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1.
Int J Radiat Oncol Biol Phys ; 116(3): 696-697, 2023 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-37270255
2.
Int J Radiat Oncol Biol Phys ; 115(3): 719-732, 2023 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-36245124

RESUMO

PURPOSE: This study suggested that lenvatinib may incapacitate hepatocellular carcinoma (HCC) to radiation treatment by abrogating radiation-induced Src/signal transducer and the activator of transcription 3 signaling (STAT3)/nuclear factor-κB (NF-κB) to escalate radiation-induced extrinsic and intrinsic apoptosis. These findings uncover the role of targeting Src and its arbitrating epithelial-mesenchymal transition (EMT), which could increase the anti-HCC efficacy of radiation therapy (RT). Lenvatinib and sorafenib are multikinase inhibitors used to treat HCC. Lenvatinib is noninferior to sorafenib in the therapeutic response in HCC. However, whether lenvatinib intensifies the anti-HCC efficacy of RT is ambiguous. Several oncogenic kinases and transcription factors, such as Src, STAT3, and NF-κB, enhance the radiosensitivity of cancers. Therefore, we aimed to investigate the roles of the Src/STAT3/NF-κB axis in HCC after RT treatment and assessed whether targeting Src by lenvatinib may enhance the effectiveness of RT. METHODS AND MATERIALS: Hep3B, Huh7, HepG2, and SK-Hep1 HCC cells and 2 types of animal models were used to identify the efficacy of RT combined with lenvatinib. Cellular toxicity, apoptosis, DNA damage, EMT/metastasis regulation, and treatment efficacy were validated by colony formation, flow cytometry, Western blotting, and in vivo experiments, respectively. Knockdown of Src by siRNA was also used to validate the role of Src in RT treatment. RESULTS: Silencing Src reduced STAT3/NF-κB signaling and sensitized HCC to radiation. Lenvatinib reversed radiation-elicited Src/STAT3/NF-κB signaling while enhancing the anti-HCC efficacy of radiation. Both lenvatinib and siSrc promoted the radiation effect of cell proliferation on suppression, inhibition of the invasion ability, and induction of apoptosis in HCC. Lenvatinib also alleviated radiation-triggered oncogenic and EMT-related protein expression. CONCLUSIONS: Our findings uncovered the role of the Src/STAT3/NF-κB regulatory axis in response to radiation-induced toxicity and confirmed Src as the key regulatory molecule for radiosensitization of HCC evoked by lenvatinib.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Animais , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/radioterapia , NF-kappa B/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/radioterapia , Sorafenibe/farmacologia , Sorafenibe/uso terapêutico , Transição Epitelial-Mesenquimal , Negociação , Apoptose/efeitos da radiação , Linhagem Celular Tumoral , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo
3.
Anticancer Res ; 42(5): 2495-2505, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35489726

RESUMO

BACKGROUND/AIM: AKT/ERK signaling transduction and anti-apoptosis effects have both been recognized as important mediators of hepatocellular carcinoma (HCC) progression. Targeting AKT/ERK signaling and mediating apoptosis may be beneficial for alleviating HCC growth. Lenvatinib, a tyrosine kinase inhibitor, has been approved by the FDA to treat HCC since 2018 as a monotherapy with limited efficacy. Amentoflavone, a biflavonoid in natural plants, has been shown to have the potential to suppress HCC progression in previous studies. Whether the combination of lenvatinib and amentoflavone may show superior HCC suppression is unclear. MATERIALS AND METHODS: We used MTT, flow cytometry and western blotting assays to identify the role of lenvatinib and amentoflavone in both Hep3B and Huh7 cells. RESULTS: We found that amentoflavone enhances the suppressive effect of AKT/ERK signaling induced by lenvatinib and, thus, sensitizes HCC to lenvatinib. The intrinsic/extrinsic apoptosis pathways induced by lenvatinib were also boosted by amentoflavone. CONCLUSION: Amentoflavone sensitization of HCC to lenvatinib is associated with AKT/ERK inactivation and apoptosis induction.


