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Background@#Recent studies suggest that MEK1/2 inhibitors, including binimetinib, significantly improve malignant melanoma (MM) patient survival. Growing evidence suggests that phytochemicals, especially curcumin, can overcome drug resistance in cancer cells through a variety of mechanisms. @*Objective@#This study aims to examine curcumin’s efficacy in vitro combined with binimetinib in human MM cells. @*Methods@#We used 2D monolayer and 3D spheroid human epidermal melanocyte culture models, HEMn-MP (human epidermal melanocytes, neonatal, moderately pigmented), and two human MM cell lines, G361 and SK-MEL-2, to evaluate cell viability, proliferation, migration, death, and reactive oxygen species (ROS) production following single therapy treatment, with either curcumin or binimetinib, or a combination of both. @*Results@#Compared to MM cells treated with single therapy, those with combination therapy showed significantly decreased cell viability and increased ROS production. We observed apoptosis following both single and combination therapies. However only those who had had combination therapy had necroptosis. @*Conclusion@#Collectively, our data demonstrates that curcumin exerts significant synergistic anticancer effects on MM cells by inducing ROS and necroptosis when combined with binimetinib. Therefore, a strategy of adding curcumin to conventional anticancer agents holds promise for treating MM.
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The therapeutic effects of mesenchymal stem cells (MSCs) in musculoskeletal diseases (MSDs) have been verified in many human and animal studies. Although some tissues contain MSCs, the number of cells harvested from those tissues and rate of proliferation in vitro are not enough for continuous transplantation. In order to produce and maintain stable MSCs, many attempts are made to induce differentiation from pluripotent stem cells (iPSCs) into MSCs. In particular, it is also known that the paracrine action of stem cell-secreted factors could promote the regeneration and differentiation of target cells in damaged tissue. MicroRNAs (miRNAs), one of the secreted factors, are small non-coding RNAs that regulate the translation of a gene. It is known that miRNAs help communication between stem cells and their surrounding niches through exosomes to regulate the proliferation and differentiation of stem cells. While studies have so far been underway targeting therapeutic miRNAs of MSDs, studies on specific miRNAs secreted from MSCs are still minimal. Hence, our ultimate goal is to obtain sufficient amounts of exosomes from iPSC-MSCs and develop them into therapeutic agents, furthermore to select specific miRNAs and provide safe cell-free clinical setting as a cell-free status with purpose of delivering them to target cells. This review article focuses on stem cell therapy on MSDs, specific microRNAs regulating MSDs and updates on novel approaches.
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The therapeutic effects of mesenchymal stem cells (MSCs) in musculoskeletal diseases (MSDs) have been verified in many human and animal studies. Although some tissues contain MSCs, the number of cells harvested from those tissues and rate of proliferation in vitro are not enough for continuous transplantation. In order to produce and maintain stable MSCs, many attempts are made to induce differentiation from pluripotent stem cells (iPSCs) into MSCs. In particular, it is also known that the paracrine action of stem cell-secreted factors could promote the regeneration and differentiation of target cells in damaged tissue. MicroRNAs (miRNAs), one of the secreted factors, are small non-coding RNAs that regulate the translation of a gene. It is known that miRNAs help communication between stem cells and their surrounding niches through exosomes to regulate the proliferation and differentiation of stem cells. While studies have so far been underway targeting therapeutic miRNAs of MSDs, studies on specific miRNAs secreted from MSCs are still minimal. Hence, our ultimate goal is to obtain sufficient amounts of exosomes from iPSC-MSCs and develop them into therapeutic agents, furthermore to select specific miRNAs and provide safe cell-free clinical setting as a cell-free status with purpose of delivering them to target cells. This review article focuses on stem cell therapy on MSDs, specific microRNAs regulating MSDs and updates on novel approaches.
