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Though epigallocatechin-3-gallate (EGCG), a major compound of green tea, has anti-diabetes, anti-obesity, anti-inflammatory, and antitumor effects, the underlying antitumor molecular mechanism of EGCG was not fully understood so far. Here the sensitizing effect of EGCG to tumor-necrosis-factor-related apoptosis-inducing ligand (TRAIL) was examined in colorectal cancers. Cotreatment of EGCG and TRAIL synergistically enhanced cytotoxicity and sub G1 accumulation, increased the number of terminal deoxynucleotidyl transferase-dT-mediated dUTP nick end labelling (TUNEL)-positive cells in SW480 and HCT116 cells. Furthermore, this cotreatment promoted the cleavages of poly (adenosine diphosphate-ribose) polymerase (PARP) and induced caspase 8 activation compared to TRAIL or EGCG alone in SW480 and HCT116 cells. Of note, cotreatment of EGCG and TRAIL increased the expression of death receptor 5 (DR5) at protein and mRNA levels and also DR5 cell surface level in colon cancer cells. Conversely, depletion of DR5 reduced the apoptotic activity of cotreatment of EGCG and TRAIL to increase cytotoxicity, sub-G1 population and PARP cleavages in colon cancer cells. Overall, our findings provide evidence that EGCG can be a sensitizer of TRAIL via DR5 and caspase 8 mediated apoptosis in colorectal cancer cells.
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The underlying interaction between melatonin (MLT) and daily fruit intake still remains unclear to date, despite multibiological effects of MLT. Herein, the apoptotic mechanism by co-treatment of MLT and pterostilbene (Ptero) contained mainly in grape and blueberries was elucidated in colorectal cancers (CRCs). MLT and Ptero co-treatment (MLT+Ptero) showed synergistic cytotoxicity compared with MLT or Ptero alone, reduced the number of colonies and Ki67 expression, and also increased terminal deoxynucleotidyl transferase dUTP nick end labeling- (TUNEL) positive cells and reactive oxygen species (ROS) production in CRCs. Consistently, MLT+Ptero cleaved caspase 3 and poly (ADP-ribose) polymerase (PARP), activated sex-determining region Y-Box10 (SOX10), and also attenuated the expression of Bcl-xL, neural precursor cell expressed developmentally downregulated protein 9 (NEDD9), and SOX9 in CRCs. Additionally, MLT+Ptero induced differentially expressed microRNAs (upregulation: miR-25-5p, miR-542-5p, miR-711, miR-4725-3p, and miR-4484; downregulation: miR-4504, miR-668-3p, miR-3121-5p, miR-195-3p, and miR-5194) in HT29 cells. Consistently, MLT +Ptero upregulated miR-25-5p at mRNA level and conversely NEDD9 overexpression or miR-25-5p inhibitor reversed the ability of MLT+Ptero to increase cytotoxicity, suppress colony formation, and cleave PARP in CRCs. Furthermore, immunofluorescence confirmed miR-25-5p inhibitor reversed the reduced fluorescence of NEDD9 and increased SOX10 by MLT+Ptero in HT29 cells. Taken together, our findings provided evidence that MLT+Ptero enhances apoptosis via miR-25-5p mediated NEDD9 inhibition in colon cancer cells as a potent strategy for colorectal cancer therapy.
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[This corrects the article DOI: 10.1155/2013/879746.].