Assuntos
Antineoplásicos , Biflavonoides , Carcinoma Hepatocelular , Neoplasias Hepáticas , Antineoplásicos/farmacologia , Apoptose , Biflavonoides/farmacologia , Biflavonoides/uso terapêutico , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Humanos , Neoplasias Hepáticas/patologia , Compostos de Fenilureia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Quinolinas
4.
J Food Biochem ; 46(7): e14128, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35312087

RESUMO

Hepatocellular carcinoma (HCC) is the most frequently occurring liver malignancy in Asia. Glycyrrhizic acid is known to reduce the risk of HCC formation in patients with chronic hepatitis C. To identify whether glycyrrhizic acid may play a role in anti-HCC therapy as an adjuvant is important. However, the inhibitory effect of glycyrrhizic acid on cell cycle progression in HCC cells and the mechanism of such have not been fully elucidated. This study used the comet assay, cell cycle analysis, immunofluorescence staining, the TUNEL assay, and Western blotting to identify the anti-HCC role of glycyrrhizic acid. Glycyrrhizic acid may induce DNA damage, apoptosis, activation of ATM, and expression of p21, and p27 in HCC cells. In addition, glycyrrhizic acid may also induce G1 phase arrest and suppress NF-κB-mediated Cyclin D1 expression. DNA damage and NF-κB inactivation may be associated with glycyrrhizic acid-induced G1 phase arrest in HCC cells.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Dano ao DNA , Ácido Glicirrízico/farmacologia , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , NF-kappa B/genética , NF-kappa B/metabolismo
5.
Anticancer Res ; 41(3): 1251-1259, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33788716

RESUMO

BACKGROUND/AIM: Sorafenib, an oral multi-kinase inhibitor, has been shown to improve the outcome of patients with osteosarcoma (OS). However, the anti-OS effect and mechanism of sorafenib has not yet been fully understood. The main purpose of this study was to investigate the effect of sorafenib on apoptotic signaling and Nuclear Factor-κB (NF-κB)-mediated anti-apoptotic and metastatic potential in OS in vitro. MATERIALS AND METHODS: The effect of sorafenib on apoptotic signaling transduction, anti-apoptotic, and metastatic potential of OS U-2 cells was verified with flow cytometry, trans-well invasion/migration, and western blotting assay. RESULTS: Sorafenib induced the extrinsic and intrinsic apoptotic pathways. In addition, sorafenib reduced the invasion and migration ability of OS cells, induced NF-κB activation, and the expression of anti-apoptotic proteins and metastasis-associated proteins encoded by NF-κB target genes. CONCLUSION: Sorafenib led to stimulation of extrinsic/intrinsic apoptotic pathways and NF-κB inactivation in U-2 OS cells.


Assuntos
Apoptose/efeitos dos fármacos , Neoplasias Ósseas/tratamento farmacológico , NF-kappa B/antagonistas & inibidores , Osteossarcoma/tratamento farmacológico , Sorafenibe/farmacologia , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Humanos , NF-kappa B/fisiologia , Invasividade Neoplásica , Metástase Neoplásica , Osteossarcoma/patologia , Osteossarcoma/secundário
6.
Biomed Pharmacother ; 128: 110319, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32502841

RESUMO

Active epidermal growth factor receptors (EGFR) signaling mediates the progression of colorectal cancer (CRC) through activation of downstream kinases and transcription factors. The increased expression of EGFR was associated with worse prognosis in patients with metastatic CRC (mCRC). Regorafenib, the oral kinase inhibitor approved for the treatment of mCRC, has been shown to reduce activation of downstream kinases of EGFR signal pathway in hepatocellular carcinoma and osteosarcoma. However, whether EGFR inactivation was participates in regorafenib-inhibited progression of CRC still remaining ambiguous. The major purpose of present study was to verify effect of regorafenib on EGFR signaling-mediated progression of CRC. Here, we investigated the effect of regorafenib or erlotinib (EGFR inhibitor) on tumor cell growth, invasion ability, apoptotic, and EGFR signal transduction in CRC in vitro and in vivo. Our results indicated regorafenib reduced EGF-induced EGFR and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activity. Both regorafenib and erlotinib significantly reduced cell invasion ability, activation of protein kinase C-δ (PKCδ), protein kinase B (AKT), extracellular signal-regulated kinases (ERK), and NF-κB. Regorafenib can trigger the inhibition of tumor cell growth and the induction of apoptosis through extrinsic/intrinsic apoptosis pathways. In addition, the expression of NF-κB-mediated proteins involved in tumor progression was also suppressed by regorafenib treatment. Taken together, regorafenib acts as a inhibitor of EGFR signaling that attenuated the activation of EGFR and EGFR related downstream signaling cascades in CRC. Our results suggested that the suppression of EGFR signaling was associated with regorafenib-inhibited progression of CRC.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Receptores ErbB/antagonistas & inibidores , Compostos de Fenilureia/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Animais , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/enzimologia , Neoplasias Colorretais/patologia , Progressão da Doença , Receptores ErbB/metabolismo , Células HT29 , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , NF-kappa B/metabolismo , Invasividade Neoplásica , Neovascularização Patológica , Proteína Quinase C-delta/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Am J Chin Med ; 48(1): 223-244, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32054305

