RESUMEN

Rotenone is a pesticide that causes complex I inhibition and is widely known to induce motor disability and experimental Parkinson's disease (PD) in rodents. Evidence suggests a crucial role for sirtuin/nuclear factor-kappaB/nod-like receptor family, pyrin domain-containing 3 (SIRT1/NFκB/NLRP3) signaling and inflammation in PD and rotenone neurotoxicity. Hesperetin (C16H14O6) is a citrus flavonoid with documented anti-inflammatory activity. We investigated the value of hesperetin in delaying rotenone-induced PD in mice and the possible modulation of inflammatory burden. PD was induced in mice via rotenone injections. Groups were assigned as a vehicle, PD, or PD + hesperetin (50 or 100 mg/kg) and compared for the motor function, protein level (by ELISA), and gene expression (by real-time PCR) of the target proteins, histopathology, and immunohistochemistry for tyrosine hydroxylase enzyme. Hesperetin (50 or 100 mg/kg) alleviated the motor disability and the striatal dopamine level and decreased the expression of NLRP3 and NF-κB but increased SIRT1 expression (p < 0.05). Further, it enhanced the neural viability and significantly decreased neural degeneration in the substantia nigra, hippocampus, and cerebral cortex (p < 0.05). Taken together, we propose that hesperetin mediates its neuroprotective function via alleviating modulation of the SIRT1/NFκB/NLRP3 pathway. Therefore, hesperetin might delay the PD progression.

RESUMEN

Postmenopausal osteoporosis is a common and disabling disorder that increases the risk of bone fractures due to estrogen deprivation; this can be simulated in rats by ovariectomy. Hypoxia inducible factor-1 alpha (HIF-1α) expression in osteoclasts predominantly leads to its activation increasing bone resorption. Premenopausal, estrogen prevents HIF-1α expression maintaining bone density. Unfortunately postmenopausal estrogen replacement therapy is not recommended due to its potential tumor development risk. Isoquercitrin, a common edible plants phytoestrogen, is known to inhibit HIF-1α. This study was conducted to investigate the potential antiosteoporotic activity of isoquercitrin (15, 30 and 60 mg/kg/day) in ovariectomized rats with reference to 17ß-estradiol (25 mcg/kg/day). Animals were bilaterally ovariectomized to induce osteoporosis and one month later they were assigned into groups and administered isoquercitrin and 17ß-estradiol for 8 weeks. Ovariectomy reduced lumbar compression strength, distorted bone microscopic architecture, inducing cartilage and trabecular dystrophy, and increased the markers of bone turnover (serum alkaline phosphatase and osteocalcin and urinary calcium, phosphorus and creatinine). It also increased the gene expression of HIF-1α and the levels of nuclear factor-kappa B (NF-κB) and decreased the expression of vascular endothelial growth factor (VEGF) and ß-catenin in the femurs. Isoquercitrin was found to improve bone histological features, increase lumbar strength and improve most of the biochemical markers of bone turnover in a manner comparable to 17ß-estradiol. Isoquercitrin also attenuated the increased HIF-1α expression while increased that of the VEGF and ß-catenin. It also decreased the levels of NF-κB. Therefore isoquercitrin may be considered a safer alternative for managing osteoporosis.

Asunto(s)

Subunidad alfa del Factor 1 Inducible por Hipoxia/antagonistas & inhibidores , Osteoporosis/tratamiento farmacológico , Quercetina/análogos & derivados , Animales , Femenino , Fémur/efectos de los fármacos , Fémur/metabolismo , Fémur/patología , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Vértebras Lumbares/efectos de los fármacos , Vértebras Lumbares/fisiología , FN-kappa B/metabolismo , Ovariectomía , Quercetina/uso terapéutico , Ratas Wistar , Factor A de Crecimiento Endotelial Vascular/genética , beta Catenina/genética

