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1.
Cancer Lett ; 522: 119-128, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34534615

RESUMO

Anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs) have improved clinical outcomes in non-small cell lung cancer (NSCLC) harboring ALK- rearrangements. However, a small population of tumor cells survives due to adaptive resistance under drug pressure and ultimately acquires drug resistance. Thus, it is necessary to elucidate the mechanisms underlying the prevention of drug resistance to improve the prognosis of patients with ALK-rearranged NSCLC. We identified novel adaptive resistance, generated through c-Jun N-terminal kinase (JNK)/c-Jun signaling, to initial ALK-TKIs-alectinib and brigatinib-in ALK-rearranged NSCLC. Inhibition of JNK/c-Jun axis showed suppression of growth and promotion of apoptosis induced by ALK-TKIs in drug-tolerant cells. JNK inhibition, in combination with the use of ALK-TKIs, increased cell apoptosis through repression of the Bcl-xL proteins, compared with ALK-TKI monotherapy. Importantly, combination therapy targeting JNK and ALK significantly delayed the regrowth following cessation of these treatments. Together, our results demonstrated that JNK pathway activation plays a pivotal role in the intrinsic resistance to ALK-TKIs and the emergence of ALK-TKI-tolerant cells in ALK-rearranged NSCLC, thus indicating that optimal inhibition of tolerant signals combined with ALK-TKIs may potentially improve the outcome of ALK-rearranged NSCLC.

2.
Int J Mol Sci ; 22(16)2021 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-34445749

RESUMO

Cigarette smoking and alcohol consumption are major risk factors for lifestyle-related diseases. Although it has been reported that the combination of these habits worsens risks, the underlying mechanism remains elusive. Reactive carbonyl species (RCS) cause chemical modifications of biological molecules, leading to alterations in cellular signaling pathways, and total RCS levels have been used as a lipid peroxidation marker linked to lifestyle-related diseases. In this study, at least 41 types of RCS were identified in the lipophilic fraction of plasma samples from 40 subjects using liquid chromatography/electrospray ionization tandem mass spectrometry (LC/ESI-MS/MS). Higher levels of 10 alkanals, 5 trans-2-alkenals, 1 cis-4-alkenal, and 3 alkadienals were detected in the smoking/drinking group (N = 10) as compared to those with either habit (N = 10 each) or without both habits (N = 10) in the analysis of covariances adjusted for age and BMI. The levels of 3 alkanals, 1 trans-2-alkenal, 1 alkadienal, and 1 4-hydroxy-2-alkenal in the smoking/drinking group were significantly higher than those in the no-smoking/drinking and no-smoking/no-drinking groups. These results strongly indicate that the combination of cigarette smoking and alcohol drinking synergistically increases the level and variety of RCS in the circulating blood, and may further jeopardize cellular function.


Assuntos
Consumo de Bebidas Alcoólicas/sangue , Aldeídos/sangue , Fumar Cigarros/sangue , Cetonas/sangue , Idoso , Idoso de 80 Anos ou mais , Consumo de Bebidas Alcoólicas/efeitos adversos , Cromatografia Líquida , Fumar Cigarros/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Carbonilação Proteica , Espectrometria de Massas por Ionização por Electrospray
3.
Cancer Sci ; 112(10): 4166-4175, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34288272

RESUMO

Various molecular-targeting drugs have markedly improved the treatment of patients with breast cancer. As yet, therapies for triple-negative breast cancer are mainly cytotoxic agents. To investigate the novel therapy for triple-negative breast cancer, we herein examined the effects of a new combination therapy comprising a RAF/MEK inhibitor CH5126766, also known as VS-6766, which we originally discovered, and eribulin. The combination of CH5126766 and eribulin potently inhibited cell growth in the triple-negative breast cancer cell lines tested. The underlying mechanism in the efficacy of this combination treatment in vitro and in vivo was due to enhanced apoptosis through the suppression of survivin and Bcl-2 family proteins. We also showed the suppressed expression of programmed cell death ligand 1 (PD-L1) in combination therapy in vivo. We found that combination therapy with eribulin and CH5126766 for triple-negative breast cancer inhibited cell growth by apoptosis and raised a possibility that immune responses through suppression of PD-L1 might partially contribute to inhibition of tumor growth, indicating the potential of this combination as a novel strategy for triple-negative breast cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cumarínicos/uso terapêutico , Furanos/uso terapêutico , Cetonas/uso terapêutico , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-raf/antagonistas & inibidores , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Antígeno B7-H1/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Proteína Oncogênica v-akt/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Distribuição Aleatória , Survivina/metabolismo , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/metabolismo , Ensaio Tumoral de Célula-Tronco
4.
Cancer Gene Ther ; 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-33402732