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Galbanic acid (GBA) is known a sesquiterpene coumarin to have apoptotic, anti-hypoxic, anti-proliferative, anti-hepatitis, anti-angiogenic, anti-bacteria and anti-thrombotic effects. Also, antitumor effect of GBA was reported in prostate, ovary, breast and lung cancers. Nevertheless, the underlying molecular mechanism of GBA was not fully understood to overcome chemoresistance in resistant lung cancer so far. Thus, synergistic antitumor mechanism of GBA and TNF-related apoptosis-inducing ligand (TRAIL) was elucidated in H460 and resistant H460/R non-small cell lung cancer cells (NSCLCs). Combination of GBA and TRAIL significantly exerted cytotoxicity in a dose dependent manner compared to GBA or TRAIL alone in H460/R cells. Also, GBA and TRAIL significantly increased the number of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) positive cells and sub-G1 population in a dose dependent manner in H460/R cells. Consistently, GBA and TRAIL induced cleavages of poly (ADP-ribose) polymerase (PARP), caspase-9 and caspase-8 along with upregulation of death receptor 5 (DR5) and also attenuated the expression of B-cell lymphoma-extra-large (Bcl-xL), B-cell lymphoma 2 (Bcl-2), X-linked inhibitor of apoptosis protein (XIAP) in H460/R cells. Furthermore, combination of GBA and TRAIL remarkably inhibited the expression of decoy receptor 1 (DcR1) and multidrug resistance 1(MDR1) in H460/R cells. Consistently, GBA and TRAIL effectively maintained Rhodamine 123 accumulation in H460/R cells compared to GBA or TRAIL alone by blocking multidrug efflux pump from the cells. Overall, our findings suggest that galbanic acid enhances TRAIL induced apoptosis via inhibition of MDR1 and activation of caspases and DR5 in H460/R cells as a potent TRAIL sensitizer.
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Apoptosis/efectos de los fármacos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Cumarinas/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Caspasa 8/metabolismo , Caspasa 9/metabolismo , Línea Celular Tumoral , Humanos , Neoplasias Pulmonares/metabolismo , Poli(ADP-Ribosa) Polimerasas/metabolismo , Proteína Inhibidora de la Apoptosis Ligada a X/metabolismoRESUMEN
BACKGROUND/AIM: Recently, the development of ultrasonography (US)-guided vacuum-assisted breast biopsy (VABB) has enabled the excision of benign breast tumors with normal surrounding breast tissues; thus, complete excision is possible without residual tumor tissue. We sought to identify the clinicopathological characteristics and recurrence rates of benign phyllodes tumors diagnosed by US-guided VABB. PATIENTS AND METHODS: Data from 11,221 US-guided VABBs performed at the Gangnam Cha Medical Center over 12 years were analyzed. Eighty-three lesions were diagnosed as benign phyllodes tumors; 67 with >24 months of follow-up data were investigated. All lesions were excised using an 8-gauge probe without residual tissue; patients underwent follow-up US every 3-6 months. RESULTS: Five patients (7.46%) experienced local recurrence during a mean follow-up period of 27.8 months; no distant metastases occurred. The mean tumor size was 3.0 cm in the recurrence group and 1.87 cm in the non-recurrence group (p=0.05). CONCLUSION: Benign phyllodes tumors excised and diagnosed using VABB showed a low recurrence rate during the follow-up period; thus, these tumors, particularly those <3 cm, can be safely monitored with ultrasonography instead of performing immediate re-excision.
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Neoplasias de la Mama/patología , Neoplasias de la Mama/cirugía , Biopsia Guiada por Imagen/métodos , Recurrencia Local de Neoplasia , Tumor Filoide/patología , Tumor Filoide/cirugía , Ultrasonografía Intervencional , Adolescente , Adulto , Niño , Femenino , Humanos , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Factores de Riesgo , Seúl , Factores de Tiempo , Resultado del Tratamiento , Carga Tumoral , Vacio , Adulto JovenRESUMEN
[This corrects the article DOI: 10.18632/oncotarget.2152.].
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Though Tanshinone I (Tan I), a phenolic compound from Salvia miltiorrhiza, is known to have anticancer activity in several cancers, its anticancer mechanisms are not fully understood in colon cancer cells. Thus, in the present study, the underlying molecular mechanism of Tan I was explored in HCT116 and HT29 colorectal cancer cells (CRCs). Here, Tan I suppressed viability in HCT116 and HT29 cells in a time- and dose-dependent manner. Also, Tan I increased the number of terminal deoxynucleotide transferase-mediated dUTP nick end labeling (TUNEL)-positive cells and sub-G1 population in HCT116 and HT29 cells. Consistently, Tan I cleaved poly (adenosine diphosphate-ribose) polymerase (PARP) and caspase-8, caspase-3, attenuated the expression of Bid and activated tBid as a caspase-8 substrate and activated phosphorylation of p38 MAPK in HCT116and HT29 cells. Of note, Tan I generated reactive oxygen species (ROS) and conversely an ROS scavenger, N-acetyl-L -cysteine, reversed ROS production, PARP cleavage, caspase-3 activation, and p38 MAPK phosphorylation induced by Tan I in HCT116 cells. Furthermore, p38 MAPK inhibitor SB203580 reduced cytotoxicity, increase of TUNEL-positive cells, cleavages of PARP and caspase-3 induced by Tan I in HCT116 cells. Overall, our findings for the first time suggest that ROS-dependent activation of p38 MAPK and caspase-3 is critically involved in Tan I induced apoptosis in CRCs as a potent anticancer agent.
