PLGA-PEG-NPs) were fabricated using double emulsion solvent evaporation method to target CD44 receptor expressed on cancerous cells. The developed nanoconstructs were characterized for various in vitro parameters, including size distribution, zeta potential, morphology, drug loading and in vitro release. The HA content on the HA-PLGA-PEG-NPs was quantified by a turbidimetric method. The in vitro anticancer study in human ovarian cancer (SKOV-3) cells showed significantly (p<0.05) higher cytotoxicity of CP-HA-PLGA-PEG NPs as compared to free cisplatin and non-targeted nanoparticles (CP-PLGA-PEG NPs). Further, laser scanning confocal microscopy revealed that there was enhanced cellular uptake of HA-PLGA-PEG NPs in CD44-over expressing ovarian cancer cell line (SKOV-3). The in vivo antitumor activity of CP-HA-PLGA-PEG-NPs was significantly (p<0.05) higher than free cisplatin and CP-PLGA-PEG-NPs in Ehrlich tumor (solid) bearing mice. The results demonstrated the potential of target specific nanoconstruct of cisplatin in the improved cancer chemotherapy.


Asunto(s)
Cisplatino/uso terapéutico , Ácido Hialurónico/química , Nanopartículas/química , Neoplasias/tratamiento farmacológico , Poliésteres/química , Polietilenglicoles/química , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Cisplatino/farmacología , Liberación de Fármacos , Endocitosis/efectos de los fármacos , Humanos , Nanopartículas/ultraestructura , Neoplasias/patología , Tamaño de la Partícula , Espectroscopía Infrarroja por Transformada de Fourier , Electricidad Estática
4.
BMC Cell Biol ; 18(1): 26, 2017 07 20.
Artículo en Inglés | MEDLINE | ID: mdl-28728544

RESUMEN

BACKGROUND: Endophytes have proven to be an invaluable resource of chemically diverse secondary metabolites that act as excellent lead compounds for anticancer drug discovery. Here we report the promising cytotoxic effects of Cladosporol A (HPLC purified >98%) isolated from endophytic fungus Cladosporium cladosporioides collected from Datura innoxia. Cladosporol A was subjected to in vitro cytotoxicity assay against NCI60 panel of human cancer cells using MTT assay. We further investigated the molecular mechanism(s) of Cladosporol A induced cell death in human breast (MCF-7) cancer cells. Mechanistically early events of cell death were studied using DAPI, Annexin V-FITC staining assay. Furthermore, immunofluorescence studies were carried to see the involvement of intrinsic pathway leading to mitochondrial dysfunction, cytochrome c release, Bax/Bcl-2 regulation and flowcytometrically measured membrane potential loss of mitochondria in human breast (MCF-7) cancer cells after Cladosporol A treatment. The interplay between apoptosis and autophagy was studied by microtubule dynamics, expression of pro-apoptotic protein p21 and autophagic markers monodansylcadaverine staining and LC3b expression. RESULTS: Among NCI60 human cancer cell line panel Cladosporol A showed least IC50 value against human breast (MCF-7) cancer cells. The early events of apoptosis were characterized by phosphatidylserine exposure. It disrupts microtubule dynamics and also induces expression of pro-apoptotic protein p21. Moreover treatment of Cladosporol A significantly induced MMP loss, release of cytochrome c, Bcl-2 down regulation, Bax upregulation as well as increased monodansylcadaverine (MDC) staining and leads to LC3-I to LC3-II conversion. CONCLUSION: Our experimental data suggests that Cladosporol A depolymerize microtubules, sensitize programmed cell death via ROS mediated autophagic flux leading to mitophagic cell death. The proposed mechanism of Cladosporol A -triggered apoptotic as well as autophagic death of human breast cancer (MCF-7) cells. The figure shows that Cladosporol A induced apoptosis through ROS mediated mitochondrial pathway and increased p21 protein expression in MCF-7 cells in vitro.