RESUMO

Metabolic reprogramming leading to aerobic glycolysis, termed the "Warburg effect," is a critical property of cancer cells. However, the precise mechanisms underlying this phenomenon are not fully understood. A growing body of evidence indicates that γ-glutamylcyclotransferase (GGCT), an enzyme involved in glutathione homeostasis that is highly expressed in many types of cancer, represents a promising therapeutic target. In this study, we identified GGCT as a novel regulator of hypoxia-inducible factor-1α (HIF-1α), a transcription factor that plays a role in hypoxia adaptation promoting aerobic glycolysis. In multiple human cancer cell lines, depletion of GGCT downregulated HIF-1α at the mRNA and protein levels. Conversely, in NIH3T3 mouse fibroblasts, overexpression of GGCT upregulated HIF-1α under normoxia. Moreover, depletion of GGCT downregulated HIF-1α downstream target genes involved in glycolysis, whereas overexpression of GGCT upregulated those genes. Metabolomic analysis revealed that modulation of GGCT expression induced a metabolic switch from the citric acid cycle to glycolysis under normoxia. In addition, we found that GGCT regulates expression of HIF-1α protein via the AMPK-mTORC1-4E-BP1 pathway in PC3 cells. Thus GGCT regulates the expression of HIF-1α in cancer cells, causing a switch to glycolysis.

5.
J BUON ; 25(1): 464-471, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32277670

RESUMO

PURPOSE: Myxofibrosarcoma is characterized by a high rate of recurrence after surgery. Since myxofibrosarcoma is refractory to conventional cytotoxic chemotherapy, the established radical treatment is primary wide resection. The effects of histone deacetylase (HDAC) inhibitors on myxofibrosarcoma have not yet been investigated. Therefore, the main purpose of the present study was to examine the effects of a HDAC inhibitor on myxofibrosarcoma. METHODS: The effects of the HDAC inhibitor OBP-801 on human myxofibrosarcoma cells were examined using cell viability assay, flow cytometric analysis of the cell cycle and apoptosis, and Western blotting. The effects of combinations of OBP-801 with pazopanib or Akt-mTOR inhibitors were also investigated using cell viability assay. RESULTS: OBP-801 inhibited the growth of myxofibrosarcoma NMFH-1 and NMFH-2 cells. It also induced cell cycle arrest at the G2 phase and apoptosis in both cell lines. The inhibitory effects of pazopanib and Akt-mTOR inhibitors on the growth of myxofibrosarcoma cells were enhanced by the combination with OBP-801. CONCLUSIONS: The present results demonstrated that OBP-801 exerted therapeutic effects in myxofibrosarcoma in both single and concomitant administrations. Therefore, OBP-801 has potential as a novel treatment for myxofibrosarcoma.


Assuntos
Fibrossarcoma/tratamento farmacológico , Inibidores de Histona Desacetilases/uso terapêutico , Humanos
6.
Int J Oncol ; 56(3): 848-856, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32124968

RESUMO

Squamous cell lung carcinoma (SQCLC) is an aggressive type of lung cancer. In contrast with the marked advances that have been achieved in the treatment of lung adenocarcinoma, there are currently no effective targeted therapies for SQCLC, for with cytotoxic drugs are still the main treatment strategy. Therefore, the present study aimed to develop novel combination therapies for SQCLC. The results demonstrated that a combined treatment with the potent histone deacetylase (HDAC) inhibitor OBP­801 and the third­generation anthracycline amrubicin synergistically inhibited the viability of SQCLC cell lines by inducing apoptosis signal­regulating kinase 1 (ASK1)­dependent, as well as JNK­ and p38 mitogen­activated protein kinase (MAPK)­independent apoptosis. OBP­801 treatment strongly induced the protein expression levels of thioredoxin­interacting protein (TXNIP), and amrubicin treatment increased the levels of intracellular reactive oxygen species (ROS), which suggested that this combination oxidized and dissociated thioredoxin 2 (Trx2) from mitochondrial ASK1 and activated ASK1. Moreover, mouse xenograft experiments using human H520 SQCLC cells revealed that the co­treatment potently suppressed tumor growth in vivo. These results suggested that a combined treatment with OBP­801 and amrubicin may have potential as a therapeutic strategy for SQCLC.