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Abietanos/farmacología , Apoptosis/efectos de los fármacos , Neoplasias del Colon/patología , Sistema de Señalización de MAP Quinasas , Especies Reactivas de Oxígeno/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Caspasa 3/metabolismo , Caspasa 8/metabolismo , Línea Celular Tumoral , Neoplasias del Colon/tratamiento farmacológico , Células HCT116 , Células HT29 , Humanos , Fosforilación , Poli(ADP-Ribosa) Polimerasas/metabolismo , Salvia miltiorrhiza/química , Transducción de Señal/efectos de los fármacosRESUMEN
Here the underlying antitumor mechanism of melatonin and its potency as a sensitizer of paclitaxel was investigated in X02 cancer stem cells. Melatonin suppressed sphere formation and induced G2/M arrest in X02 cells expressing nestin, CD133, CXCR4, and SOX-2 as biomarkers of stemness. Furthermore, melatonin reduced the expression of CDK2, CDK4, cyclin D1, cyclin E, and c-Myc and upregulated cyclin B1 in X02 cells. Notably, genes of c-Myc related mRNAs were differentially expressed in melatonin-treated X02 cells by microarray analysis. Consistently, melatonin reduced the expression of c-Myc at mRNA and protein levels, which was blocked by MG132. Of note, overexpression of c-Myc increased the expression of nestin, while overexpression of nestin enhanced c-Myc through crosstalk despite different locations, nucleus, and cytoplasm. Interestingly, melatonin attenuated small ubiquitin-related modifier-1 (SUMO-1) more than SUMO-2 or SUMO-3 and disturbed nuclear translocation of nestin for direct binding to c-Myc by SUMOylation of SUMO-1 protein by immunofluorescence and immunoprecipitation. Also, melatonin reduced trimethylated histone H3K4me3 and H3K36me3 more than dimethylation in X02 cells by Western blotting and chromatin immunoprecipitation assay. Notably, melatonin upregulated MT1, not MT2, in X02 cells and melatonin receptor inhibitor luzindole blocked the ability of melatonin to decrease the expression of nestin, p-c-Myc(S62), and c-Myc. Furthermore, melatonin promoted cytotoxicity, sub-G1 accumulation, and apoptotic body formation by Paclitaxcel in X02 cells. Taken together, these findings suggest that melatonin inhibits stemness via suppression of c-Myc, nestin, and histone methylation via MT1 activation and promotes anticancer effect of Paclitaxcel in brain cancer stem cells.
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Neoplasias Encefálicas/tratamiento farmacológico , Metaloproteinasa 14 de la Matriz/metabolismo , Melatonina/farmacología , Células Madre Neoplásicas/metabolismo , Nestina/metabolismo , Paclitaxel/farmacología , Proteínas Proto-Oncogénicas c-myc/metabolismo , Sumoilación/efectos de los fármacos , Células A549 , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Células HEK293 , Células Hep G2 , Humanos , Metaloproteinasa 14 de la Matriz/genética , Células Madre Neoplásicas/patología , Nestina/genética , Proteínas Proto-Oncogénicas c-myc/genéticaRESUMEN
BACKGROUND/AIM: To evaluate the usefulness and safety of vacuum-assisted breast biopsy (VABB) for breast lesion diagnosis and treatment. PATIENTS AND METHODS: Clinical and histopathological data of 8,748 patients, who underwent 11,221 VABB procedures were analyzed. RESULTS: Most patients (58.2%) were <40 years old. Most lesions (39.6%) were 0.6-1.0 cm in diameter while 3.2% were ≥3.0 cm; fibroadenomas were the most common (46.6%). Eight (14% of 57) cases of atypical ductal hyperplasia were underestimated. The positive predictive values (PPVs) of breast imaging reporting and data system (BI-RADS) ultrasound category were 0.6%, 3.4%, 34.8%, 66.2%, and 93.8% for category 3, 4a, 4b, 4c, and 5 lesions, respectively. The mean number of core specimens was 9.5±8.8; the mean procedure time was 3.4±2.7 min. No residual lesions were found in 94.4% of the 7,480 patients. CONCLUSION: VABB could replace ultrasound-guided core biopsy and surgical excisional biopsy for the diagnosis of breast disease and the treatment of benign breast lesions.