RESUMO

A previous study presented that glycyrrhizic acid as the hepatoprotective agent inhibits total parenteral nutrition-associated acute liver injury in rats. However, the anticancer effect and mechanism of glycyrrhizic acid in human hepatocellular carcinoma (HCC) is ambiguous. The purpose of the present study was to investigate the effect of glycyrrhizic acid on apoptosis dysregulation and metastatic potential in HCC in vitro and in vivo. Both SK-Hep1 and Hep3B cells were treated with different concentrations of glycyrrhizic acid for 24 or 48h. SK-Hep1/luc2 tumor-bearing mice were treated with vehicle or glycyrrhizic acid (50mg/kg/day by intraperitoneal injection) for 7 days. Tumor cells growth, apoptotic, and metastatic signaling transduction were evaluated by using MTT assay, digital caliper, bioluminescence imaging (BLI), flow cytometry, western blotting assay, and immunohistochemistry (IHC) staining. The results demonstrated glycyrrhizic acid significantly inhibits tumor cell growth, cell invasion, and expression of AKT (Ser473), extracellular-signal-regulated kinase (ERK), epidermal growth factor receptor (EGFR) phosphorylation, anti-apoptotic and metastatic proteins in HCC in vitro and in vivo. Glycyrrhizic acid also significantly triggered apoptosis and extrinsic/intrinsic apoptotic signaling transduction. In addition, PD98059 (ERK inhibitor) and LY294002 (AKT inhibitor) obviously reduced cell invasion and expression of metastasis-associated proteins. Taken together, these results indicated that glycyrrhizic acid induces apoptosis through extrinsic/intrinsic apoptotic signaling pathways and diminishes EGFR/AKT/ERK-modulated metastatic potential in HCC in vitro and in vivo.


Assuntos
Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/tratamento farmacológico , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Ácido Glicirrízico/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Humanos , Camundongos
8.
Environ Toxicol ; 35(2): 167-175, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31714653

RESUMO

Although hepatitis B and/or hepatitis C virus were recognized as major risk factor for the development of hepatocellular carcinoma (HCC), certain occupational, environmental, and lifestyle factors also play key roles in HCC tumorigenesis. Moreover, in molecular signaling route, extracellular signal-regulated kinase (ERK)/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling was found to be overexpressed and linked to poor prognosis in HCC. Thus, to identify possible nature compound that can suppress ERK/NF-κB may be benefit to HCC patient. Magnolol, a natural compound derived from herbal plant Magnolia officinalis, has been recognized as a liver protection and antitumor reagent. However, whether magnolol-inhibited HCC progression correlates with disruption of ERK/NF-κB signaling is remained unclear. In this studies, we performed SK-Hep1/luc2 HCC bearing animal model to investigate the anticancer efficacy and mechanism of magnolol on tumor progression. Tumor size and tumor growth rate were dramatically suppressed after treatment of magnolol. In addition, expression of phospho-ERK (p-ERK), NF-κB p65 (Ser536), and tumor progression-associated proteins, such as matrix metallopeptidase 9 (MMP-9), vascular endothelial growth factor (VEGF), X-linked inhibitor of apoptosis protein (XIAP), and CyclinD1 were all significantly decreased by magnolol. Most important, major extrinsic and intrinsic apoptosis signaling factors, including active caspase-8 and caspase-9 were both enhanced by magnolol. This study indicated that apoptosis induction through extrinsic/intrinsic pathways and blockage of ERK/NF-κB activation were associated with magnolol-inhibited tumor progression in HCC in vivo.