RESUMEN

Diabetic retinopathy (DR) is recognized as one of the leading causes of blindness worldwide. Searching and validation for a novel therapeutic strategy to prevent its progress are promising. This work aimed to assess the retinal protective effects of duloxetine (DLX) in Alloxan-induced diabetic mice model. Animals were equally and randomly divided to four groups (eight mice per group); group 1: is the control group, 2: diabetic group, 3&4: diabetic and after 9 weeks received DLX for 4 weeks (15 mg/kg and 30 mg/kg), respectively. Quantitative real-time PCR (qPCR) analysis revealed nerve growth factor (NGF), inducible nitric oxide synthase (iNOS) and transforming growth factor beta (TGF-ß) genes upregulation in the diabetic group compared to controls. Also, increased retinal malondialdehyde (MDA) and the decline of reduced glutathione (GSH) levels were observed. The morphometric analysis of diabetic retina revealed a significant reduction in total retinal thickness compared to control. Diabetic retinal immunostaining and Western blot analyses displayed glial fibrillary acidic protein (GFAP) and vascular endothelial cell growth factor (VEGF) proteins expression upregulation as well as glucose transporter-1 (GLUT-1) downregulation comparing to controls. However, DLX-treated groups showed downregulated NGF, iNOS, and TGF-ß that was more obviously seen in the DLX-30 mg/kg group than DLX-15 mg/kg group. Furthermore, these groups showed amelioration of the oxidative markers; MDA and GSH, retaining the total retinal thickness nearly to control, GFAP and VEGF downregulation, and GLUT-1 upregulation compared to diabetic group. Taken together, it could be summarized that duloxetine can attenuate DR via the anti-inflammatory and the anti-oxidative properties as well as modulating the angiogenic and the neurotrophic factors expressions. This could hopefully pave the road to be included in the novel list of the therapeutic regimen for DR after validation in the clinic.

Asunto(s)

Retinopatía Diabética/tratamiento farmacológico , Clorhidrato de Duloxetina/uso terapéutico , Proteína Ácida Fibrilar de la Glía/metabolismo , Factores de Crecimiento Nervioso/metabolismo , Fármacos Neuroprotectores/uso terapéutico , Retina/metabolismo , Análisis de Varianza , Animales , Diabetes Mellitus Experimental , Modelos Animales de Enfermedad , Regulación hacia Abajo , Masculino , Ratones

RESUMEN

Obesity constitutes a major worldwide problem in which hyperlipidemia and insulin resistance represents adverse metabolic consequences of it. The present study was conducted to elucidate the role of raspberry ketones (RKs) in controlling body weight gain, hyperlipidemia and insulin resistance in male obese rats through affecting the expression of various adipocytokines. As Aquaporin-7 is co-related with the expression of various adipocytokines and has recently emerged as a modulator of adipocyte metabolism, the present study evaluated the effect of RKs on adipose tissue expression of aquaporin-7(AQP7) in high-fat (HF) diet-fed rats. Groups of male rats were assigned to normal, HF diet-fed control rats and RKs-treated (250 and 500 mg/kg) groups. RKs administration effectively abrogated hyperlipidemia and oxidative burden and enhanced insulin sensitivity. In addition, treatment with RKs ameliorated adipose tissue and liver indices and the reduced adipocyte diameters. Moreover, administration of the low dose of RKs ameliorated the expression of apelin and its receptor, and visfatin with upregulating adiponectin expression compared to HF diet control rats. However, both doses effectively downregulated leptin expression. It was obvious that both RKs doses revealed effectiveness in upregulating the AQP7 expression. The present data suggest the promising therapeutic role of RKs in HF diet-induced obesity that is likely attributable, at least in part, to upregulation of AQP7 expression.