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Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/terapia , Mama/patología , Biopsia Guiada por Imagen/métodos , Ultrasonografía Intervencional/métodos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biopsia con Aguja/efectos adversos , Biopsia con Aguja/métodos , Biopsia con Aguja/estadística & datos numéricos , Mama/diagnóstico por imagen , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/patología , Niño , Femenino , Humanos , Biopsia Guiada por Imagen/efectos adversos , Biopsia Guiada por Imagen/estadística & datos numéricos , Persona de Mediana Edad , Estudios Retrospectivos , Ultrasonografía Intervencional/efectos adversos , Ultrasonografía Intervencional/estadística & datos numéricos , Vacio , Adulto JovenRESUMEN
INTRODUCTION: Although many caspase inhibitors have been patented, caspase inhibitors have not entered the market due to their toxicity and poor pharmacokinetic profile. AREAS COVERED: In this article, we review patents (2013-2015) for peptide and non-peptide caspase inhibitors and their compositions. EXPERT OPINION: Noteworthy patents include a peptidic caspase-2 inhibitor for nasal administration and a peptidomimetic caspase-6 inhibitor that can be administered via several routes for the treatment of neurodegenerative diseases. Furthermore, caspase-1 inhibitors for contact dermatitis and inflammation, cardiovascular diseases, and liver diseases and a caspase-3 inhibitor for cerebral stroke have been patented. Of particular interest is the novel use of tyrosine kinase inhibitors (sunitinib and its derivatives) for the prevention and treatment of age-related ocular diseases via inhibition of the caspase-3, dual-leucine zipper kinase (DLK) and leucine zipper-bearing kinase (LZK) pathways. However, for effective clinical application of caspase inhibitors, novel peptidic and nonpeptidic caspase inhibitors with lower toxicity and improved efficacy should be developed via structural modifications, and further animal studies and preclinical and clinical trials are needed. In addition, the poor pharmacokinetic properties of classic caspase inhibitors may be improved by using advanced drug delivery systems that employ liposomes, polymers, and nanoparticles through effective administration routes.
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Inhibidores de Caspasas/farmacología , Diseño de Fármacos , Péptidos/farmacología , Animales , Inhibidores de Caspasas/administración & dosificación , Inhibidores de Caspasas/efectos adversos , Caspasas/efectos de los fármacos , Caspasas/metabolismo , Sistemas de Liberación de Medicamentos , Humanos , Patentes como Asunto , Péptidos/administración & dosificación , Péptidos/efectos adversosRESUMEN
Though ursolic acid (UA) isolated from Oldenlandia diffusa was known to exhibit anti-cancer, anti-inflammatory, and anti-obesity effects, the underlying antitumor mechanism of ursolic acid was not fully understood to date. Thus, in the present study, the apoptotic mechanism of ursolic acid was elucidated in HCT116 and HT29 colorectal cancer cells in association with STAT3 and microRNA-4500 (miR-4500) by MTT assay, Terminal deoxynucleotidyl transferase-dT-mediated dUTP nick end labelling (TUNEL) assay, cell cycle analysis, immunofluorescence, and Western blotting. Ursolic acid significantly exerted cytotoxicity, increased TUNEL positive cells and sub-G1 apoptotic portion, induced cleavage of poly (adenosine diphosphate-ribose) polymerase (PARP) and caspase 3 in HCT116 and HT29 cells. Of note, ursolic acid attenuated the expression of anti-apoptotic proteins such as Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) and also blocked nuclear translocation of STAT3 in colorectal cancer cells. Notably, ursolic acid increased the expression level of miR-4500 in HCT116 cells by qRT-PCR analysis and conversely miR-4500 inhibitor reversed cytotoxic, anti-proliferative, and apoptotic effects by increasing TUNEL positive cells, PARP cleavage and inhibiting p-STAT3 in ursolic acid treated colorectal cancer cells. Overall, our findings provide evidence that usolic acid induces apoptosis in colorectal cancer cells partially via upregulation of miR-4500 and inhibition of STAT3 phosphorylation as a potent anti-cancer agent for colorectal cancer therapy.