Assuntos
Apoptose/efeitos dos fármacos , Compostos de Bifenilo/farmacologia , Carcinoma Hepatocelular/prevenção & controle , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Lignanas/farmacologia , Neoplasias Hepáticas Experimentais/prevenção & controle , NF-kappa B/metabolismo , Animais , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Progressão da Doença , Humanos , Neoplasias Hepáticas Experimentais/metabolismo , Neoplasias Hepáticas Experimentais/patologia , Medicina Tradicional Chinesa , Transdução de Sinais , Fator de Transcrição RelA/metabolismo
9.
In Vivo ; 32(3): 549-554, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29695559

RESUMO

BACKGROUND/AIM: A previous study indicated that amentoflavone inhibits tumor growth of breast cancer. However, the anti-cancer effects and mechanism of amentoflavone in hepatocellular carcinoma (HCC) have not been elucidated. The aim of the present study was to verify the effect of amentoflavone on tumor progression in HCC. MATERIALS AND METHODS: HCC SK-Hep1 cells were treated with different concentrations of amentoflavone or 10 µM PD98059 (extracellular signal-regulated kinases (ERK) inhibitor) for 48 h, respectively, and then cell viability, NF-κB activation, levels of tumor progression-associated proteins, and cell invasion were evaluated with 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), NF-κB reporter gene assay, western blotting, and cell invasion assay. RESULTS: The results demonstrated that both amentoflavone and PD98059 not only significantly reduced cell viability, NF-κB activation, and cell invasion, but also inhibited the expression of tumor progression-associated proteins. In addition, we found that amentoflavone suppresses ERK phosphorylation. CONCLUSION: The results of the present study suggest that amentoflavone down-regulates ERK-modulated tumor progression in HCC.


Assuntos
Antineoplásicos/farmacologia , Biflavonoides/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Apoptose/efeitos dos fármacos , Biomarcadores , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , NF-kappa B/metabolismo , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
10.
Biosci Rep ; 38(3)2018 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-29535278

RESUMO

Regorafenib has been demonstrated in our previous study to trigger apoptosis through suppression of extracellular signal-regulated kinase (ERK)/nuclear factor-κB (NF-κB) activation in hepatocellular carcinoma (HCC) SK-Hep1 cells in vitro However, the effect of regorafenib on NF-κB-modulated tumor progression in HCC in vivo is ambiguous. The aim of the present study is to investigate the effect of regorafenib on NF-κB-modulated tumor progression in HCC bearing mouse model. pGL4.50 luciferase reporter vector transfected SK-Hep1 (SK-Hep1/luc2) and Hep3B 2.1-7 tumor bearing mice were established and used for the present study. Mice were treated with vehicle or regorafenib (20 mg/kg/day by gavage) for 14 days. Effects of regorafenib on tumor growth and protein expression together with toxicity of regorafenib were evaluated with digital caliper and bioluminescence imaging (BLI), ex vivo Western blotting immunohistochemistry (IHC) staining, and measurement of body weight and pathological examination of liver tissue, respectively, in SK-Hep1/luc2 and Hep3B 2.1-7 tumor bearing mice. The results indicated regorafenib significantly reduced tumor growth and expression of phosphorylated ERK, NF-κB p65 (Ser536), phosphorylated AKT, and tumor progression-associated proteins. In addition, we found regorafenib induced both extrinsic and intrinsic apoptotic pathways. Body weight and liver morphology were not affected by regorafenib treatment. Our findings present the mechanism of tumor progression inhibition by regorafenib is linked to suppression of ERK/NF-κB signaling in SK-Hep1/luc2 and Hep3B 2.1-7 tumor bearing mice.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , NF-kappa B/genética , Compostos de Fenilureia/administração & dosagem , Piridinas/administração & dosagem , Animais , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Anticancer Res ; 38(4): 2119-2125, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29599330