Asunto(s)

Adipoquinas/genética , Tejido Adiposo/efectos de los fármacos , Acuaporinas/genética , Butanonas/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Hiperlipidemias/tratamiento farmacológico , Resistencia a la Insulina , Tejido Adiposo/metabolismo , Animales , Butanonas/uso terapéutico , Dieta Alta en Grasa/efectos adversos , Relación Dosis-Respuesta a Droga , Hiperlipidemias/complicaciones , Hiperlipidemias/genética , Hiperlipidemias/patología , Masculino , Obesidad/inducido químicamente , Obesidad/complicaciones , Ratas , Ratas Wistar

RESUMEN

Recently, nanotechnology has received great attention in war against cancer. The present study investigated the antitumor efficacy of molecularly imprinted nanopreparation of 5-fluorouracil (nano-5-FU) against Ehrlich ascites carcinoma (EAC) solid tumors grown in mice. Tumor cells were transplanted into female albino mice. Mice were allocated into 5 groups; Group 1: control EAC bearing mice. Groups 2&3: EAC-bearing mice treated orally with 5-FU (5 and 10 mg/kg) twice weekly. Groups 4&5: EAC bearing mice treated with nano-5-FU (5 and 10 mg/kg) twice weekly. Treatment with nano-5-FU showed higher antitumor effect compared to free 5-FU as indicated by enhanced apoptosis and reduction in tumor weight. Additionally, lower number of mitotic figures and greater area for necrosis were observed in the tumor specimens alongside with a decline in the number of intratumoral proliferating nuclei in comparison to free 5-FU. Furthermore, the results showed a significant down-regulation in tumoral expression of caspase-3 and vascular endothelial growth factor. Together, these results further support the potential of using nanotechnology to enhance anticancer efficacy of 5-FU.

Asunto(s)

Antineoplásicos/farmacología , Carcinoma de Ehrlich/tratamiento farmacológico , Fluorouracilo/farmacología , Impresión Molecular , Nanopartículas/química , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Carcinoma de Ehrlich/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Fluorouracilo/síntesis química , Fluorouracilo/química , Ratones , Tamaño de la Partícula , Relación Estructura-Actividad

RESUMEN

The current study aimed to investigate the potential protective role of boswellic acids (BAs) against doxorubicin- (DOX-) induced hepatotoxicity. Also, the possible mechanisms underlying this protection; antioxidant, as well as the modulatory effect on the Nrf2 transcription factor/hem oxygenase-1 (Nrf2/HO-1) pathway in liver tissues, was investigated. Animals were allocated to five groups: group 1: the saline control, group 2: the DOX group, animals received DOX (6 mg/kg, i.p.) weekly for a period of three weeks, and groups 3-5: animals received DOX (6 mg/kg, i.p.) weekly and received protective doses of BAs (125, 250, and 500 mg/kg/day). Treatment with BAs significantly improved the altered liver enzyme activities and oxidative stress markers. This was coupled with significant improvement in liver histopathological features. BAs increased the Nrf2 and HO-1 expression, which provided protection against DOX-induced oxidative insult. The present results demonstrated that BAs appear to scavenge ROS and inhibit lipid peroxidation and DNA damage of DOX-induced hepatotoxicity. The antioxidant efficacy of BAs might arise from its modulation of the Nrf2/HO-1 pathway and thereby protected liver from DOX-induced oxidative injury.

Asunto(s)

Antibióticos Antineoplásicos/toxicidad , Antioxidantes/farmacología , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Doxorrubicina/toxicidad , Transducción de Señal/efectos de los fármacos , Triterpenos/farmacología , Animales , Hemo-Oxigenasa 1/efectos de los fármacos , Hemo-Oxigenasa 1/metabolismo , Masculino , Proteínas de la Membrana/efectos de los fármacos , Proteínas de la Membrana/metabolismo , Ratones , Factor 2 Relacionado con NF-E2/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo/efectos de los fármacos