Asunto(s)
Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Neoplasias de la Mama/fisiopatología , Naftoles/farmacología , Especies Reactivas de Oxígeno/metabolismo , Acetilcisteína/antagonistas & inhibidores , Apoptosis/fisiología , Autofagia/fisiología , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cromosomas/efectos de los fármacos , Cromosomas/metabolismo , Cladosporium/clasificación , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Citocromos c/metabolismo , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Células MCF-7 , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Potencial de la Membrana Mitocondrial/fisiología , Microtúbulos/efectos de los fármacos , Microtúbulos/metabolismo , Especies Reactivas de Oxígeno/antagonistas & inhibidores
5.
Biomed Pharmacother ; 92: 175-186, 2017 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-28549290

RESUMEN

Hentriacontane, has various pharmacological effects including anti-inflammatory, antitumor and antimicrobial activities. Its anti-inflammatory potential has been demonstrated in peritoneal macrophages. However detailed studies on other models elucidating the mechanistic description of the mode of action has not been done. Hence, the aim of the present study is to evaluate the anti-inflammatory potential of hentriacontane both in-vivo (Balb/c mice) and in-vitro (RAW 264.7 cells). Cytokine inhibition of both pro-inflammatory (TNF-α, IL-6, MCP-1 and IL-1ß) and anti-inflammatory (IL-10) cytokines was studied in RAW 264.7 cells and Balb/c mice. Suppressive potential of hentriacontane on NO, PGE2, LTB4 and on LPS induced translocation of NF-κB in RAW 264.7 cells was studied. Further investigations on the effect of hentriacontane on phagocytic index, carrageenan induced paw oedema in mice and on organ weight were done. It was found that hentriacontane significantly reduced all the parameters of inflammation in the experiments under study at all the concentrations, 10µM, 5µM and 1µM (in-vitro) and 5mg/kg, 2mg/kg and 1mg/kg (in-vivo). The highest concentration used in the two models presented the most significant results. The results indicate that hentriacontane is a potent suppressor of inflammatory cytokines and other mediators. Moreover it also has regulatory effect on NF-κB. Hence, hentriacontane is a potential candidate for investigations to develop anti-inflammatory drug.


Asunto(s)
Antiinflamatorios/farmacología , Hidrocarburos/farmacología , Mediadores de Inflamación/metabolismo , Lipopolisacáridos/toxicidad , Macrófagos/metabolismo , Animales , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Citocinas/antagonistas & inhibidores , Citocinas/metabolismo , Relación Dosis-Respuesta a Droga , Femenino , Mediadores de Inflamación/antagonistas & inhibidores , Macrófagos/efectos de los fármacos , Macrófagos/patología , Ratones , Ratones Endogámicos BALB C , FN-kappa B/antagonistas & inhibidores , FN-kappa B/metabolismo , Células RAW 264.7
6.
J Med Chem ; 60(8): 3484-3497, 2017 04 27.
Artículo en Inglés | MEDLINE | ID: mdl-28368585

RESUMEN

l-Vasicine is a quinazoline alkaloid with an electron dense ring and additional functionalities in its structure. Employing target oriented synthesis (TOS) based on in silico studies, molecules with significant docking scores containing different derivatives of l-vasicine as caps were synthesized. Interestingly, one molecule, i.e., 4a, which contained 3-hyroxypyrrolidine as a cap group and a six carbon long aliphatic chain as a linker was found to inhibit HDACs. 4a showed more specificity toward class I HDAC isoforms. Also 4a was found to be less cytotoxic toward normal cell lines as compared to cancer cell lines. 4a inhibited cancer cell growth and induced cell death by various mechanisms. However, 4a was found to induce cell death independent of ROS generation, and unlike many natural product based HDAC inhibitors, 4a was found to be nontoxic under in vivo conditions. Importantly, we for the first time report the possibility of using a 3-hydroxypyrrolidine cap for the synthesis of HDAC inhibitors with good potency.


Asunto(s)
Alcaloides/química , Antineoplásicos/química , Inhibidores de Histona Desacetilasas/química , Quinazolinas/química , Alcaloides/farmacología , Antineoplásicos/farmacología , Línea Celular Tumoral , Inhibidores de Histona Desacetilasas/farmacología , Humanos , Quinazolinas/farmacología
7.
Mol Neurobiol ; 54(7): 5061-5073, 2017 09.
Artículo en Inglés | MEDLINE | ID: mdl-27541286