Assuntos
Antraciclinas/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Inibidores de Histona Desacetilases/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , MAP Quinase Quinase Quinase 5/metabolismo , Peptídeos Cíclicos/administração & dosagem , Animais , Antraciclinas/farmacologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Humanos , Neoplasias Pulmonares/metabolismo , Camundongos , Peptídeos Cíclicos/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Clin Cancer Res ; 26(9): 2244-2256, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31953310

RESUMO

PURPOSE: Currently, an optimal therapeutic strategy comprising molecularly targeted agents for treating EGFR-mutated non-small cell lung cancer (NSCLC) patients with acquired resistance to osimertinib is not available. Therefore, the initial therapeutic intervention is crucial for the prolonged survival of these patients. The activation of anexelekto (AXL) signaling is known to be associated with intrinsic and acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs). In this study, we investigated the best therapeutic strategy to combat AXL-induced tolerance to EGFR-TKIs using the novel AXL inhibitor ONO-7475. EXPERIMENTAL DESIGN: We examined the efficacy of ONO-7475 in combination with EGFR-TKIs in EGFR-mutated NSCLC cells using in vitro and in vivo experiments. We investigated the correlation between AXL expression in tumors and clinical outcomes with osimertinib for EGFR-mutated NSCLC patients with acquired resistance to initial EGFR-TKIs. RESULTS: ONO-7475 sensitized AXL-overexpressing EGFR-mutant NSCLC cells to the EGFR-TKIs osimertinib and dacomitinib. In addition, ONO-7475 suppressed the emergence and maintenance of EGFR-TKI-tolerant cells. In the cell line-derived xenograft models of AXL-overexpressing EGFR-mutated lung cancer treated with osimertinib, initial combination therapy of ONO-7475 and osimertinib markedly regressed tumors and delayed tumor regrowth compared with osimertinib alone or the combination after acquired resistance to osimertinib. AXL expression in EGFR-TKI refractory tumors did not correlate with the sensitivity of osimertinib. CONCLUSIONS: These results demonstrate that ONO-7475 suppresses the emergence and maintenance of tolerant cells to the initial EGFR-TKIs, osimertinib or dacomitinib, in AXL-overexpressing EGFR-mutated NSCLC cells, suggesting that ONO-7475 and osimertinib is a highly potent combination for initial treatment.


Assuntos
Acrilamidas/farmacologia , Compostos de Anilina/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Mutação , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Quinolinas/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Animais , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos SCID , Proteínas Proto-Oncogênicas/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Oncol Lett ; 18(4): 4253-4261, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31579089

RESUMO

Sulforaphane and Lactobacilli induce apoptosis in several cancer cells. Sulforaphane, a dietary isothiocyanate, is an attractive agent due to its potent anticancer effects. Sulforaphane suppresses the proliferation of various cancer cells in vitro and in vivo. The present study investigated the effect of sulforaphane and a co-culture with Lactobacillus-treated peripheral blood mononuclear cells (PBMCs) in human colon cancer cells. The combination markedly induced apoptosis in human colon cancer HCT116 and SW480 cells. A pan-caspase inhibitor markedly inhibited apoptosis, and a tumor necrosis factor (TNF) receptor/Fc chimera partially inhibited apoptosis in both cells. The amount of TNFα secretion in the culture supernatant was significantly increased by co-culture with Lactobacillus-treated normal human PBMCs. On the other hand, the expression of cellular inhibitor of apoptosis-2 (cIAP-2), an anti-apoptotic protein, was increased by co-culture with Lactobacillus-treated PBMCs in colon cancer cells, but sulforaphane treatment significantly suppressed the induction of cIAP-2. The present results revealed that sulforaphane enhances apoptosis in human colon cancer cells under co-culture with Lactobacillus-treated PBMCs via the TNFα signaling pathway.