RESUMEN

There is evidence that inflammation and oxidative stress contribute to the neurodegenerative changes observed in Parkinson's disease. Unfortunately, there is a lack of curative treatment for this debilitating movement disorder. Boswellic acids (BAs) are pentacyclic triterpene molecules of plant origin that have been utilized for treating many inflammatory conditions. The current study was conducted to explore the protective role of BAs against rotenone-induced experimental parkinsonism. Twenty-four rats were assigned to one of four treatment groups. The first two groups were a vehicle group (no rotenone) and a rotenone control group in which rats received rotenone (1 mg/kg) every 48 h. The next 2 groups received rotenone (1 mg/kg every 48 h) plus protective oral doses of BAs (125 or 250 mg/kg daily). Rats in the rotenone group showed motor dysfunction when tested in the open-field arena and cylinder and rotarod tests. Moreover, inflammatory markers increased, whereas the dopamine level was lower in the striata of rats in the rotenone group versus those in the vehicle group. BAs taken by rats with rotenone-induced parkinsonism showed enhanced general motor performance, reduced inflammatory markers, and increased striatal dopamine level and nigral tyrosine hydroxylase immunostaining. In conclusion, BAs are promising agents in slowing the progression of Parkinson's disease if appropriate data become available about their safety and efficacy in humans.

Asunto(s)

Antiinflamatorios/farmacología , Fármacos Neuroprotectores/farmacología , Trastornos Parkinsonianos/inducido químicamente , Trastornos Parkinsonianos/tratamiento farmacológico , Rotenona/efectos adversos , Triterpenos/farmacología , Animales , Antiinflamatorios/uso terapéutico , Locomoción/efectos de los fármacos , Masculino , Fármacos Neuroprotectores/uso terapéutico , Trastornos Parkinsonianos/fisiopatología , Ratas , Triterpenos/uso terapéutico

RESUMEN

BACKGROUND: Despite the efficacy of cisplatin as a chemotherapeutic agent against various cancers, its clinical utility is limited by serious adverse reactions including nephrotoxicity. AIM: The current study aims to investigate the protective potential of tangeretin, a citrus flavone with marked antioxidant actions, against cisplatin-induced renal injury in rats. METHODS: Tangeretin was administered at 50 and 100 mg/kg p.o. for 1 week starting one day before cisplatin (7.5 mg/kg i.p.) injection. Likewise, silymarin was administered at 100 mg/kg orally. Renal function tests, histopathology, oxidative stress and inflammatory events were investigated. RESULTS: Tangeretin mitigated the increased levels of serum creatinine, blood urea nitrogen and histopathologic alterations evoked by cisplatin. It alleviated renal oxidative stress due to cisplatin by lowering lipid peroxides, nitric oxide and Nrf2 levels with concomitant enhancement of GSH and GPx. Tangeretin also suppressed the upregulated inflammatory response seen with cisplatin treatment by downregulation of activated NF-κB p65 protein expression together with its downstream effectors e.g., iNOS and TNF-α, with restoration of the anti-inflammatory interleukin IL-10. Additionally, it down-regulated the expression of caspase-3, an apoptotic marker, thus favoring renal cell survival. Importantly, tangeretin enhanced the cytotoxic actions of cisplatin in Hep3B and HCT-116 human cancer cell lines. CONCLUSION: Together, these findings accentuate the dual benefit of tangeretin: mitigation of renal injury-induced by cisplatin and enhancement of its cytotoxic effects.

Asunto(s)

Cisplatino/administración & dosificación , Flavonas/farmacología , Inflamación/patología , Riñón/patología , Estrés Oxidativo/efectos de los fármacos , Animales , Antioxidantes/farmacología , Nitrógeno de la Urea Sanguínea , Caspasa 3/metabolismo , Línea Celular Tumoral , Creatinina/sangre , Glutatión/metabolismo , Glutatión Peroxidasa/metabolismo , Humanos , Interleucina-10/metabolismo , Riñón/efectos de los fármacos , Peroxidación de Lípido/efectos de los fármacos , Masculino , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Ratas Wistar , Factor de Transcripción ReIA/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo

RESUMEN

BACKGROUND: Currently, natural products have built a well-recognized role in the management of many degenerative diseases, mainly rheumatoid arthritis. Recent studies suggest that Spirulina, a unicellular blue-green alga, may have a variety of health benefits and curative properties and is also competent of acting as an anti-inflammatory, antioxidant and recently anti-angiogenic agent. In the present study, the antioxidant and the immunomodulatory effect of Spirulina platensis as well as its anti-angiogenic effect against complete Freund's adjuvant-induced arthritis (AIA) in rat model were tested. RESULTS: We found that the development of arthritis was concealed; moreover it successfully inhibited the development of macroscopic as well as microscopic and histopathological lesions in AIA rats when compared to control. Spirulina treated group showed a higher survival rate and moreover, it reduced the clinical score of RA in a dose dependent manner. Furthermore, Spirulina decreased serum levels of COX-2, TNF-α, IL-6, TBARS, VEGF and increased serum levels of GSH compared to the RA non-treated group. CONCLUSIONS: The present study concluded that Spirulina is able to restrain the changes produced through adjuvant-induced arthritis. The suppressing effect of Spirulina could be attributed, at least in part, to anti-inflammatory, antioxidant and anti-angiogenic properties.

Asunto(s)

Inhibidores de la Angiogénesis/farmacología , Antioxidantes/farmacología , Artritis Experimental/tratamiento farmacológico , Adyuvante de Freund/efectos adversos , Spirulina/fisiología , Inhibidores de la Angiogénesis/farmacocinética , Inhibidores de la Angiogénesis/uso terapéutico , Animales , Antioxidantes/farmacocinética , Antioxidantes/uso terapéutico , Artritis Experimental/sangre , Artritis Experimental/inducido químicamente , Disponibilidad Biológica , Inmunomodulación/efectos de los fármacos , Interleucina-6/sangre , Masculino , Ratas , Ratas Wistar , Suspensiones , Factor de Necrosis Tumoral alfa/sangre , Factor A de Crecimiento Endotelial Vascular/sangre

RESUMEN

Non-alcoholic fatty liver disease (NAFLD) is closely linked to insulin resistance, oxidative stress, and cytokine imbalance. Boswellic acids, a series of pentacyclic triterpene molecules that are produced by plants in the genus Boswellia, has been traditionally used for the treatment of a variety of diseases. This study aimed at evaluating the protective effect of boswellic acids in a model of diet-induced NAFLD in rats in comparison to the standard insulin sensitizer, pioglitazone. Rats were fed with a high-fat diet (HFD) for 12 weeks to induce NAFLD. Starting from week 5, rats received boswellic acids (125 or 250 mg/kg) or pioglitazone parallel to the HFD. Feeding with HFD induced hepatic steatosis and inflammation in rats. In addition, liver index, insulin resistance index, activities of liver enzymes, and serum lipids deviated from normal. Further, serum tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and cyclooxygenase 2 were elevated; this was associated with an increase in hepatic expression of inducible nitric oxide synthase (iNOS) and formation of 4-hydroxy-2-nonenal (HNE). Rats treated with boswellic acids (125 or 250 mg/kg) or pioglitazone showed improved insulin sensitivity and a reduction in liver index, activities of liver enzymes, serum TNF-α and IL-6 as well as hepatic iNOS expression and HNE formation compared to HFD group. Furthermore, at the cellular level, boswellic acids (250 mg/kg) ameliorated the expression of thermogenesis-related mitochondrial uncoupling protein-1 and carnitine palmitoyl transferase-1 in white adipose tissues. Data from this study indicated that boswellic acids might be a promising therapy in the clinical management of NAFLD if appropriate safety and efficacy data are available.

Asunto(s)

Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Sustancias Protectoras/uso terapéutico , Tiazolidinedionas/uso terapéutico , Triterpenos/uso terapéutico , Alanina Transaminasa/sangre , Aldehídos/metabolismo , Fosfatasa Alcalina/sangre , Animales , Aspartato Aminotransferasas/sangre , Peso Corporal/efectos de los fármacos , Carnitina O-Palmitoiltransferasa/genética , Colesterol/sangre , Ciclooxigenasa 2/sangre , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Ingestión de Alimentos/efectos de los fármacos , Metabolismo Energético , Resistencia a la Insulina , Interleucina-6/sangre , Canales Iónicos/genética , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Masculino , Proteínas Mitocondriales/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo , Enfermedad del Hígado Graso no Alcohólico/sangre , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , Pioglitazona , Sustancias Protectoras/farmacología , Ratas Wistar , Tiazolidinedionas/farmacología , Triglicéridos/sangre , Triterpenos/farmacología , Factor de Necrosis Tumoral alfa/sangre , Proteína Desacopladora 1