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BACKGROUND/OBJECTIVES@#The study was conducted to investigate the efficacy of the combination treatment of phytochemical resveratrol and the anticancer drug docetaxel (DTX) on prostate carcinoma LNCaP cells, including factors related to detailed cell death mechanisms.MATERIALS/METHODS: Using 2-dimensional monolayer and 3-dimensional spheroid culture systems, we examined the effects of resveratrol and DTX on cell viability, reactive oxygen species (ROS) levels, mitochondrial membrane potential, apoptosis, and necroptosis by MTT, flow cytometry, and Western blotting. @*RESULTS@#At concentrations not toxic to normal human prostate epithelial cells, resveratrol effectively decreased the viability of LNCaP cells depending on concentration and time. The combination treatment of resveratrol and DTX exhibited synergistic inhibitory effects on cell growth, demonstrated by an increase in the sub-G0/G1 peak, Annexin V-phycoerythrin positive cell fraction, ROS, mitochondrial dysfunction, and DNA damage response as well as concurrent activation of apoptosis and necroptosis. Apoptosis and necroptosis were rescued by pretreatment with ROS scavenger N-acetylcysteine. @*CONCLUSIONS@#We report resveratrol as an adjuvant drug candidate for improving the outcome of treatment in DTX therapy. Although the underlying mechanisms of necroptosis should be investigated comprehensively, targeting apoptosis and necroptosis simultaneously in the treatment of cancer can be a useful strategy for the development of promising drug candidates.
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Background@#Studies have reported that epithelial cell proliferation may be involved in the pathogenesis of nasal polyps (NPs). Estrogen receptor (ER)-α, one type of ER, is related to antiinflammatory action and cell survival in certain tissues. In this study, we examined the presence or absence of ER-α in NPs and healthy inferior turbinate mucosae. We also investigated the effect of dexamethasone on ER-α expression, cell viability, and apoptosis in RPMI 2650 cells. @*Methods@#Immunohistochemical staining and Western blot analysis were conducted to determine the expression of ER-α in 15 NPs and 15 healthy inferior turbinate mucosae. After treating RPMI 2650 cells with dexamethasone, ER-α expression was analyzed using Western blot analysis and cell viability was determined using the MTT assay. Western blot analysis and annexin V-phycoerythrin (PE) staining were used to examine apoptotic cell death. @*Results@#Western blot analysis showed that ER-α expression was upregulated in 13 of the 15 NP tissues. Immunohistochemical staining for ER-α confirmed the results of the Western blot analysis. When RPMI 2650 cells were treated with dexamethasone, both ER-α expression and cell viability were decreased. Furthermore, the treatment of RPMI 2650 cells with dexamethasone increased apoptotic cell death, as shown by increased levels of BAX and cleaved caspase-3, decreased levels of Bcl-2, and an increased percentage of positive annexin V-PE stained cells. @*Conclusion@#ER-α expression was higher in NPs than in healthy inferior turbinate mucosae. When RPMI 2650 cells were treated with dexamethasone, ER-α expression was downregulated, cell viability decreased, and apoptosis increased. The decreased cell viability may be related, at least in part, to the decreased ER-α protein levels, which likely contributed to the induction of apoptotic cell death in RPMI 2650 cells.
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Apigenin, a naturally occurring flavonoid, is known to exhibit significant anticancer activity. This study was designed to determine the effects of apigenin on two malignant mesothelioma cell lines, MSTO-211H and H2452, and to explore the underlying mechanism(s). Apigenin significantly inhibited cell viability with a concomitant increase in intracellular reactive oxygen species (ROS) and caused the loss of mitochondrial membrane potential (ΔΨm), and ATP depletion, resulting in apoptosis and necroptosis in monolayer cell culture. Apigenin upregulated DNA damage response proteins, including the DNA double strand break marker phospho (p)-histone H2A.X. and caused a transition delay at the G2 /M phase of cell cycle. Western blot analysis showed that apigenin treatment upregulated protein levels of cleaved caspase-3, cleaved PARP, p-MLKL, and p-RIP3 along with an increased Bax/Bcl-2 ratio.ATP supplementation restored cell viability and levels of DNA damage-, apoptosisand necroptosis-related proteins that apigenin caused. In addition, N-acetylcysteine reduced ROS production and improved ΔΨm loss and cell death that were caused by apigenin. In a 3D spheroid culture model, ROS-dependent necroptosis was found to be a mechanism involved in the anti-cancer activity of apigenin against malignant mesothelioma cells. Taken together, our findings suggest that apigenin can induce ROS-dependent necroptotic cell death due to ATP depletion through mitochondrial dysfunction. This study provides us a possible mechanism underlying why apigenin could be used as a therapeutic candidate for treating malignant mesothelioma.