9.
Biochem Biophys Res Commun ; 505(4): 1203-1210, 2018 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-30327144

RESUMO

Sulindac sulfone is a metabolite of sulindac, a non-steroidal anti-inflammatory drug (NSAID), without anti-inflammatory ability. However, sulindac sulfone has been reported to significantly reduce polyps in patients with colorectal adenomatous polyposis in clinical trials. Thus, sulindac sulfone is expected to be useful for the chemoprevention of neoplasia with few side effects related to anti-inflammatory ability. To date, the molecular targets of sulindac sulfone have not yet fully investigated. Therefore, in order to newly identify sulindac sulfone-binding proteins, we generated sulindac sulfone-fixed FG beads and purified sulindac sulfone-binding proteins from human colon cancer HT-29 cells. we identified mitochondrial outer membrane proteins voltage-dependent anion channel (VDAC) 1 and VDAC2 as novel molecular targets of sulindac sulfone, and sulindac sulfone directly bound to both VDAC1 and VDAC2. Double knockdown of VDAC1 and VDAC2 by siRNA inhibited growth and arrested the cell cycle at G1 phase in HT-29 cells. Depletion of VDAC1 and VDAC2 also inhibited the mTORC1 pathway with a reduction in cyclin D1. Interestingly, these effects were consistent with those of sulindac sulfone against human colon cancer cells, suggesting that sulindac sulfone negatively regulates the function of VDAC1 and VDAC2. In the present study, our data suggested that VDAC1 and VDAC2 are direct targets of sulindac sulfone which suppresses the mTORC1 pathway and induces G1 arrest.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Antineoplásicos/farmacologia , Neoplasias do Colo/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Sulindaco/análogos & derivados , Canal de Ânion 1 Dependente de Voltagem/antagonistas & inibidores , Canal de Ânion 2 Dependente de Voltagem/antagonistas & inibidores , Trifosfato de Adenosina/biossíntese , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/metabolismo , Antineoplásicos/química , Antineoplásicos/metabolismo , Pontos de Checagem do Ciclo Celular , Neoplasias do Colo/patologia , Células HT29 , Humanos , Sulindaco/química , Sulindaco/metabolismo , Sulindaco/farmacologia , Canal de Ânion 1 Dependente de Voltagem/metabolismo , Canal de Ânion 2 Dependente de Voltagem/metabolismo
10.
Breast Cancer Res Treat ; 171(1): 43-52, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29752686

RESUMO

PURPOSE: Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. Eribulin was approved for the treatment of metastatic breast cancer through the EMBRACE trial, and a subgroup analysis in this clinical trial indicated the efficacy of eribulin in patients with TNBC. However, the prognosis of patients with TNBC is still poor due to various molecular characteristics. Therefore, there is an urgent need for a more effective treatment for the management of TNBC. METHODS: We investigated the synergistic effect of a novel histone deacetylase (HDAC) inhibitor, OBP-801, and eribulin in TNBC cell lines because OBP-801 has been known to enhance the anti-tumor activities of other chemotherapeutic agents. The cell growth was analyzed, and the flow cytometry analysis was conducted to evaluate the effects on cell cycle and the induction of apoptosis. The mechanism underlying the enhancement of inhibition of TNBC cell growth was investigated through Western blot analyses. RESULTS: The combination treatment of OBP-801 with eribulin showed the synergistic inhibition of the growth in TNBC cells, involved with the enhancement of apoptosis. We, for the first time, found that eribulin upregulated survivin and also that OBP-801 could remarkably suppress the upregulation of survivin by eribulin. Moreover, this combination potently suppressed Bcl-xL and the MAPK pathway compared with either agent alone. CONCLUSION: We found that the combination of OBP-801 and eribulin synergistically inhibited the growth with apoptosis in TNBC cells, suggesting that this combination might be a promising novel strategy for treating TNBC patients.


Assuntos
Furanos/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Cetonas/farmacologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Peptídeos Cíclicos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Survivina/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Proteína bcl-X/metabolismo , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Feminino , Humanos , Proteínas Quinases Ativadas por Mitógeno/genética , Survivina/genética , Neoplasias de Mama Triplo Negativas/genética , Proteína bcl-X/genética
11.
Oncol Rep ; 39(2): 627-632, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29207153