RESUMEN

The use of innocuous naturally occurring compounds to overcome drug resistance and cancer recalcitrance is now in the forefront of cancer research. Thymoquinone (TQ) is a bioactive constituent of the volatile oil derived from seeds of Nigella sativa Linn. TQ has shown promising anti-carcinogenic and anti-tumor activities through different mechanisms. However, the effect of TQ on cell signaling and survival pathways in resistant cancer cells has not been fully delineated. Here, we report that TQ greatly inhibits doxorubicin-resistant human breast cancer MCF-7/DOX cell proliferation. TQ treatment increased cellular levels of PTEN proteins, resulting in a substantial decrease of phosphorylated Akt, a known regulator of cell survival. The PTEN expression was accompanied with elevation of PTEN mRNA. TQ arrested MCF-7/DOX cells at G2/M phase and increased cellular levels of p53 and p21 proteins. Flow cytometric analysis and agarose gel electrophoresis revealed a significant increase in Sub-G1 cell population and appearance of DNA ladders following TQ treatment, indicating cellular apoptosis. TQ-induced apoptosis was associated with disrupted mitochondrial membrane potential and activation of caspases and PARP cleavage in MCF-7/DOX cells. Moreover, TQ treatment increased Bax/Bcl2 ratio via up-regulating Bax and down-regulating Bcl2 proteins. More importantly, PTEN silencing by target specific siRNA enabled the suppression of TQ-induced apoptosis resulting in increased cell survival. Our results reveal that up-regulation of the key upstream signaling factor, PTEN, in MCF-7/DOX cells inhibited Akt phosphorylation, which ultimately causes increase in their regulatory p53 levels affecting the induction of G2/M cell cycle arrest and apoptosis. Overall results provide mechanistic insights for understanding the molecular basis and utility of the anti-tumor activity of TQ.

Asunto(s)

Apoptosis/efectos de los fármacos , Benzoquinonas/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Fosfohidrolasa PTEN/metabolismo , Benzoquinonas/química , Western Blotting , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Caspasas/metabolismo , División Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Fragmentación del ADN/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Doxorrubicina/farmacología , Femenino , Fase G2/efectos de los fármacos , Humanos , Estructura Molecular , Fosfohidrolasa PTEN/genética , Poli(ADP-Ribosa) Polimerasas/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Interferencia de ARN , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Proteína p53 Supresora de Tumor/metabolismo , Regulación hacia Arriba/efectos de los fármacos , Proteína X Asociada a bcl-2/metabolismo

RESUMEN

Cisplatin is one of the most widely used anticancer agents, displaying activity against a wide variety of tumors. However, development of drug resistance presents a challenging barrier to successful cancer treatment by cisplatin. To understand the mechanism of cisplatin resistance, we investigated the role of damaged DNA binding protein complex subunit 2 (DDB2) in cisplatin-induced cytotoxicity and apoptosis. We show that DDB2 is not required for the repair of cisplatin-induced DNA damage, but can be induced by cisplatin treatment. DDB2-deficient noncancer cells exhibit enhanced resistance to cell growth inhibition and apoptosis induced by cisplatin than cells with fully restored DDB2 function. Moreover, DDB2 expression in cisplatin-resistant ovarian cancer cell line CP70 and MCP2 was lower than their cisplatin-sensitive parental A2780 cells. Overexpression of DDB2 sensitized CP70 cells to cisplatin-induced cytotoxicity and apoptosis via activation of the caspase pathway and downregulation of antiapoptotic Bcl-2 protein. Further analysis indicates that the overexpression of DDB2 in CP70 cells downregulates Bcl-2 expression through decreasing Bcl-2 mRNA level. These results suggest that ovarian cancer cells containing high level of DDB2 become susceptible to cisplatin by undergoing enhanced apoptosis.