RESUMEN

Withania somnifera has immense pharmacologic and clinical uses. Owing to its similar pharmacologic activity as that of Korean Ginseng tea, it is popularly called as Indian ginseng. In most cases, extracts of this plant have been evaluated against various diseases or models of disease. However, little efforts have been made to evaluate individual constituents of this plant for neurodegenerative disorders. Present study was carried out to evaluate Withanone, one of the active constituents of Withania somnifera against NMDA-induced excitotoxicity in retinoic acid, differentiated Neuro2a cells. Cells were pre-treated with 5, 10 and 20 µM doses of Withanone and then exposed to 3-mM NMDA for 1 h. MK801, a specific NMDA receptor antagonist, was used as positive control. The results indicated that NMDA induces significant death of cells by accumulation of intracellular Ca2+, generation of reactive oxygen species (ROS), loss of mitochondrial membrane potential, crashing of Bax/Bcl-2 ratio, release of cytochrome c, increased caspase expression, induction of lipid peroxidation as measured by malondialdehyde levels and cleavage of poly(ADP-ribose) polymerase-1 (Parp-1), which is indicative of DNA damage. All these parameters were attenuated with various doses of Withanone pre-treatment. These results suggest that Withanone may serve as potential neuroprotective agent.


Asunto(s)
Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Neuronas/efectos de los fármacos , Triterpenos/farmacología , Animales , Diferenciación Celular/efectos de los fármacos , Ratones , Mitocondrias/metabolismo , Enfermedades Neurodegenerativas/tratamiento farmacológico , Enfermedades Neurodegenerativas/metabolismo , Neuronas/metabolismo , Fármacos Neuroprotectores/farmacología , Poli(ADP-Ribosa) Polimerasas/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Witanólidos
8.
Mater Sci Eng C Mater Biol Appl ; 68: 109-116, 2016 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-27524002

RESUMEN

Cisplatin is widely used for the treatment of various cancers including cervical, ovarian, lung and head and neck, however, its clinical success is limited owing to the dose-dependent adverse effects, mainly nephrotoxicity and neurotoxicity. In order to address this limitation, the present study was undertaken to investigate growth inhibitory effect of cisplatin in combination with a triterpenediol (3a, 24-dihydroxyurs-12-ene and 3a, 24-dihydroxyolean-12-ene, TPD) on human ovarian cancer cell line. Poly(dl-lactic-co-glycolic) acid nanoparticles loaded with TPD (TPD-PLGA-NPs) were successfully developed by emulsion solvent evaporation method. The TPD-PLGA-NPs were characterized for size distribution and zeta potential which was in order of 152.56±3.01nm and -17.36±0.37mV respectively. The morphological evaluation was carried out by transmission electron microscopy and the formulation was also characterized using Fourier transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC). The drug loading of the optimized formulation was 51.03±1.52µg/mg and the formulation exhibited sustained drug release profile. The in vitro cellular uptake study of coumarin-6 loaded PLGA nanoparticles in OVCAR-5 cells demonstrated a time dependent increase in uptake efficiency. Further, growth inhibitory effect of cisplatin was investigated in combination with TPD-PLGA-NPs. The combination index (CI) was <1, indicating a synergistic interaction. Further, at 75% of cell growth inhibition (ED75) the dose of cisplatin was reduced to 3.8 folds using this combination. The results indicated the potential of cisplatin and TPD-PLGA-NPs combination in order to reduce to dose limiting toxicities of the former.


Asunto(s)
Cisplatino , Portadores de Fármacos , Nanopartículas/química , Neoplasias/tratamiento farmacológico , Triterpenos Pentacíclicos , Línea Celular Tumoral , Cisplatino/química , Cisplatino/farmacocinética , Cisplatino/farmacología , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ácido Láctico/química , Ácido Láctico/farmacocinética , Ácido Láctico/farmacología , Neoplasias/metabolismo , Neoplasias/patología , Triterpenos Pentacíclicos/química , Triterpenos Pentacíclicos/farmacocinética , Triterpenos Pentacíclicos/farmacología , Ácido Poliglicólico/química , Ácido Poliglicólico/farmacocinética , Ácido Poliglicólico/farmacología , Copolímero de Ácido Poliláctico-Ácido Poliglicólico
9.
J Cell Biochem ; 117(12): 2864-2874, 2016 12.
Artículo en Inglés | MEDLINE | ID: mdl-27167447