RESUMO

In advanced bladder cancer, cisplatin-based chemotherapy has been the standard treatment for many years, but there are many problems in terms of side-effects. Recently, a number of clinical trials using molecular-targeted agents have been conducted, and new therapies are expected that could replace conventional cytotoxic chemotherapy. We herein report that concurrent treatment with fibroblast growth factor receptor (FGFR) inhibitor BGJ398 and the novel histone deacetylase (HDAC) inhibitor OBP-801/YM753/spiruchostatin A synergistically inhibited cell growth and markedly induced apoptosis in high-grade bladder cancer cells. This combination activated caspase-3, -8 and -9, and the pan-caspase inhibitor zVAD-fmk significantly reduced the apoptotic response to the combined treatment. The combination upregulated the expression of Bim, one of the pro-apoptotic molecules. In the present study, Bim siRNA efficiently reduced apoptosis induced by the co-treatment of BGJ398 and OBP-801. Therefore, the apoptosis induced by the combination was shown to be at least partially dependent on Bim. Taken together, these results suggest that the combination of BGJ398 and OBP-801 is a novel high potential therapeutic strategy for muscle-invasive bladder cancer.


Assuntos
Antineoplásicos/farmacologia , Proteína 11 Semelhante a Bcl-2/metabolismo , Caspases/metabolismo , Peptídeos Cíclicos/farmacologia , Compostos de Fenilureia/farmacologia , Pirimidinas/farmacologia , Neoplasias da Bexiga Urinária/metabolismo , Caspase 3/metabolismo , Caspase 8/metabolismo , Caspase 9/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias da Bexiga Urinária/tratamento farmacológico
12.
Wound Repair Regen ; 25(2): 224-233, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28120534

RESUMO

Keloids are fibroproliferative diseases characterized by the accumulation of an extracellular matrix including collagen. Various growth factors, or cytokines, and their receptors are overexpressed in keloids, and they are expected to be therapy targets. Sulforaphane, a dietary isothiocyanate, has recently shown anti-tumor, anti-inflammatory, and anti-fibrotic properties. In this study, we found that sulforaphane inhibited cell growth and reduced collagen at the mRNA and protein levels in keloid fibroblasts. Moreover, sulforaphane markedly suppressed the expression of IL-6 and α-SMA and inhibited Stat3 and Smad3 signaling pathways in keloid fibroblast KF112 cells. Sulforaphane induced G2/M cell-cycle arrest with the induction of p21 in KF112 cells. In addition, sulforaphane inhibited cell growth and suppressed the expression of collagen in keloid fibroblasts under a coculture with peripheral blood mononuclear cells. Furthermore, sulforaphane suppressed IL-6, Stat3, and Smad3 signaling in the coculture system. This study suggests that sulforaphane may be a novel keloid treatment.


Assuntos
Proliferação de Células/efeitos dos fármacos , Colágeno/metabolismo , Fibroblastos/efeitos dos fármacos , Isotiocianatos/farmacologia , Queloide/tratamento farmacológico , Queloide/patologia , Western Blotting , Células Cultivadas , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/fisiologia , Fibroblastos/fisiologia , Regulação da Expressão Gênica , Humanos , Interleucina-6 , Reação em Cadeia da Polimerase em Tempo Real , Fator de Transcrição STAT3 , Transdução de Sinais/efeitos dos fármacos , Proteína Smad3
13.
Mol Cancer Ther ; 15(9): 2066-75, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27406983

RESUMO

The prognosis of muscle-invasive bladder cancer with metastasis is poor. There have been no therapeutic improvements for many years, and an innovative therapy for muscle-invasive bladder cancer has been awaited to replace the conventional cytotoxic chemotherapy. Here, we show a candidate method for the treatment of bladder cancer. The combined treatment with a novel histone deacetylase (HDAC) inhibitor, OBP-801, and celecoxib synergistically inhibited cell growth and markedly induced apoptosis through the caspase-dependent pathway in high-grade bladder cancer cells. Furthermore, the combined treatment induced expression of death receptor 5 (DR5). We identified that knockdown of DR5 by small interfering RNA (siRNA) significantly suppressed apoptosis by the combined treatment. Therefore, we conjectured that the apoptosis induced by OBP-801 and celecoxib is at least partially dependent on DR5. However, it was interesting that the combined treatment drastically suppressed expression of DR5 ligand, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). These data suggest that there is no involvement of TRAIL in the induction of apoptosis by the combination, regardless of the dependence of DR5. Moreover, xenograft studies using human bladder cancer cells showed that the combined therapy suppressed tumor growth by upregulating expressions of DR5 and Bim. The inhibition of tumor growth was significantly more potent than that of each agent alone, without significant weight loss. This combination therapy provided a greater benefit than monotherapy in vitro and in vivo These data show that the combination therapy with OBP-801 and celecoxib is a potential novel therapeutic strategy for patients with muscle-invasive bladder cancer. Mol Cancer Ther; 15(9); 2066-75. ©2016 AACR.