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Apoptosis/efectos de los fármacos , Neoplasias Colorrectales/metabolismo , MicroARNs/genética , Triterpenos/farmacología , Células HCT116 , Células HT29 , Humanos , Janus Quinasa 2/metabolismo , MicroARNs/metabolismo , Fosforilación , Poli(ADP-Ribosa) Polimerasas/metabolismo , Factor de Transcripción STAT3/metabolismo , Transducción de Señal , Regulación hacia Arriba , Ácido UrsólicoRESUMEN
INTRODUCTION: Among several genetic alterations involved in the progression of prostate cancer, B cell lymphoma gene number 2 (BCL-2) is an important target molecule in the progression of androgen-independent prostate cancer (AIPC) after androgen ablation or castration. Nevertheless, the molecular mechanism of BCL-2 in prostate cancer progression remains elusive and controversial. In the current review, we discuss the critical role of BCL-2 in the carcinogenesis of prostate cancer with experimental evidences on the BCL-2 molecular networks in AIPC and androgen-dependent prostate cancer (ADPC) and subsequently suggest perspective research targeting BCL-2. Areas covered: This review focused on the molecular implications of BCL-2 in association with other molecules and signaling pathways involved in the progression and carcinogenesis of prostate cancer. Expert opinion: BCL-2 plays a pivotal role in the progression of AIPC than in ADPC since androgen represses BCL-2. BCL-2 acts as a pro-survival molecule in association with androgen-related signaling in the progression of ADPC, while BCL-2 upregulation, PTEN loss, PI3K/AKT phosphorylation and receptor tyrosine kinase (RTK) activation are primarily involved in AIPC. To identify more effective prostate cancer therapy, further mechanistic studies are required with BCL-2 inhibitors in AIPC and ADPC, considering a multi-target therapy against BCL-2 and its related signaling.
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Andrógenos/metabolismo , Neoplasias de la Próstata/patología , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Animales , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Neoplasias de la Próstata/genética , Proteínas Proto-Oncogénicas c-bcl-2/genética , Transducción de Señal , Regulación hacia ArribaRESUMEN
Though Astragalin (kaempferol-3-glucoside) contained in Paeonia lactiflora and other plants was known to have anti-oxidant, antiinflammatory, and anti-tumor activity, the anti-tumor mechanism of Astragalin has never been reported in melanomas until now. Thus, in the present study, the underlying apoptotic mechanism of Astragalin isolated from Aceriphyllum rossii was elucidated in A375P and SK-MEL-2 melanoma cells. Astragalin exerted cytotoxicity in A375P and SK-MEL-2 cells in a concentration-dependent manner. Also, Astragalin significantly increased the number of TdT-mediated dUTP nick end labeling positive cells and sub-G1 population as a feature of apoptosis in A375P and SK-MEL-2 cells compared with untreated control. Consistently, western blotting revealed that Astragalin activated caspase 9/3 and Bax, cleaved poly (ADP-ribose) polymerase, and attenuated the expression of cyclin D1, Mcl-1, and Sry-related HMg-Box gene 10 (SOX10) in A375P and SK-MEL-2 cells. Of note, ectopic expression of SOX10 reduced the apoptotic ability of Astragalin to inhibit proliferation, cleave poly (ADP-ribose) polymerase, and caspase 3 in A375P and SK-MEL-2 melanoma cells. Overall, our findings provide evidence that Astragalin induces apoptosis in A375P and SK-MEL-2 melanoma cells via activation of caspase9/3 and inhibition of SOX10 signaling. Copyright © 2017 John Wiley & Sons, Ltd.