RESUMO

BACKGROUND/AIM: In a previous study, we showed that amentoflavone promotes sorafenib-induced apoptosis in hepatocellular carcinoma (HCC) cells in vitro. However, whether amentoflavone augments anticancer efficacy of sorafenib in HCC in vivo is unknown. The aim of the present study was to verify the anticancer effect of amentoflavone combined with sorafenib in HCC in vivo. MATERIALS AND METHODS: HCC SK-Hep1 tumor-bearing mice were treated with vehicle, sorafenib, amentoflavone, or combination for 14 days, respectively. Effect of sorafenib, amentoflavone, or their combination on tumor growth, anti-apoptotic potential, apoptotic signaling and general toxicity were evaluated with digital caliper, immunohistochemistry staining and body weight. RESULTS: Our results demonstrated that amentoflavone significantly enhanced sorafenib-inhibited tumor growth and expression of ERK/AKT phosphorylation and anti-apoptotic proteins compared to single-agent treatment. Additionally, amentoflavone also triggered sorafenib-induced apoptosis through extrinsic and intrinsic apoptotic pathways. CONCLUSION: Amentoflavone boosts therapeutic efficacy of sorafenib through blockage of anti-apoptotic potential and induction of apoptosis in HCC in vivo.


Assuntos
Antineoplásicos/farmacologia , Proteínas Reguladoras de Apoptose/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Biflavonoides/farmacologia , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Niacinamida/análogos & derivados , Compostos de Fenilureia/farmacologia , Animais , Antineoplásicos/administração & dosagem , Biflavonoides/administração & dosagem , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Sinergismo Farmacológico , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Camundongos , Camundongos Nus , Niacinamida/administração & dosagem , Niacinamida/farmacologia , Compostos de Fenilureia/administração & dosagem , Sorafenibe , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Anticancer Res ; 37(9): 4911-4918, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28870912

RESUMO

AIM: The study goal was to investigate effect of amentoflavone on nuclear factor-κB (NF-κB)-modulated metastatic mechanism in osteosarcoma U2OS cells. U2OS cells were treated with amentoflavone, NF-κB inhibitor, protein kinase B (PKB or AKT) inhibitor or mitogen-activated protein kinase (MAPK) inhibitor. Change of cell viability, NF-κB activation, expression of metastasis-associated proteins, signal transduction, and cell migration and invasion were evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, NF-κB reporter gene assay, western blotting, and cell migration and invasion assays. The results demonstrated that inhibition of activation of extracellular signal-regulated kinases (ERK) was a key point for suppression of NF-κB-modulated metastatic mechanism. Amentoflavone significantly inhibited NF-κB activation, ERK phosphorylation, expression of metastasis-associated proteins, and cell migration and invasion. Our findings indicate that amentoflavone reduces metastatic potential through suppression of ERK and NF-κB activation in osteosarcoma U2OS cells.


Assuntos
Biflavonoides/farmacologia , Neoplasias Ósseas/tratamento farmacológico , Movimento Celular/efeitos dos fármacos , Inibidores do Citocromo P-450 CYP2C9/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , NF-kappa B/antagonistas & inibidores , Osteossarcoma/tratamento farmacológico , Apoptose/efeitos dos fármacos , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Proliferação de Células/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , NF-kappa B/metabolismo , Osteossarcoma/metabolismo , Osteossarcoma/secundário , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Células Tumorais Cultivadas
13.
Oncol Rep ; 37(2): 1036-1044, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28000898

RESUMO

The aim of the present study was to investigate the role of NF-κB inactivation in regorafenib-induced apoptosis in human hepatocellular carcinoma SK-HEP-1 cells. SK-HEP-1 cells were treated with different concentrations of the NF-κB inhibitor 4-N-[2-(4-phenoxyphenyl)ethyl]quinazoline-4,6-diamine (QNZ) or regorafenib for different periods. The effects of QNZ and regorafenib on cell viability, expression of NF-κB-modulated anti-apoptotic proteins and apoptotic pathways were analyzed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, western blotting, DNA gel electrophoresis, flow cytometry and NF-κB reporter gene assay. Inhibitors of various kinases including AKT, c-Jun N-terminal kinase (JNK), P38 and extracellular signal-regulated kinase (ERK) were used to evaluate the mechanism of regorafenib-induced NF-κB inactivation. The results demonstrated that both QNZ and regorafenib significantly inhibited the expression of anti-apoptotic proteins and triggered extrinsic and intrinsic apoptosis. We also demonstrated that regorafenib inhibited NF-κB activation through ERK dephosphorylation. Taken all together, our findings indicate that regorafenib triggers extrinsic and intrinsic apoptosis through suppression of ERK/NF-κB activation in SK-HEP-1 cells.