Assuntos
Apoptose/efeitos dos fármacos , Celecoxib/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Peptídeos Cíclicos/farmacologia , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Transdução de Sinais/efeitos dos fármacos , Neoplasias da Bexiga Urinária/metabolismo , Animais , Proteína 11 Semelhante a Bcl-2/metabolismo , Caspases/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Sinergismo Farmacológico , Feminino , Humanos , Camundongos , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/genética , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Int J Oncol ; 48(2): 854, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26648205

RESUMO

After the publication of the article, the authors noted that in Fig. 5c, the image of ß-actin is incorrect. The corrected version of Fig. 5c is shown below. In Fig. 6a, the histogarms are incorrect, and the corrected Fig. 6a is shown below. In Fig. 7, the figure of PrEC is incorrect, and the corrected Fig. 7 (PrEC) is shown below. The corrected figures demonstrate the same findings as the original figures. These corrections do not alter the interpretation of the results and conclusions. [the original article was published in the International Journal of Oncology 40: 1483-1491, 2012; DOI: 10.3892/ijo.2012.1353].

15.
PLoS One ; 10(5): e0125779, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25955843

RESUMO

Although many chemotherapeutic strategies against cancer have been developed, pancreatic cancer is one of the most aggressive and intractable types of malignancies. Therefore, new strategies and anti-cancer agents are necessary to treat this disease. Metformin is a widely used drug for type-2 diabetes, and is also known as a promising candidate anti-cancer agent from recent studies in vitro and in vivo. However, the mechanisms of metformin's anti-cancer effects have not been elucidated. We demonstrated that metformin suppressed the expression of miR-221, one of the most well-known oncogenic microRNAs, in human pancreatic cancer PANC-1 cells. Moreover, we showed that the down-regulation of miR-221 by metformin caused G1-phase arrest via the up-regulation of p27, one of the direct targets of miR-221. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is also a promising agent for cancer treatment. While recent studies showed that treatment with only TRAIL was not effective against pancreatic cancer cells, the present data showed that metformin sensitized p53-mutated pancreatic cancer cells to TRAIL. Metformin induced the expressions of death receptor 5 (DR5), a receptor for TRAIL, and Bim with a pro-apoptotic function in the downstream of TRAIL-DR5 pathway. We suggest that the up-regulation of these proteins may contribute to sensitization of TRAIL-induced apoptosis. The combination therapy of metformin and TRAIL could therefore be effective in the treatment of pancreatic cancer.


Assuntos
Antineoplásicos/toxicidade , Regulação para Baixo/efeitos dos fármacos , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Metformina/toxicidade , MicroRNAs/metabolismo , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Proteína 11 Semelhante a Bcl-2 , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Proteínas de Membrana/metabolismo , MicroRNAs/antagonistas & inibidores , Oligonucleotídeos Antissenso/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Proteínas Proto-Oncogênicas/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/toxicidade , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Regulação para Cima/efeitos dos fármacos
16.
J Dermatol Sci ; 78(1): 44-50, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25726712

RESUMO

BACKGROUND: Angiosarcoma is a rare and aggressive malignant neoplasm of endothelial cells. Recent studies have shown that the mTOR pathway is also aberrantly activated in cutaneous angiosarcoma. New therapeutic strategies are required because the prognosis of this disease is still poor. OBJECTIVE: The aim of the present study was to determine the driver gene of angiosarcoma useful for the screening of small molecule inhibitors. METHODS: We investigated the sensitivity of inhibitors for the PI3K/AKT/mTOR pathway in ISOS-1 and ISO-HAS cutaneous angiosarcoma cell lines. Flow cytometric analysis was conducted to evaluate cell-cycle progression and apoptosis. Western blot analyses were performed to elucidate the possible underlying mechanisms of growth inhibition. The colony formation assay was conducted to evaluate the clonogenic potential. We used the siRNA for PDK1 to examine the role of PDK1 on the growth of angiosarcoma cells. RESULTS: The PI3K inhibitor and mTOR inhibitor inhibited the growth of both cell lines in a dose-dependent manner. The PI3K inhibitor more effectively induced cell-cycle arrest at the G1 phase with the downregulated expression of cyclin D in ISOS-1 cells than the mTOR inhibitor. The PI3K inhibitor and mTOR inhibitor weakly but significantly induced G1 cell cycle arrest at the same degree in ISO-HAS cells. The expression of cyclin D was downregulated by the treatment with siRNA for PDK1, but not by the AKT inhibitor in ISOS-1 and ISO-HAS cells. The knock down of PDK1 with siRNA was more effective at reducing colony numbers than the mTOR inhibitor in ISOS-1 cells. CONCLUSION: These data showed that PDK1 played a pivotal role in the growth of angiosarcoma cells. Therefore, inhibition of PDK1, but not AKT, may be a more appropriate strategy than that of mTORC1 for the treatment of cutaneous angiosarcoma; the PDK1 inhibitor is promising as a therapeutic agent.