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Background@#Studies have reported that epithelial cell proliferation may be involved in the pathogenesis of nasal polyps (NPs). Estrogen receptor (ER)-α, one type of ER, is related to antiinflammatory action and cell survival in certain tissues. In this study, we examined the presence or absence of ER-α in NPs and healthy inferior turbinate mucosae. We also investigated the effect of dexamethasone on ER-α expression, cell viability, and apoptosis in RPMI 2650 cells. @*Methods@#Immunohistochemical staining and Western blot analysis were conducted to determine the expression of ER-α in 15 NPs and 15 healthy inferior turbinate mucosae. After treating RPMI 2650 cells with dexamethasone, ER-α expression was analyzed using Western blot analysis and cell viability was determined using the MTT assay. Western blot analysis and annexin V-phycoerythrin (PE) staining were used to examine apoptotic cell death. @*Results@#Western blot analysis showed that ER-α expression was upregulated in 13 of the 15 NP tissues. Immunohistochemical staining for ER-α confirmed the results of the Western blot analysis. When RPMI 2650 cells were treated with dexamethasone, both ER-α expression and cell viability were decreased. Furthermore, the treatment of RPMI 2650 cells with dexamethasone increased apoptotic cell death, as shown by increased levels of BAX and cleaved caspase-3, decreased levels of Bcl-2, and an increased percentage of positive annexin V-PE stained cells. @*Conclusion@#ER-α expression was higher in NPs than in healthy inferior turbinate mucosae. When RPMI 2650 cells were treated with dexamethasone, ER-α expression was downregulated, cell viability decreased, and apoptosis increased. The decreased cell viability may be related, at least in part, to the decreased ER-α protein levels, which likely contributed to the induction of apoptotic cell death in RPMI 2650 cells.
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Objective: To investigate the effect of Opuntia humifusa aqueous extract on gastric ulcers. Methods: An ethanol-induced model was used to examine the protective effect of Opuntia humifusa against gastric ulcers. The gastric ulcer index was evaluated via clinical observation and image analysis. Various inflammatory indicators were determined by RT-PCR and Western blotting assays. Results: The gastric ulcer index was reduced to 8% in the group treated with Opuntia humifusa aqueous extract compared with that in the control group. RT-PCR analysis revealed that MUC5AC expression was reduced to 39% in the control group compared with the non-treated group, whereas the omeprazole and Opuntia humifusa aqueous extract-treated groups increased the expression to 95% and 79%, respectively. Moreover, the expressions of various cytokines including TNF-α, IL-1β, and IL-6 were increased in the control group, while decreasing in Opuntia humifusa aqueous extract-treated group. Opuntia humifusa aqueous extract also suppressed the expressions of iNOS, COX-2, and its transcription factor NF-κB and increased mucus content considerably as compared to the control group. Conclusions: These results suggest that Opuntia humifusa aqueous extract is suitable as an alternative remedy for gastric ulcer treatment.
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Background@#The definitive pathologic diagnosis of cardiac sarcoidosis requires observation of a granuloma in the myocardial tissue. It is common, however, to receive a “negative” report for a clinically probable case. We would like to advise pathologists and clinicians on how to interpret “negative” biopsies. @*Methods@#Our study samples were 27 endomyocardial biopsies from 25 patients, three cardiac transplantation and an autopsied heart with suspected cardiac sarcoidosis. Pathologic, radiologic, and clinical features were compared. @*Results@#The presence of micro-granulomas or increased histiocytic infiltration was always (6/6 or 100%) associated with fatty infiltration and confluent fibrosis, and they showed radiological features of sarcoidosis. Three of five cases (60%) with fatty change and confluent fibrosis were probable for cardiac sarcoidosis on radiology. When either confluent fibrosis or fatty change was present, one-third (3/9) were radiologically probable for cardiac sarcoidosis. We interpreted cases with micro-granuloma as positive for cardiac sarcoidosis (five of 25, 20%). Cases with both confluent fibrosis and fatty change were interpreted as probable for cardiac sarcoidosis (seven of 25, 28%). Another 13 cases, including eight cases with either confluent fibrosis or fatty change, were interpreted as low probability based on endomyocardial biopsy. @*Conclusions@#The presence of micro-granuloma could be an evidence for positive diagnosis of cardiac sarcoidosis. Presence of both confluent fibrosis and fatty change is necessary for probable cardiac sarcoidosis in the absence of granuloma. Either of confluent fibrosis or fatty change may be an indirect pathological evidence but they are interpreted as nonspecific findings.