Assuntos
Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , NF-kappa B/metabolismo , Compostos de Fenilureia/farmacologia , Piridinas/farmacologia , Antineoplásicos/farmacologia , Apoptose/fisiologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Ativação Enzimática/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , NF-kappa B/antagonistas & inibidores , NF-kappa B/genética , Éteres Fenílicos/farmacologia , Fosforilação/efeitos dos fármacos , Quinazolinas/farmacologia , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo
14.
Proteomics ; 15(22): 3865-74, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26314240

RESUMO

Total parenteral nutrition (TPN) is provided as the primary nitrogen source to manage patients with intestinal failure who were not able to sustain themselves on enteral feeds. The most common complication of long-term TPN use is hepatitis. A proteomic approach was used to identify proteins that are differentially expressed in the plasma of rats following TPN-related acute liver injury. Six male rats were randomly assigned to either the saline infusion control group or the TPN infusion group. Our results demonstrate that TPN infusion in rats resulted in hepatic dysfunction and hepatocyte apoptosis. Five proteins that were differentially expressed between TPN infusion and normal rats were determined and validated in vivo. Fascinatingly, the proteomic differential displays, downregulated proteins included peroxiredoxin 2 (PRDX2), alpha-1-antiproteinase (A1AT), and fibrinogen gamma chain (FIBG), which were involved in oxidative stress, inflammatory respondence and cells apoptosis. After TPN infusion, two protein spots showed increased expression, namely, the glucagon receptor (GLR) protein and apolipoprotein A-1 (APOA1), which may mediate the effects of TPN administration on glycogen and lipid metabolism. In this study, proteomic analysis suggested TPN-related acute liver injury could be involved in limiting cellular protection mechanisms against oxidative stress-induced apoptosis. On the basis of the results, we also give molecular evidences replying TPN-related hepatitis.


Assuntos
Hepatite/metabolismo , Falência Hepática/metabolismo , Nutrição Parenteral Total/efeitos adversos , Proteoma/metabolismo , Animais , Cromatografia Líquida , Eletroforese em Gel de Poliacrilamida , Hepatite/etiologia , Fígado/metabolismo , Falência Hepática/etiologia , Masculino , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem
15.
Int J Mol Sci ; 14(6): 12563-80, 2013 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-23771023

RESUMO

Total parenteral nutrition (TPN) is an artificial way to support daily nutritional requirements by bypassing the digestive system, but long-term TPN administration may cause severe liver dysfunction. Glycyrrhizin is an active component of licorice root that has been widely used to treat chronic hepatitis. The aim of this study is to investigate the hepatoprotective effect of glycyrrhizin on TPN-associated acute liver injury in vivo. Liver dysfunction was induced by intravenous infusion of TPN at a flow rate of 20 mL/kg/h for three h in Sprague Dawley rats. The rats were pretreated with Glycyrrhizin (1, 3 and 10 mg/kg intravenously). After receiving TPN or saline (control group) for three h, the rats were sacrificed, blood samples were collected for biochemical analyses and liver tissue was removed for histopathological and immunohistochemical examination. We found that aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (TB) and triglyceride (TG) levels were significantly increased in the TPN group without glycyrrhizin pretreatment and decreased in the glycyrrhizin-pretreated TPN group in a dose-dependent manner. The stained liver sections showed that glycyrrhizin relieved acute liver injury. The upregulation of serum protein biomarkers of reactive nitrogen species, including nitrotyrosine and inducible NO synthase (iNOS), were attenuated by glycyrrhizin pretreatment. Levels of endoplasmic reticulum (ER) stress factors, such as phosphorylation of JNK1/2, p38 MAPK and CHOP, were decreased by glycyrrhizin pretreatment. In summary, our results suggest that glycyrrhizin decreases TPN-associated acute liver injury factors by suppressing endoplasmic reticulum stress and reactive nitrogen stress.