Assuntos
Proteínas Quinases Dependentes de 3-Fosfoinositídeo/metabolismo , Proliferação de Células , Hemangiossarcoma/enzimologia , Terapia de Alvo Molecular , Transdução de Sinais , Neoplasias Cutâneas/enzimologia , Proteínas Quinases Dependentes de 3-Fosfoinositídeo/genética , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ciclina D/metabolismo , Relação Dose-Resposta a Droga , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Hemangiossarcoma/tratamento farmacológico , Hemangiossarcoma/genética , Hemangiossarcoma/patologia , Humanos , Fosfatidilinositol 3-Quinase/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Interferência de RNA , Transdução de Sinais/efeitos dos fármacos , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Transfecção
17.
PLoS One ; 9(11): e113217, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25422890

RESUMO

Although melanoma is the most aggressive skin cancer, recent advances in BRAF and/or MEK inhibitors against BRAF-mutated melanoma have improved survival rates. Despite these advances, a treatment strategy targeting NRAS-mutated melanoma has not yet been elucidated. We discovered CH5126766/RO5126766 as a potent and selective dual RAF/MEK inhibitor currently under early clinical trials. We examined the activity of CH5126766/RO5126766 in a panel of malignant tumor cell lines including melanoma with a BRAF or NRAS mutation. Eight cell lines including melanoma were assessed for their sensitivity to the BRAF, MEK, or RAF/MEK inhibitor using in vitro growth assays. CH5126766/RO5126766 induced G1 cell cycle arrest in two melanoma cell lines with the BRAF V600E or NRAS mutation. In these cells, the G1 cell cycle arrest was accompanied by up-regulation of the cyclin-dependent kinase inhibitor p27 and down-regulation of cyclinD1. CH5126766/RO5126766 was more effective at reducing colony formation than a MEK inhibitor in NRAS- or KRAS-mutated cells. In the RAS-mutated cells, CH5126766/RO5126766 suppressed the MEK reactivation caused by a MEK inhibitor. In addition, CH5126766/RO5126766 suppressed the tumor growth in SK-MEL-2 xenograft model. The present study indicates that CH5126766/RO5126766 is an attractive RAF/MEK inhibitor in RAS-mutated malignant tumor cells including melanoma.


Assuntos
Cumarínicos/farmacologia , Genes ras , Mutação , Neoplasias/patologia , Inibidores de Proteínas Quinases/farmacologia , Animais , Linhagem Celular Tumoral , Cumarínicos/uso terapêutico , Humanos , MAP Quinase Quinase Quinases/antagonistas & inibidores , Camundongos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Inibidores de Proteínas Quinases/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto , Quinases raf/antagonistas & inibidores
18.
Sci Rep ; 4: 6000, 2014 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-25102912

RESUMO

A combined therapy of sulindac sulfide and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising strategy for the treatment of cancer. Sulindac sulfide had been shown to induce the expression of death receptor 5 (DR5), a receptor for TRAIL, and sensitize cancer cells to TRAIL-induced apoptosis; however, the molecular mechanism underlying the upregulation of DR5 has not yet been elucidated. We demonstrate here that myeloid zinc finger 1 (MZF1) mediates the induction of DR5 by sulindac sulfide. Sulindac sulfide induced the expression of DR5 at the protein and mRNA levels in colon cancer SW480 cells. Furthermore, sulindac sulfide increased DR5 promoter activity. We showed that sulindac sulfide stimulated DR5 promoter activity via the -301 to -253 region. This region contained a putative MZF1-binding site. Site-directed mutations in the site abrogated the enhancement in DR5 promoter activity by sulindac sulfide. MZF1 directly bound to the putative MZF1-binding site of the DR5 promoter and the binding was increased by sulindac sulfide. The expression of MZF1 was also increased by sulindac sulfide, and MZF1 siRNA attenuated the upregulation of DR5 by sulindac sulfide. These results indicate that sulindac sulfide induces the expression of DR5 by up-regulating MZF1.