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Apoptosis , Caspasa 3/metabolismo , Caspasa 9/metabolismo , Quempferoles/farmacología , Melanoma/metabolismo , Factores de Transcripción SOXE/metabolismo , Neoplasias Cutáneas/metabolismo , Línea Celular Tumoral , Ciclina D1/metabolismo , Humanos , Melanoma/tratamiento farmacológico , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Poli(ADP-Ribosa) Polimerasas/metabolismo , Transducción de Señal/efectos de los fármacos , Neoplasias Cutáneas/tratamiento farmacológico , Proteína X Asociada a bcl-2/metabolismoRESUMEN
Although auraptene, a prenyloxy coumarin from Citrus species, was known to have anti-oxidant, anti-bacterial, antiinflammatory, and anti-tumor activities, the underlying anti-tumor mechanism of auraptene in prostate cancers is not fully understood to date. Thus, in the present study, we have investigated the anti-tumor mechanism of auraptene mainly in PC3 and DU145 prostate cancer cells, because auraptene suppressed the viability of androgen-independent PC3 and DU145 prostate cancer cells better than androgen-sensitive LNCaP cells. Also, auraptene notably increased sub-G1 cell population and terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells as features of apoptosis in two prostate cancer cells compared with untreated control. Consistently, auraptene cleaved poly(ADP-ribose) polymerase, activated caspase-9 and caspase-3, suppressed the expression of anti-apoptotic proteins, including Bcl-2 and myeloid cell leukemia 1 (Mcl-1), and also activated pro-apoptotic protein Bax in both prostate cancer cells. However, Mcl-1 overexpression reversed the apoptotic effect of auraptene to increase sub-G1 population and induce caspase-9/3 in both prostate cancer cells. Taken together, the results support scientific evidences that auraptene induces apoptosis in PC3 and DU145 prostate cancer cells via Mcl-1-mediated activation of caspases as a potent chemopreventive agent for prostate cancer prevention and treatment. Copyright © 2017 John Wiley & Sons, Ltd.
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Apoptosis/efectos de los fármacos , Caspasa 3/metabolismo , Caspasa 9/metabolismo , Cumarinas/farmacología , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Neoplasias de la Próstata/patología , Línea Celular Tumoral , Humanos , Masculino , Poli(ADP-Ribosa) Polimerasas/metabolismo , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteína X Asociada a bcl-2/metabolismoRESUMEN
Although obovatol, a phenolic compound from the bark of Magnolia obovata, was known to have antioxidant, neuroprotective, antiinflammatory, antithrombotic and antitumour effects, its underlying antitumour mechanism is poorly understood so far. Thus, in the present study, the antitumour molecular mechanism of obovatol was investigated in non-small cell lung cancer cells (NSCLCs). Obovatol exerted cytotoxicity in A549 and H460 NSCLCs, but not in BEAS-2B cells. Also, obovatol increased sub-G1 accumulation and early and late apoptotic portion in A549 and H460 NSCLCs. Consistently, obovatol cleaved PARP, activated caspase 9/3 and Bax and attenuated the expression of cyclin D1 in A549 and H460 NSCLCs. Interestingly, obovatol upregulated the expression of endoplasmic reticulum stress proteins such as C/EBP homologous protein (CHOP), IRE1α, ATF4 and p-elF2 in A549 and H460 NSCLCs. Conversely, depletion of CHOP blocked the apoptotic activity of obovatol to increase sub-G1 accumulation in A549 and H460 NSCLCs. Overall, our findings support scientific evidences that obovatol induces apoptosis via CHOP activation in A549 and H460 NSCLCs. Copyright © 2016 John Wiley & Sons, Ltd.
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Apoptosis/efectos de los fármacos , Compuestos de Bifenilo/química , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Éteres Fenílicos/química , Factor de Transcripción CHOP/metabolismo , Animales , Compuestos de Bifenilo/farmacología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Línea Celular Tumoral , Humanos , Neoplasias Pulmonares/metabolismo , Éteres Fenílicos/farmacologíaRESUMEN
Though Farnesiferol c (FC) has been reported to have anti-angiogenic and antitumor activity, the underlying antitumor mechanism of FC still remains unclear. Thus, in the present study, we investigated the apoptotic mechanism of FC in human H1299 and H596 non-small lung cancer cells (NSCLCs). FC significantly showed cytotoxicity, increased sub-G1 accumulation, and attenuated the expression of Bcl-2, Bcl-xL, Survivin and procaspase 3 in H1299 and H596 cells. Furthermore, FC effectively suppressed the mRNA expression of G1 arrest related genes such as Cyclin D1, E2F1 transcription factor and CDC25A by RT-PCR. Interestingly, FC inhibited the expression of c-Myc, ribosomal protein L11 (L11) and nucleolin (NCL) in H1299 and H596 cells. Of note, silencing of L11 by siRNA transfection enhanced the expression of c-Myc through a negative feedback mechanism, while c-Myc knockdown downregulated L11 in H1299 cells. Additionally, combined treatment of FC and puromycin/doxorubicin promoted the activation of caspase 9/3, and attenuated the expression of c-Myc, Cyclin D1 and CDK4 in H1299 cells compared to single treatment. Taken together, our findings suggest that FC induces apoptosis and G1 arrest via regulation of ribosomal protein L11 and c-Myc and also enhances antitumor effect of puromycin or doxorubicin in NSCLCs.