RESUMEN

Cancer therapeutics is a hot subject and PI3K class 1A isoforms (p110α and p110ß) are pursued as major targets. Genetic analysis, biochemical approaches, and structural studies have demonstrated crucial roles for these isoforms in several physiological processes. p110α is critical for insulin signaling, whereas p110ß is essential for the growth and differs from p110α in many ways. Here, we have generated GFP-fusion clones of wildtype and mutant version of p110α and p110ß and expressed them in HEK293 and cancer cells to examine their subcellular localization and their impact on downstream signaling. In HEK293 cells, p110ß GFP-fusion protein is translocated into the nucleus, whereas p110α-GFP stays exclusively in the cytoplasm. This study demonstrates that p110α and p110ß oncogenecity, kinase activity, and interaction with p85 regulatory subunit does not have any impact on their subcellular localization. PI3K pathway specific inhibitor, LY294002, abrogated PI3K signaling by reducing pAkt levels, however, the subcellular localization of p110α and p110ß remained unchanged. Furthermore, we analyzed the expression of recombinant p110α and p110ß in a panel of human cancer cells and observed remarkable differences in their expression levels. The differential expression of recombinant p110α and p110ß was observed to be mainly regulated by the endogenous levels of pAkt. Unlike in HEK293, p110α showed nuclear localization in cancer cells in a similar fashion to p110ß. Moreover, we observed the PI3K signaling activities in low pAkt expressing cells are mediated by PDK1 and S6K proteins. Finally, p110α and p110ß were seen to play an essential role in promoting the cell cycle progression in MCF-7 and HCT-116 cells. J. Cell. Biochem. 117: 2864-2874, 2016. © 2016 Wiley Periodicals, Inc.


Asunto(s)
Transformación Celular Neoplásica/metabolismo , Fosfatidilinositol 3-Quinasa Clase Ia/metabolismo , Proteínas Fluorescentes Verdes/metabolismo , Neoplasias/metabolismo , Proteínas Recombinantes de Fusión/metabolismo , Apoptosis , Western Blotting , Ciclo Celular , Proliferación Celular , Transformación Celular Neoplásica/patología , Células Cultivadas , Células HEK293 , Humanos , Neoplasias/patología , Fosforilación , Isoformas de Proteínas , Transducción de Señal
10.
Cancer Lett ; 374(2): 250-60, 2016 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-26921131

RESUMEN

Phosphatidylinositol 3-kinase (PI3K) pathway drives cancer progression through direct regulation of most oncogenic properties. Here, we report that PI3K pathway signaling up-regulates cancer cell proliferation, metastasis and angiogenesis through modulation of cancer metabolism. These oncogenic metabolic processes were disrupted, by a novel PI3K inhibitor, 3-Dihydro-2-(naphthalene-1-yl) quinazolin-4(1H)-one (DHNQ) in colon cancer cells. DHNQ inhibited the Warburg effect and lipid synthesis by reducing gene expression of glycolytic and lipogenesis regulatory enzymes. This downregulation at gene level by DHNQ inhibited metabolic flux to repress proliferation, migration and invasion characteristics of colon cancer. Furthermore, the metabolic attenuation caused repression of in vitro/in vivo angiogenesis providing new insights in PI3K regulated angiogenesis via metabolic alterations. Our results suggest that multifaceted targeting of oncogenic metabolism by their upstream PI3K regulatory signaling may be an effective cancer treatment approach.


Asunto(s)
Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/metabolismo , Naftalenos/farmacología , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/farmacología , Quinazolinonas/farmacología , Animales , Procesos de Crecimiento Celular , Movimiento Celular/efectos de los fármacos , Neoplasias Colorrectales/irrigación sanguínea , Neoplasias Colorrectales/enzimología , Glucólisis/efectos de los fármacos , Células HCT116 , Células HEK293 , Células Endoteliales de la Vena Umbilical Humana , Humanos , Lipogénesis/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología
11.
Planta Med ; 82(4): 344-55, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26848704