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Purpose@#We investigated the expression of Nrf2 in colorectal cancer and its correlation with clinicopathological characteristics as well as mechanisms and roles of Nrf2 expression including cell signaling pathway, survival, proliferation, and migration. @*Methods@#Nrf2 expression was measured in 12 and 30 different colorectal cancer (CRC) tissues by western blot (WB) and immunohistochemistry (IHC), respectively. SW480 cells were used for cell proliferation and cell migration tests. The correlation between the expression of Nrf2 and clinicopathologic parameters were evaluated using the chi-square or Fisher exact test. Data are expressed as the mean ± standard deviation for 3 independent experiments. P < 0.05 was considered statistically significant. @*Results@#Analysis of WB demonstrated that Nrf2 proteins were increased in CRC tissues, and decreased in normal tissues. IHC staining showed that the Nrf2 expression was elevated in CRC tissues, compared to matched normal tissues. When SW480 cells were suppressed with small interfering RNA of Nrf2, cell viability was inhibited, and cell apoptosis was increased. These results were found along with suppression of the phosphorylated form of extracellular signal-regulated kinase 1/2 and AKT. @*Conclusion@#This study suggests that overexpression of Nrf2 may be related to carcinogenesis and progression of CRC.
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Apigenin, a naturally occurring flavonoid, is known to exhibit significant anticancer activity. This study was designed to determine the effects of apigenin on two malignant mesothelioma cell lines, MSTO-211H and H2452, and to explore the underlying mechanism(s). Apigenin significantly inhibited cell viability with a concomitant increase in intracellular reactive oxygen species (ROS) and caused the loss of mitochondrial membrane potential (ΔΨm), and ATP depletion, resulting in apoptosis and necroptosis in monolayer cell culture. Apigenin upregulated DNA damage response proteins, including the DNA double strand break marker phospho (p)-histone H2A.X. and caused a transition delay at the G2 /M phase of cell cycle. Western blot analysis showed that apigenin treatment upregulated protein levels of cleaved caspase-3, cleaved PARP, p-MLKL, and p-RIP3 along with an increased Bax/Bcl-2 ratio.ATP supplementation restored cell viability and levels of DNA damage-, apoptosisand necroptosis-related proteins that apigenin caused. In addition, N-acetylcysteine reduced ROS production and improved ΔΨm loss and cell death that were caused by apigenin. In a 3D spheroid culture model, ROS-dependent necroptosis was found to be a mechanism involved in the anti-cancer activity of apigenin against malignant mesothelioma cells. Taken together, our findings suggest that apigenin can induce ROS-dependent necroptotic cell death due to ATP depletion through mitochondrial dysfunction. This study provides us a possible mechanism underlying why apigenin could be used as a therapeutic candidate for treating malignant mesothelioma.
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The affiliations were published incorrectly.
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Children who have been raped some years back may have hymenal scars. However, medical professionals are not accustomed in assessing these scars because of the lack of experience in performing physical examinations of the external genitalia of children who suffered from rape some years back. Moreover, the importance of physical examination of the victim's external genitalia is sometimes overlooked. Two cases of rape victims with hymenal scars who visited Daegu Child Sexual Abuse Response Center several years after their first sexual abuse along with a literature review are presented here.
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Criança , Feminino , Humanos , Abuso Sexual na Infância , Cicatriz , Genitália , Hímen , Exame Físico , Estupro , Delitos SexuaisRESUMO
Common methods of suicide are hanging, toxic substance ingestion, descent from height, and drowning. However, suicide by cutting the tongue is very rare and there are almost no reported cases in the literature. A 76-year-old man who had terminal gastric cancer with multiple liver metastases was found dead in his home. Upon autopsy, it was noted that his tongue was cut by a pair of scissors four times and copious blood was identified in the stomach and intestine. The total loss of blood volume was approximately 750 mL. He had also cut his finger-tip and stabbed his abdomen with a pair of scissors. We concluded that lingual artery injury by scissors was the cause of death.