Asunto(s)

Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Cisplatino/farmacología , Proteínas de Unión al ADN/metabolismo , Resistencia a Antineoplásicos/efectos de los fármacos , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Western Blotting , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Proteínas de Unión al ADN/genética , Femenino , Fibroblastos/citología , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Citometría de Flujo , Humanos , Neoplasias Ováricas/tratamiento farmacológico , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa

RESUMEN

Combination of innocuous dietary components with anticancer drugs is an emerging new strategy for cancer chemotherapy to increase antitumor responses. Tangeretin is a citrus flavonoid known to inhibit cancer cell proliferation. Here, we show an enhanced response of A2780/CP70 and 2008/C13 cisplatin-resistant human ovarian cancer cells to various combination treatments of cisplatin and tangeretin. Pretreatment of cells with tangeretin before cisplatin treatment synergistically inhibited cancer cell proliferation. This combination was effective in activating apoptosis via caspase cascade as well as arresting cell cycle at G(2)-M phase. Moreover, phospho-Akt and its downstream substrates, e.g., NF-kappaB, phospho-GSK-3beta, and phospho-BAD, were downregulated upon tangeretin-cisplatin treatment. The tangeretin-cisplatin-induced apoptosis in A2780/CP70 cells was increased by phosphoinositide-3 kinase (PI3K) inhibition and siRNA-mediated Akt silencing, but reduced by overexpression of constitutively activated Akt and GSK-3beta inhibition. The overall results indicated that tangeretin exposure preconditions cisplatin-resistant human ovarian cancer cells for a conventional response to low-dose cisplatin-induced cell death occurring through downregulation of PI3K/Akt signaling pathway. Thus, effectiveness of tangeretin combinations, as a promising modality in the treatment of resistant cancers, warrants systematic clinical studies.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Cisplatino/farmacología , Flavonas/farmacología , Proteína Oncogénica v-akt/metabolismo , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/enzimología , Fosfatidilinositol 3-Quinasas/metabolismo , Apoptosis/efectos de los fármacos , División Celular/efectos de los fármacos , Procesos de Crecimiento Celular/efectos de los fármacos , Cisplatino/administración & dosificación , Regulación hacia Abajo/efectos de los fármacos , Esquema de Medicación , Sinergismo Farmacológico , Femenino , Flavonas/administración & dosificación , Fase G2/efectos de los fármacos , Glucógeno Sintasa Quinasa 3/metabolismo , Glucógeno Sintasa Quinasa 3 beta , Humanos , Neoplasias Ováricas/patología , Transducción de Señal/efectos de los fármacos

RESUMEN

The p38 MAPK is a family of serine/threonine protein kinases that play important roles in cellular responses to external stress signals, e.g. UV irradiation. To assess the role of p38 MAPK pathway in nucleotide excision repair (NER), the most versatile DNA repair pathway, we determined the efficiency of NER in cells treated with p38 MAPK inhibitor SB203580 and found that p38 MAPK is required for the prompt repair of UV-induced DNA damage CPD. We further investigated the possible mechanism through which p38 MAPK regulates NER and found that p38 MAPK mediates UV-induced histone H3 acetylation and chromatin relaxation. Moreover, p38 MAPK also regulates UV-induced DDB2 ubiquitylation and degradation via phosphorylation of the target protein. Finally, our results showed that p38 MAPK is required for the recruitment of NER factors XPC and TFIIH to UV-induced DNA damage sites. We conclude that p38 MAPK regulates chromatin remodeling as well as DDB2 degradation for facilitating NER factor assembly.

Asunto(s)

Proteínas de Unión al ADN/metabolismo , Regulación Enzimológica de la Expresión Génica , Histonas/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Cromatina/metabolismo , Inhibidores Enzimáticos/farmacología , Células HeLa , Humanos , Imidazoles/farmacología , Modelos Biológicos , Modelos Químicos , Fosforilación , Piridinas/farmacología , Ubiquitina/metabolismo , Rayos Ultravioleta