RESUMEN

The endophytic fungus strain MRCJ-326, isolated from Allium schoenoprasum, which is also known as Snow Mountain Garlic or Kashmiri garlic, was identified as Penicillium pinophilum on the basis of morphological characteristics and internal transcribed spacer region nucleotide sequence analysis. The endophytic fungus extract was subjected to 2D-SEPBOX bioactivity-guided fractionation and purification. The anthraquinone class of the bioactive secondary metabolites were isolated and characterized as oxyskyrin (1), skyrin (2), dicatenarin (3), and 1,6,8-trihydroxy-3-hydroxy methylanthraquinone (4) by spectral analysis. Dicatenarin and skyrin showed marked growth inhibition against the NCI60/ATCC panel of human cancer cell lines with least IC50 values of 12 µg/mL and 27 µg/mL, respectively, against the human pancreatic cancer (MIA PaCa-2) cell line. The phenolic hydroxyl group in anthraquinones plays a crucial role in the oxidative process and bioactivity. Mechanistically, these compounds, i.e., dicatenarin and skyrin, significantly induce apoptosis and transmit the apoptotic signal via intracellular reactive oxygen species generation, thereby inducing a change in the mitochondrial transmembrane potential and induction of the mitochondrial-mediated apoptotic pathway. Our data indicated that dicatenarin and skyrin induce reactive oxygen species-mediated mitochondrial permeability transition and resulted in an increased induction of caspase-3 apoptotic proteins in human pancreatic cancer (MIA PaCa-2) cells. Dicatenarin showed a more pronounced cytotoxic/proapopotic effect than skyrin due to the presence of an additional phenolic hydroxyl group at C-4, which increases oxidative reactive oxygen species generation. This is the first report from P. pinophilum secreating these cytotoxic/proapoptotic secondary metabolites.


Asunto(s)
Antraquinonas/farmacología , Antineoplásicos/farmacología , Penicillium/química , Antraquinonas/química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Cebollino/microbiología , ADN de Hongos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Datos de Secuencia Molecular , Estructura Molecular , Neoplasias Pancreáticas , Penicillium/aislamiento & purificación , Especies Reactivas de Oxígeno/metabolismo , Análisis de Secuencia de ADN
12.
Mol Carcinog ; 55(12): 2135-2155, 2016 12.
Artículo en Inglés | MEDLINE | ID: mdl-26764221

RESUMEN

Phosphatidylinositol-3-kinase (PI3K) pathway deregulation is responsible for initiation, chemo-resistance, and poor prognosis of colorectal cancer (CRC). Therefore, PI3K pathway inhibition can provide a plausible way of attaining CRC treatment. We report PI3K target specific synthesis and selection of a potent molecule, that is, 2,3-dihydro-2-(naphthalene-1-yl) quinazolin-4(1H)-one (DHNQ) from quinazolinone series based on the structural activity relationship after evaluation in diverse cancers. This molecule inhibited the PI3K enzyme activity and transcriptional as well as translational expression levels in colorectal cancer (CRC) models. This was associated with subsequent decrease in phosphorylation of its downstream effector proteins, that is, p-Akt(Ser-473) and p-mTORC1(Ser-2448) and decreased ERK signaling. Furthermore, DHNQ decreased expression of cyclins that caused G1 arrest and decreased Bcl-2/Bax ratio after mitochondrial membrane potential loss, reactive oxygen species generation, and an increase in cytosolic Ca2+ loads that is responsible for the decreased CRC cell proliferation and survival. These biochemical changes triggered apoptotic cell death with altered autophagic Beclin-1 and LC3ß expression. It seemed that the PI3K-Akt signaling regulated apoptosis and autophagy through different mechanisms but mTORC1 mediated autophagy appeared not to be involved in the cell death induction by DHNQ. The molecule also showed significant anticancer efficacy in in vivo tumor models without any mortality indicating its non-toxic nature with possible clinical significance. Overall, the selective elucidation of DHNQ molecular mechanism will provide the possible strategies for the clinical development in CRC that may respond to this specific, potent and novel P13K inhibitor. © 2016 Wiley Periodicals, Inc.


Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Neoplasias Colorrectales/tratamiento farmacológico , Fosfatidilinositol 3-Quinasa/metabolismo , Quinazolinonas/farmacología , Transducción de Señal/efectos de los fármacos , Antineoplásicos/química , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Colon/efectos de los fármacos , Colon/metabolismo , Colon/patología , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Humanos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Quinazolinonas/química , Recto/efectos de los fármacos , Recto/metabolismo , Recto/patología
13.
Bioorg Med Chem Lett ; 26(1): 76-81, 2016 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-26608550

RESUMEN

A series of ß-boswellic acid derivatives were synthesized and evaluated for anticancer activity. One of the lead analog 4f displayed significant anticancer activity against a panel of cancer cells as well as substantially inhibited colony formation in HCT-116 cells. Furthermore, 4f was found to be a potent inducer of apoptosis confirmed by loss of mitochondrial membrane potential, DAPI staining, Western blotting and ROS generation.


Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Triterpenos/química , Triterpenos/farmacología , Antineoplásicos/química , Antineoplásicos/metabolismo , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células HCT116 , Humanos , Conformación Molecular , Relación Estructura-Actividad , Triterpenos/síntesis química
14.
Mol Carcinog ; 55(5): 864-81, 2016 May.
Artículo en Inglés | MEDLINE | ID: mdl-25969134

RESUMEN

Here, we provide evidences that natural product derivative 3-azido Withaferin A (3-AWA) abrogated EMT and invasion by modulating ß-catenin localization and its transcriptional activity in the prostate as well as in breast cancer cells. This study, for the first time, reveals 3-AWA treatment consistently sequestered nuclear ß-catenin and augmented its cytoplasmic pool as evidenced by reducing ß-catenin transcriptional activity in these cells. Moreover, 3-AWA treatment triggered robust induction of pro-apoptotic intracellular Par-4, attenuated Akt activity and rescued Phospho-GSK3ß (by Akt) to promote ß-catenin destabilization. Further, our in vitro studies demonstrate that 3-AWA treatment amplified E-cadherin expression along with sharp downregulation of c-Myc and cyclin D1 proteins. Strikingly, endogenous Par-4 knock down by siRNA underscored 3-AWA mediated inhibition of nuclear ß-catenin was Par-4 dependent and suppression of Par-4 activity, either by Bcl-2 or by Ras transfection, restored the nuclear ß-catenin level suggesting Par-4 mediated ß-catenin regulation was not promiscuous. In vivo results further demonstrated that 3-AWA was effective inhibitor of tumor growth and immunohistochemical studies indicated that increased expression of total ß-catenin and decreased expression of phospho-ß-catenin and Par-4 in breast cancer tissues as compared to normal breast tissue suggesting Par-4 and ß-catenin proteins are mutually regulated and inversely co-related in normal as well as cancer condition. Thus, strategic regulation of intracellular Par-4 by 3-AWA in diverse cancers could be an effective tool to control cancer cell metastasis. Conclusively, this report puts forward a novel approach of controlling deregulated ß-catenin signaling by 3-AWA induced Par-4 protein.


Asunto(s)
Antineoplásicos Fitogénicos/administración & dosificación , Proteínas Reguladoras de la Apoptosis/metabolismo , Neoplasias/tratamiento farmacológico , Witanólidos/agonistas , beta Catenina/metabolismo , Animales , Antineoplásicos Fitogénicos/farmacología , Apoptosis , Línea Celular Tumoral , Transición Epitelial-Mesenquimal/efectos de los fármacos , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Células MCF-7 , Ratones , Neoplasias/metabolismo , Fosforilación/efectos de los fármacos , Plantas Medicinales/química , Transducción de Señal/efectos de los fármacos
15.
Life Sci ; 142: 76-85, 2015 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-26482203

RESUMEN

AIMS: Cisplatin is one of the most potent chemotherapeutic agents acting against a variety of tumors, however, its use is mainly limited due to the dose limiting toxicities and acquired resistance to cisplatin. Folate functionalized albumin nanoparticles were developed for targeted delivery of drug to limit the adverse effects of cisplatin. MAIN METHODS: Cisplatin loaded nanoparticles functionalized with folate (CP-FA-BSA-NPs) were developed and characterized for various parameters. In order to investigate the targeting ability of folate conjugated nanoparticles, in vitro cellular uptake study was performed in folate receptor over expressing cells (MCF-7). Further, blood urea nitrogen (BUN) level, plasma creatinine level, body weight and kidney weight of the mice were measured followed by histopathological examination of various tissues to have an insight into the potential of developed formulation in the reduction of drug associated adverse effects. KEY FINDINGS: The cellular uptake studies demonstrated higher internalization of folate conjugated nanoparticles as compared to plain counterpart (CP-BSA-NPs). Following two cycles of cisplatin treatment, a week apart, BUN and plasma creatinine level were found to be significantly higher in case of free cisplatin as compared to saline, CP-BSA-NPs and CP-FA-BSA-NPs treated groups. Body weight and kidney weight of free cisplatin treated mice were significantly reduced as compared to other group. Histopathological examination of kidney from CP-BSA-NPs and CP-FA-BSA-NPs treated groups revealed no kidney damage, however, a sign of nephrotoxicity was observed in the case of free cisplatin. SIGNIFICANCE: The results demonstrated the potential of developed formulation in reducing the adverse effects of cisplatin.


Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Cisplatino , Portadores de Fármacos , Nanopartículas/química , Albúmina Sérica Bovina , Animales , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Cisplatino/química , Cisplatino/farmacocinética , Cisplatino/farmacología , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacología , Femenino , Humanos , Células MCF-7 , Ratones , Ratones Endogámicos BALB C , Albúmina Sérica Bovina/química , Albúmina Sérica Bovina/farmacocinética , Albúmina Sérica Bovina/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto
16.
Colloids Surf B Biointerfaces ; 126: 414-25, 2015 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-25601092

RESUMEN

The object of the present study was to investigate the glioma targeting propensity of folic acid (F) decorated polymer-lipid hybrid nanoparticles (PLNs) encapsulating cyclo-[Arg-Gly-Asp-D-Phe-Lys] (cRGDfK) modified paclitaxel (PtxR-FPLNs). The prepared PLNs were supposed to bypass the blood-brain barrier (BBB) efficiently and subsequently target integrin rich glioma cells. The developed formulations were characterized for size, shape, drug entrapment efficiency, and in vitro release profile. PtxR-FPLNs demonstrated highest in vitro inhibitory effect, cell apoptosis and cell uptake. Pharmacokinetics and biodistribution studies showed efficacy of PtxR-FPLNs in vivo. In vivo anti-tumor studies clearly revealed that the median survival time for Balb/C mice treated with PtxR-FPLNs (42 days) was extended significantly as compared to PtxR-PLNs (35 days), free PtxR (18 days), Ptx-FPLNs (38 days), Ptx-PLNs (30 days), free Ptx (14 days) and control group (12 days). From the results it can be concluded that the developed dual targeted nanoformulation was able to efficiently cross the BBB and significantly deliver higher amounts of drug to brain tumor for better therapeutic outcome.


Asunto(s)
Neoplasias Encefálicas/metabolismo , Encéfalo/metabolismo , Sistemas de Liberación de Medicamentos , Lípidos/química , Nanopartículas/química , Paclitaxel/farmacocinética , Polímeros/química , Animales , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Encéfalo/efectos de los fármacos , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Glioblastoma/tratamiento farmacológico , Glioblastoma/metabolismo , Glioblastoma/patología , Humanos , Ratones , Ratones Endogámicos BALB C , Paclitaxel/química , Paclitaxel/farmacología , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de Xenoinjerto
17.
BMC Cell Biol ; 15: 36, 2014 Oct 10.
Artículo en Inglés | MEDLINE | ID: mdl-25303828

RESUMEN

BACKGROUND: Resistance to chemotherapy represents a major obstacle in correcting colorectal carcinomas (CRC). Inspite of recent advances in the treatment of metastatic disease, the prognosis of the patients remains poor. RLX, a vasicinone analogue has been reported to possess potent bronchodilator, anti-asthmatic and anti-inflammatory properties. However, its anti-cancer activity is unknown. RESULTS: Here, we report for the first time that RLX has anti-cancer property against panel of human cancer cell lines and most potent activity was found against HCT-116 cells with IC50 value of 12 µM and have further investigated the involvement of NFκB and caspase-3 in RLX action in CRC apoptosis. Following RLX and BEZ-235 treatment in HCT-116, we observed significant down-regulation of NFκB (1 to 0.1 fold) and up-regulation of caspase-3 (1 to 2 fold) protein expressions. Additionally, morphological studies revealed membrane blebbing, cell shrinkage, chromatin condensation and finally apoptosis in HCT-116 cells. CONCLUSIONS: Overall, these findings indicate that RLX is a potent small molecule which triggers apoptosis, and promising potential candidate to be a chemotherapeutic agent.