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Antineoplásicos/administración & dosificación , Apoptosis/efectos de los fármacos , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Cumarinas/administración & dosificación , Neoplasias Pulmonares/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteínas Ribosómicas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Ciclina D1/metabolismo , Quinasa 4 Dependiente de la Ciclina/metabolismo , Doxorrubicina/administración & dosificación , Quimioterapia Combinada , Puntos de Control de la Fase G1 del Ciclo Celular/efectos de los fármacos , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Puromicina/administración & dosificaciónRESUMEN
Though arjunic acid, a triterpene isolated from Terminalia arjuna, was known to have antioxidant, antiinflammatory, and cytotoxic effects, its underlying antitumor mechanism still remains unclear so far. Thus, in the present study, the molecular antitumor mechanism of arjunic acid was examined in A549 and H460 non-small cell lung cancer (NSCLC) cells. Arjunic acid exerted cytotoxicity by 3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyl tetrazolium bromide (MTT) assay and significantly increased sub-G1 population in A549 and H460 cells by cell cycle analysis. Consistently, arjunic acid cleaved poly (ADP-ribose) polymerase (PARP), activated Bax, and phosphorylation of c-Jun N-terminal kinases (JNK), and also attenuated the expression of pro-caspase-3 and Bcl-2 in A549 and H460 cells. Furthermore, arjunic acid upregulated the expression of endoplasmic reticulum (ER) stress proteins such as IRE1 α, ATF4, p-eIF2α, and C/EBP homologous protein (CHOP) in A549 and H460 cells. Conversely, CHOP depletion attenuated the increase of sub-G1 population by arjunic acid, and also JNK inhibitor SP600125 blocked the cytotoxicity and upregulation of IRE1 α and CHOP induced by arjunic acid in A549 and H460 cells. Overall, our findings suggest that arjunic acid induces apoptosis in NSCLC cells via JNK mediated ER stress pathway as a potent chemotherapeutic agent for NSCLC.
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Apoptosis/efectos de los fármacos , Carcinoma de Pulmón de Células no Pequeñas/patología , Estrés del Retículo Endoplásmico/efectos de los fármacos , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Triterpenos/farmacología , Antineoplásicos Fitogénicos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Caspasa 3/metabolismo , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral/efectos de los fármacos , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Fosforilación , Poli(ADP-Ribosa) Polimerasas/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Factor de Transcripción CHOP/metabolismo , Proteína X Asociada a bcl-2/metabolismoRESUMEN
Though special AT-rich sequence-binding protein 2 (SATB2) is reported as a transcriptional regulator of skeletal development and osteogenic differentiation, the underlying mechanism of SATB2 is not fully understood. Herein, we report that SATB2 is localized to the mitotic microtubules, the centrosome, and midbodies in mitotic cells with alpha-tubulin. Moreover, siRNA-mediated disruption of SATB2 in H460 cells caused the defect of nuclear morphology and multinucleate cells. SATB2 siRNA knockdown reduced the viability and downregulated the CDK2 expression in SKOV3 cells. Consistently, cell cycle analysis demonstrated that the silencing of SATB2 induced cell-cycle G1 arrest. Furthermore, proteosomal inhibitor MG132 treatment rescued the downregulation of CDK2 in SATB2-silenced SKOV3 cells. Taken together, our findings suggest that SATB2 regulates the mitosis of cell cycle and affects G1 cell cycle via interaction with CDK2.