Assuntos
Antineoplásicos/farmacologia , Fatores de Transcrição Kruppel-Like/metabolismo , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Sulindaco/análogos & derivados , Regulação para Cima/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Sítios de Ligação , Linhagem Celular Tumoral , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Fragmentação do DNA/efeitos dos fármacos , Células HCT116 , Humanos , Fatores de Transcrição Kruppel-Like/antagonistas & inibidores , Fatores de Transcrição Kruppel-Like/genética , Mutagênese Sítio-Dirigida , Regiões Promotoras Genéticas , Interferência de RNA , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/metabolismo , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/genética , Sulindaco/farmacologia , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia
19.
Nihon Eiseigaku Zasshi ; 69(1): 8-14, 2014.
Artigo em Japonês | MEDLINE | ID: mdl-24476590

RESUMO

The development of methods of cancer prevention is a particularly important issue. We have proposed a strategy termed "combination-oriented molecular-targeting prevention" of cancer. As the molecular target of our model, we focused on the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its receptor. TRAIL is a cytokine from immune cells and is important for immune surveillance and defense mechanisms against cancer cells. First, we searched for food factors inducing the expression of death receptor 5 (DR5), one of the TRAIL receptors. DR5 is specifically expressed on the membrane of cancer cells, not on that of normal cells. We found that many food factors markedly induced DR5 expression, enhancing TRAIL sensitivity against cancer cells. We next found that lactic acid bacteria induced endogenous TRAIL production in human peripheral blood mononuclear cells (PBMCs). Importantly, lactic acid bacteria increased the NK activity of PBMCs against cancer cells. Moreover, we found that butyric acid bacterium, one of the antiflatulents, induced the release of endogenous TRAIL from polymorphonuclear neutrophils. The butyric acid bacterium was proven effective against cancer cells by inducing apoptosis in vivo as well as in vitro. Taken together, these results strongly suggest that the strategy of "combination of DR5-inducing food factors and TRAIL-inducing food factors" as molecular-targeting prevention of cancer will be a practical approach.


Assuntos
Apoptose/efeitos dos fármacos , Terapia de Alvo Molecular , Neoplasias/prevenção & controle , Neoplasias/terapia , Animais , Humanos , Leucócitos Mononucleares/metabolismo , Terapia de Alvo Molecular/métodos , Neoplasias/imunologia , Transdução de Sinais , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo
20.
Oncol Rep ; 31(2): 947-54, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24276615

RESUMO

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is known to cause apoptosis in several types of malignant tumor cells through its interaction with the death domain-containing receptor, death receptor 5 (DR5). In the present study, we showed that co-treatment with troglitazone (TGZ), a synthetic ligand of peroxisome proliferator-activated receptor γ (PPARγ), and TRAIL synergistically induced apoptosis through DR5 upregulation in human colon cancer DLD-1 cells. TGZ elevated DR5 expression at the promoter level through the CCAAT/enhancer-binding protein homologous protein (CHOP) binding site. These results suggest that combined treatment with TGZ and TRAIL may be promising as a new therapy against malignant tumors.


Assuntos
Apoptose/genética , Cromanos/farmacologia , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/genética , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia , Tiazolidinedionas/farmacologia , Fator de Transcrição CHOP/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/farmacologia , Sítios de Ligação , Linhagem Celular Tumoral , Neoplasias do Colo/patologia , Sinergismo Farmacológico , Estresse do Retículo Endoplasmático/fisiologia , Humanos , PPAR gama , Regiões Promotoras Genéticas , Ligação Proteica , Interferência de RNA , RNA Interferente Pequeno , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/biossíntese , Fator de Transcrição CHOP/biossíntese , Fator de Transcrição CHOP/genética , Troglitazona
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