Asunto(s)
Alcaloides/química , Alcaloides/farmacología , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Neoplasias Colorrectales/tratamiento farmacológico , FN-kappa B/metabolismo , Acanthaceae/química , Caspasa 3/genética , Caspasa 3/metabolismo , Movimiento Celular , Neoplasias Colorrectales/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Células HCT116 , Humanos , Potencial de la Membrana Mitocondrial , Regulación hacia Arriba/efectos de los fármacos
18.
Eur J Med Chem ; 77: 47-55, 2014 Apr 22.
Artículo en Inglés | MEDLINE | ID: mdl-24607588

RESUMEN

A facile synthetic approach to construct the O-propargyl derivatives of 4α and 4ß-(1,2,3-triazol-4-yl)-podophyllotoxin (9a-k & 10a-k) and 4'-Demethyl-4'-4ß-(1,2,3-triazol-4-yl)-epipodophyllotoxin (12a-d) were synthesized by means of click chemistry. The chemical structures were confirmed by (1)H, (13)C, 2D NMR and HRMS spectral analysis and their cytotoxicities were measured against diverse human cancer cell lines viz. PC-3, PANC-1, COLO-205 and A-549 by MTT assay. Some of the compounds were found more potent than the parent molecule Podophyllotoxin, like; 9a &10a, 9h &10h, 9k &10k, 10d, 8 and 12a. The most potent molecule discovered was compound 9k that exhibited the highest cytotoxicity on all the four cancer cell lines with IC50 values of 3.8-22 nM. The compound further found to induce apoptosis and strongly hindered the motility of aggressive prostate cancer PC-3 cells.


Asunto(s)
Alquinos/química , Antineoplásicos/farmacología , Antineoplásicos/toxicidad , Azidas/química , Podofilotoxina/análogos & derivados , Triazoles/farmacología , Triazoles/toxicidad , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular , Ciclización , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Podofilotoxina/síntesis química , Podofilotoxina/química , Podofilotoxina/farmacología , Podofilotoxina/toxicidad , Relación Estructura-Actividad , Triazoles/síntesis química , Triazoles/química , Células Tumorales Cultivadas
20.
Mol Pharm ; 11(3): 697-715, 2014 Mar 03.
Artículo en Inglés | MEDLINE | ID: mdl-24512060

RESUMEN

Some specific types of tumor cells and tumor endothelial cells represented CD13 proteins and act as receptors for Asn-Gly-Arg (NGR) motifs containing peptide. These CD13 receptors can be specifically recognized and bind through the specific sequence of cyclic NGR (cNGR) peptide and presented more affinity and specificity toward them. The cNGR peptide was conjugated to the poly(ethylene glycol) (PEG) terminal end in the poly(lactic-co-glycolic) acid PLGA-PEG block copolymer. Then, the ligand conjugated nanoparticles (cNGR-DNB-NPs) encapsulating docetaxel (DTX) were synthesized from preformed block copolymer by the emulsion/solvent evaporation method and characterized for different parameters. The various studies such as in vitro cytotoxicity, cell apoptosis, and cell cycle analysis presented the enhanced therapeutic potential of cNGR-DNB-NPs. The higher cellular uptake was also found in cNGR peptide anchored NPs into HUVEC and HT-1080 cells. However, free cNGR could inhibit receptor mediated intracellular uptake of NPs into both types of cells at 37 and 4 °C temperatures, revealing the involvement of receptor-mediated endocytosis. The in vivo biodistribution and antitumor efficacy studies indicated that targeted NPs have a higher therapeutic efficacy through targeting the tumor-specific site. Therefore, the study exhibited that cNGR-functionalized PEG-PLGA-NPs could be a promising approach for therapeutic applications to efficient antitumor drug delivery.


Asunto(s)
Portadores de Fármacos , Sistemas de Liberación de Medicamentos , Fibrosarcoma/tratamiento farmacológico , Nanopartículas/administración & dosificación , Oligopéptidos/administración & dosificación , Polímeros/química , Taxoides/farmacología , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Antígenos CD13/metabolismo , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Docetaxel , Fibrosarcoma/patología , Citometría de Flujo , Hemólisis/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/citología , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Humanos , Ácido Láctico/química , Macrófagos/citología , Macrófagos/efectos de los fármacos , Ratones , Ratones Endogámicos BALB C , Nanopartículas/química , Oligopéptidos/química , Fagocitosis/efectos de los fármacos , Polietilenglicoles , Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Taxoides/farmacocinética , Distribución Tisular
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