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Idoso , Humanos , Abdome , Artérias , Autopsia , Volume Sanguíneo , Causas de Morte , Afogamento , Ingestão de Alimentos , Intestinos , Fígado , Metástase Neoplásica , Estômago , Neoplasias Gástricas , Suicídio , LínguaRESUMO
A 71-year-old man presented with pain in the left eye that revealed a 3x3 mm deep corneal stromal infiltrate, with a 2x2 mm epithelial defect. The patient started topical moxifloxacin, voriconazole 2%, and natamycin for 2 weeks. However, the treatment was not effective and the corneal infiltration worsened. Subsequently, the patient underwent therapeutic penetrating keratoplasty. Thick brown/gray mold colonies on Potato Corn Meal Tween 80 agar was isolated from excised corneal tissue and on slide culture many septated, and club-shaped ascospores were revealed. Histological findings also showed numerous hyphae scattered in corneal tissue. A. alternata colonies were confirmed by 18S rRNA sequencing. Intracameral voriconazole was injected every other day for 2 weeks to eliminate remaining fungi on the deep corneal stroma. The remaining corneal infiltration was improved one month after the injection. During 5 months postoperative follow up, the infection did not recurred. In conclusion, deep corneal infection of A. alternata was effectively treated with intracameral voriconazole injection.
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Idoso , Humanos , Ágar , Alternaria , Substância Própria , Seguimentos , Fungos , Hifas , Ceratite , Ceratoplastia Penetrante , Refeições , Natamicina , Polissorbatos , Solanum tuberosum , Zea maysRESUMO
BACKGROUND: Reactive oxygen species (ROS) play an important role in the induction of apoptosis under pathological conditions. Recently, a significant increase in ROS production and disrupted apoptosis mechanisms in keloids have been reported. Nuclear factor erythroid 2-related factor 2 (Nrf2) represents one of the most important cellular defense mechanisms against oxidative stress and is implicated in the regulation of apoptosis. Recently, it has been reported that Nrf2 upregulates Bcl-2, an anti-apoptotic protein. OBJECTIVE: To compare Nrf2 protein expression in normal skin tissues to keloid tissues. METHODS: ROS generation in keloid tissues was evaluated with OxyBlot analysis. Western blotting and/or immunohistochemical staining approaches were used to study expression of Nrf2 or Bcl-2 in keloid and normal skin tissues. Cellular fractionation was performed to examine subcellular distribution of Nrf2. Transfection of fibroblasts with Nrf2-specific small interfering RNA (siRNA) was conducted to understand the relationship between Nrf2 expression and apoptosis induction. RESULTS: Protein oxidation, a marker of oxidative stress, is increased in keloid tissues. Western blot analysis clearly showed that Nrf2 and Bcl-2 are downregulated in keloid tissues. Immunohistochemical staining of Nrf2 confirmed the results of the western blot analysis. Transfection of fibroblasts with the Nrf2-specific siRNA results in increased apoptosis and decreased cell viability. CONCLUSION: Collectively, our data indicate that Nrf2 expression is downregulated in keloid tissues, and that Nrf2 is involved in the development of apoptosis in Nrf2 siRNA-transfected fibroblasts. We propose that a defective antioxidant system and apoptotic dysregulation may participate in keloid pathogenesis.
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Apoptose , Western Blotting , Sobrevivência Celular , Mecanismos de Defesa , Fibroblastos , Queloide , Fator 2 Relacionado a NF-E2 , Estresse Oxidativo , Espécies Reativas de Oxigênio , RNA Interferente Pequeno , Pele , TransfecçãoRESUMO
BACKGROUND: Reactive oxygen species (ROS) play an important role in the induction of apoptosis under pathological conditions. Recently, a significant increase in ROS production and disrupted apoptosis mechanisms in keloids have been reported. Nuclear factor erythroid 2-related factor 2 (Nrf2) represents one of the most important cellular defense mechanisms against oxidative stress and is implicated in the regulation of apoptosis. Recently, it has been reported that Nrf2 upregulates Bcl-2, an anti-apoptotic protein. OBJECTIVE: To compare Nrf2 protein expression in normal skin tissues to keloid tissues. METHODS: ROS generation in keloid tissues was evaluated with OxyBlot analysis. Western blotting and/or immunohistochemical staining approaches were used to study expression of Nrf2 or Bcl-2 in keloid and normal skin tissues. Cellular fractionation was performed to examine subcellular distribution of Nrf2. Transfection of fibroblasts with Nrf2-specific small interfering RNA (siRNA) was conducted to understand the relationship between Nrf2 expression and apoptosis induction. RESULTS: Protein oxidation, a marker of oxidative stress, is increased in keloid tissues. Western blot analysis clearly showed that Nrf2 and Bcl-2 are downregulated in keloid tissues. Immunohistochemical staining of Nrf2 confirmed the results of the western blot analysis. Transfection of fibroblasts with the Nrf2-specific siRNA results in increased apoptosis and decreased cell viability. CONCLUSION: Collectively, our data indicate that Nrf2 expression is downregulated in keloid tissues, and that Nrf2 is involved in the development of apoptosis in Nrf2 siRNA-transfected fibroblasts. We propose that a defective antioxidant system and apoptotic dysregulation may participate in keloid pathogenesis.