Assuntos
Estresse do Retículo Endoplasmático/efeitos dos fármacos , Ácido Glicirrízico/farmacologia , Ácido Glicirrízico/uso terapêutico , Hepatopatias/etiologia , Nutrição Parenteral Total/efeitos adversos , Animais , Apoptose/efeitos dos fármacos , Bilirrubina/metabolismo , Caspase 3/metabolismo , Citocinas/sangue , Ácido Glicirrízico/química , Imuno-Histoquímica , Inflamação/complicações , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/lesões , Fígado/patologia , Hepatopatias/sangue , Hepatopatias/enzimologia , Masculino , Óxido Nítrico Sintase Tipo II/metabolismo , Fosforilação/efeitos dos fármacos , Ratos Sprague-Dawley , Espécies Reativas de Nitrogênio/metabolismo , Proteína 3 Supressora da Sinalização de Citocinas , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Fator de Transcrição CHOP/metabolismo , Triglicerídeos/metabolismo , Tirosina/análogos & derivados , Tirosina/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
16.
Taiwan J Obstet Gynecol ; 52(1): 33-8, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23548215

RESUMO

OBJECTIVE: The aim of this study was to assess the benefits of the 2009 International Federation of Gynecology and Obstetrics (FIGO) staging system for survival of patients with Stage IIA1 and IIA2 cervical cancer (Cx Ca). MATERIALS AND METHODS: A study cohort of 51 patients with Stage IIA Cx Ca was retrospectively collected from the 2004-2009 hospital-based, long-form Cx Ca data registry at Mackay Memorial Hospital (Taipei, Taiwan). The survivorship and overall survival were compared between these two groups (Stages IIA1 and IIA2) using log-rank test. RESULTS: Thirty-six and 15 patients were classified into Stages IIA1 and IIA2, respectively. Stage IIA2 patients were younger than those with Stage IIA1 disease (mean age, 47.4 vs. 55.1 years, p = 0.008), but no significant difference was observed in confirmed pelvic lymph node status (21.4% vs. 38.5%, p = 0.280) between them. Although the 2-year and 5-year overall survival was better among Stage IIA1 patients, there was no significant difference in survival between Stage IIA1 and IIA2 groups (2-year, 90.6% vs. 77.8%; 5-year, 86.3% vs. 51.9%, p = 0.218). CONCLUSION: Although there was a trend in survival difference between Stage IIA1 and IIA2 patients, the difference was not statistically significant. The revised FIGO 2009 staging system for Cx Ca defines a group of Stage IIA patients with bulky tumor (Stage IIA2) that are generally younger than Stage IIA1 patients. It is sensible to investigate an alternate or enhanced treatment scheme for Stage IIA2 patients. Ideally, the treatment scheme should prevent unnecessary radical surgery if a patient can be exposed to either chemotherapy or radiotherapy, alone or in combination.


Assuntos
Carcinoma/patologia , Neoplasias do Colo do Útero/patologia , Adulto , Idoso , Carcinoma/mortalidade , Carcinoma/terapia , Terapia Combinada , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Sistema de Registros , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento , Neoplasias do Colo do Útero/mortalidade , Neoplasias do Colo do Útero/terapia
18.
Clin Gastroenterol Hepatol ; 10(6): 677-81, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22391345

RESUMO

BACKGROUND & AIMS: The effects of end-stage renal disease (ESRD) on the mortality of patients with cirrhosis and spontaneous bacterial peritonitis (SBP) have not been determined. METHODS: We collected data from Taiwan's National Health Insurance Database on 2592 patients with cirrhosis who were hospitalized with SBP from January 1 to December 31, 2004. Patients were matched with individuals from a national mortality database; 30-day and 1-year mortalities were calculated for each group and compared to calculate hazard ratios (HRs). RESULTS: Of the patients with cirrhosis and SBP, 300 (11.5%) had renal function impairment. Of these, 145 had acute renal failure, 70 had ESRD, and 75 had chronic kidney disease. Overall, 30-day and 1-year mortality were 21.3% and 51.7%, respectively. After adjusting for age, sex, and underlying comorbidities, HRs for 30-day mortality from renal function impairment, acute renal failure, ESRD, and chronic kidney disease were 3.00, 4.68, 1.93, and 1.37, respectively. The HRs for 1-year mortality from renal function impairment, acute renal failure, ESRD, and chronic kidney disease were 2.03, 2.78, 1.70, and 1.37, respectively. The adjusted HRs for 30-day and 1-year mortality of patients with acute renal failure were 2.6 and 1.6, respectively, compared with patients with ESRD. CONCLUSIONS: Acute renal failure is a better determinant of 30-day and 1-year mortality than renal function impairment in cirrhotic patients with SBP.