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Centrosoma/metabolismo , Quinasa 2 Dependiente de la Ciclina/metabolismo , Regulación hacia Abajo , Técnicas de Silenciamiento del Gen , Proteínas de Unión a la Región de Fijación a la Matriz/metabolismo , Huso Acromático/metabolismo , Factores de Transcripción/metabolismo , Recuento de Células , Línea Celular Tumoral , Forma del Núcleo Celular/efectos de los fármacos , Centrosoma/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Puntos de Control de la Fase G1 del Ciclo Celular/efectos de los fármacos , Silenciador del Gen/efectos de los fármacos , Humanos , Leupeptinas/farmacología , Microtúbulos/efectos de los fármacos , Microtúbulos/metabolismo , Mitosis/efectos de los fármacos , Transporte de Proteínas/efectos de los fármacos , Huso Acromático/efectos de los fármacosRESUMEN
Galbanic acid (GBA), a major compound of Ferula assafoetida, was known to have cytotoxic, anti-angiogenic and apoptotic effects in prostate cancer and murine Lewis lung cancer cells; the underling apoptotic mechanism of GBA still remains unclear so far. Thus, in the present study, the apoptotic mechanism of GBA was investigated mainly in H460 non-small cell lung carcinoma (NSCLC) cells because H460 cells were most susceptible to GBA than A549, PC-9 and HCC827 NSCLC cells. Galbanic acid showed cytotoxicity in wild EGFR type H460 and A549 cells better than other mutant type PC-9 and HCC827 NSCLC cells. Also, GBA significantly increased the number of Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) positive cells and sub G1 population in H460 cells. Western blotting revealed that GBA cleaved poly (ADP-ribose) polymerase (PARP), activated Bax and caspase 9, attenuated the expression of Bcl-2, Bcl-x(L), and Myeloid cell leukemia 1 (Mcl-1) in H460 cells. However, interestingly, overexpression of Mcl-1 blocked the ability of GBA to exert cytotoxicity, activate caspase9 and Bax, cleave PARP, and increase sub G1 accumulation in H460 cells. Overall, these findings suggest that GBA induces apoptosis in H460 cells via caspase activation and Mcl-1 inhibition in H460 cells as a potent anticancer agent for NSCLC treatment.
Asunto(s)
Apoptosis/efectos de los fármacos , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Caspasas/metabolismo , Cumarinas/farmacología , Neoplasias Pulmonares/metabolismo , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Antineoplásicos Fitogénicos/farmacología , Proteínas Reguladoras de la Apoptosis/metabolismo , Línea Celular Tumoral/efectos de los fármacos , Ferula/química , Humanos , Poli(ADP-Ribosa) Polimerasas/metabolismoRESUMEN
Though tumor necrosis factor related apoptosis inducing ligand (TRAIL) has been used as a potent anticancer agent, TRAIL resistance is a hot-issue in cancer therapy. We investigated the antitumor mechanism of Tanshinone I to sensitize prostate cancer cells to TRAIL. Comibination of Tanshinone I and TRAIL exerted synergistic cytotoxicity, increased cleaved PARP, sub G1 population, the number of TUNELpositive cells, activated caspase 8, 9 and ROS production in PC-3 and DU145 cells. Of note, combination of Tanshinone I and TRAIL enhanced the protein expression of death receptor 5 (DR5) and attenuated anti-apoptotic proteins. RT-PCR and RT-qPCR analyses confirmed that co-treatment of Tanshinone I and TRAIL up-regulated DR5 and microRNA 135a-3p at mRNA level or activity of DR5 promoter and attenuated phosphorylation of extracellular signal regulated kinases in PC-3. Conversely, the silencing of DR5 blocked the increased cytotoxicity, sub G1 population and PARP cleavages induced by co-treatment of Tanshinone I and TRAIL. Interestingly, miR135a-3p mimic enhanced DR5 at mRNA, increased PARP cleavage, Bax and the number of TUNEL positive cells in Tanshinone I and TRAIL cotreated PC-3. Overall, our findings suggest that Tanshinone I enhances TRAIL mediated apoptosis via upregulation of miR135a-3p mediated DR5 in prostate cancer cells as a potent TRAIL sensitizer.