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Apoptose , Western Blotting , Sobrevivência Celular , Mecanismos de Defesa , Fibroblastos , Queloide , Fator 2 Relacionado a NF-E2 , Estresse Oxidativo , Espécies Reativas de Oxigênio , RNA Interferente Pequeno , Pele , TransfecçãoRESUMO
PURPOSE: Transforming growth factor-beta1 (TGF-beta1) plays a dual role in apoptosis and in proapoptotic responses in the support of survival in a variety of cells. The aim of this study was to determine the function of TGF-beta1 in bladder cancer cells. MATERIALS AND METHODS: The role of TGF-beta1 in bladder cancer cells was examined by observing cell viability by using the tetrazolium dye (MTT) assay after treating the bladder cancer cell lines 253J, 5637, T24, J82, HT1197, and HT1376 with TGF-beta1. Among these cell lines, the 253J and T24 cell lines were coincubated with TGF-beta1 and the pan anti-TGF-beta antibody. Fluorescence-activated cell sorter (FACS) analysis was performed to determine the mechanism involved after TGF-beta1 treatment in 253J cells. RESULTS: All six cell lines showed inhibited cellular growth after TGF-beta1 treatment. Although the T24 and J82 cell lines also showed inhibited cellular growth, the growth inhibition was less than that observed in the other 4 cell lines. The addition of pan anti-TGF-beta antibodies to the culture media restored the growth properties that had been inhibited by TGF-beta1. FACS analysis was performed in the 253J cells and the 253J cells with TGF-beta1. There were no significant differences in the cell cycle between the two treatments. However, there were more apoptotic cells in the TGF-beta1-treated 253J cells. CONCLUSIONS: TGF-beta1 did not stimulate cellular proliferation but was a growth inhibitory factor in bladder cancer cells. However, the pattern of its effects depended on the cell line. TGF-beta1 achieved growth inhibition by enhancing the level of apoptosis.
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Humanos , Antineoplásicos/administração & dosagem , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Separação Celular/métodos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Citometria de Fluxo/métodos , Fator de Crescimento Transformador beta1/administração & dosagem , Neoplasias da Bexiga Urinária/patologiaRESUMO
Mcl-1 and Bcl-xL, key anti-apoptotic proteins of the Bcl-2 family, have attracted attention as important molecules in the cell survival and drug resistance. In this study, we investigated whether inhibition of Bcl-xL influences cell growth and apoptosis against simultaneous treatment of resveratrol and clofarabine in the human malignant mesothelioma H-2452 cells. Resveratrol and clofarabine decreased Mcl-1 protein levels but had little effect on Bcl-xL levels. In the presence of two compounds, any detectable change in the Mcl-1 mRNA levels was not observed in RT-PCR analysis, whereas pretreatment with the proteasome inhibitor MG132 led to its accumulation to levels far above basal levels. The knockdown of Bcl-xL inhibited cell proliferation with cell accumulation at G2/M phase and the appearance of sub-G0/G1 peak in DNA flow cytometric assay. The suppression of cell growth was accompanied by an increase in the caspase-3/7 activity with the resultant cleavages of procaspase-3 and its substrate poly (ADP-ribose) polymerase, and increased percentage of apoptotic propensities in annexin V binding assay. Collectively, our data represent that the efficacy of resveratrol and clofarabine for apoptosis induction was substantially enhanced by Bcl-xL-lowering strategy in which the simultaneous targeting of Mcl-1 and Bcl-xL could be a more effective strategy for treating malignant mesothelioma.