Assuntos
Injúria Renal Aguda/mortalidade , Cirrose Hepática/complicações , Peritonite/complicações , Injúria Renal Aguda/epidemiologia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Taiwan/epidemiologia
19.
J Surg Res ; 176(1): 108-13, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22099600

RESUMO

BACKGROUND: Our previous study showed that preconditioned local somatothermal stimulation (LSTS) protected subsequent ischemia-reperfusion injury of the skeletal muscle. The exact mechanisms of LSTS preconditioning remain unknown. The aim of this study was to test the hypothesis stating that heat stimulation induces free radical production, increases enzymatic scavenging activity, and subsequently enhances the expression of heat shock protein 70 (HSP-70) in skeletal muscles. MATERIALS AND METHODS: After LSTS was applied onto the left quarter ventral abdomen muscle of male Sprague-Dawley rats, the underling muscles were collected at the intervals of baseline, 5-, 15-, 30-, and 60-min after LSTS. The time-dependent profiles of free radical production and enzymatic scavenging activity were measured. The influence of nitric oxide (NO) on HSP-70 expression was evaluated by pretreatment of an NO synthase inhibitor. RESULTS: The concentrations of reactive oxygen species, NO metabolites, and malondialdehyde increased significantly 5 min after LSTS, whereas the scavenging activity reduced to the lowest level 5 min (dismutase) and 15 min (catalase and glutathione) after LSTS. Expression of HSP-70 was significantly lower in the LSTS with NO synthase inhibitor group than in the LSTS group. CONCLUSIONS: LSTS induces oxidative stress and the scavenging response in the underlying skeletal muscle, which might explain the possible mechanisms of LSTS preconditioning-induced muscle plasticity.


Assuntos
Radicais Livres/metabolismo , Proteínas de Choque Térmico HSP70/metabolismo , Temperatura Alta , Músculo Esquelético/metabolismo , Estresse Oxidativo/fisiologia , Animais , Masculino , Malondialdeído/metabolismo , Modelos Animais , Óxido Nítrico/metabolismo , Estimulação Física , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Fatores de Tempo
20.
World J Gastroenterol ; 16(33): 4200-5, 2010 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-20806439

RESUMO

AIM: To investigate clinical outcomes of patients with chronic gastric volvulus (GV) who were managed conservatively over a 5-year period. METHODS: A total of 44 consecutive patients with chronic GV, as diagnosed by barium study between October 2002 and July 2008 were investigated. All of these patients received conservative management initially without anatomical correction. Their clinical manifestations, diagnostic work-ups, and clinical outcomes were analyzed. We sought to identify independent risk factors for poor outcome by using the Cox proportional hazards model. RESULTS: The enrolled patients were predominantly male (n = 37, 84%) and of advanced age (median: 71 years old, interquartile range: 57.5-78 years). Abdominal pain and fullness were the most common presentations. During the follow-up period (median: 16 mo, up to 69 mo), there was no severe complication, but symptomatic recurrence was noted in 28 patients (64%). Only one patient turned to elective surgery for frequent symptoms. Peritoneal adhesion was the only independent risk factor associated with recurrence (hazard ratio: 2.58, 95% CI: 1.08-6.13, P = 0.033). CONCLUSION: Symptomatic recurrence of chronic GV is very common although serious complications infrequently occur with conservative management. Peritoneal adhesion is independently associated with recurrence.


Assuntos
Estilo de Vida , Volvo Gástrico/terapia , Dor Abdominal/etiologia , Idoso , Feminino , Seguimentos , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Estudos Retrospectivos , Fatores de Risco , Prevenção Secundária , Volvo Gástrico/complicações , Resultado do Tratamento
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