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1.
J Environ Pathol Toxicol Oncol ; 38(3): 195-203, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31679307

RESUMO

UNCI 19 expression has been reported to be significantly higher in hepatic cancer cells (HCC). However, the clinical significance of modulating UNC119 expression in HCC is not well understood. The study described here aimed to explore the potential of curcumin in modulation of UNC119 expression in HCC by assessment with quantitative real-time PCR, western blot, and immune-histochemical analyses in HCC cell lines and tissues. The biological functions of UNC119 in the proliferation, growth, and cycle of tumor cells were analyzed both in vitro and in vivo. UNC119 expression was upregulated in HCC cell lines and tissues as indicated by comparison with normal liver cells and tissues. Cellular function assays showed that higher levels of UNC119 not only promoted proliferation but also enhanced HCC cell migration and invasion. UNC119 promoted progression of the cell cycle and significantly promoted HCC cell growth through the Wnt/ß-catenin signal pathway, and enhanced tumor migration and invasion by the TGF-ß/EMT pathway. Curcumin efficiently inhibited HCC cell proliferation by blocking the Wnt/ß-catenin pathway and inhabited migration and invasion by blocking the TGF-p/EMT signal pathway. Curcumin not only was beneficial for tumor remission but also contributed to the long-term survival of HCC-bearing mice. UNC119 was significantly upregulated and promoted cell growth in hepatic cancer cells and tissues by the Wnt/ß-catenin signal pathway and migration by TGF-ß/EMT signal pathway. Curcumin treatment inhibited cell proliferation, growth, migration, and invasion by inhibition of those pathways.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Antineoplásicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Curcumina/farmacologia , Invasividade Neoplásica/genética , Metástase Neoplásica/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Feminino , Células Hep G2 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Organismos Livres de Patógenos Específicos
2.
Medicine (Baltimore) ; 98(44): e17813, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31689867

RESUMO

BACKGROUND: To evaluate the short-term efficacy, long-term efficacy, and adverse events (AEs) of elemene plus transcatheter arterial chemoembolization (TACE) in comparison with TACE alone for the treatment of hepatocellular carcinoma (HCC). METHODS: PubMed, EMBASE, the Cochrane Library, the Chinese Scientific Journal Full-text Database, Wanfang Data, CBM, and VIP were searched by 2 reviewers using the same search strategy for clinical studies on elemene plus TACE in the treatment of HCC. These articles were screened according to pre-established inclusion and exclusion criteria, and the qualities of the included studies were assessed using the Newcastle-Ottawa scale. The primary outcomes were the objective response rate (ORR), the 1-year survival rate and AEs. Review Manager 5.3 and Stata 15.0 were used for the meta-analysis. RESULTS: A total of 10 studies involving 543 patients (TACE + elemene = 277, TACE alone = 266) were included. The results showed that the ORR was significantly improved in the combined treatment group compared to the TACE alone group (odds ratio [OR] = 2.72, 95% confidence interval [CI]: 1.84-4.00, P < .05). TACE + elemene significantly increased the 1-year survival rate (OR = 2.79, 95% CI: 1.58-4.95, P < .05). We also found no significant difference in gastrointestinal reactions (OR = 0.97, 95% CI: 0.57-1.64, P = .90), fever (OR = 0.80, 95% CI: 0.37-1.71, P = .56), or bone marrow suppression (OR = 0.73, 95% CI: 0.44-1.22, P = .23) between the 2 groups. CONCLUSION: Based on current findings, TACE + elemene injection may improve the ORR and the 1-year survival rate for HCC patients compared to TACE alone. Arterial perfusion may be superior to intravenous guttae.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Quimioembolização Terapêutica/métodos , Neoplasias Hepáticas/tratamento farmacológico , Sesquiterpenos/uso terapêutico , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Cateterismo , Quimioembolização Terapêutica/efeitos adversos , Humanos , Injeções Intra-Arteriais , Sesquiterpenos/administração & dosagem , Sesquiterpenos/efeitos adversos
3.
Tumour Biol ; 41(10): 1010428319880080, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31603389

RESUMO

Searching for new sources of safe nutraceuticals antitumor drugs is an important issue. Consequentially, this study designed to assess the antitumor activity of Pulicaria undulata extract in vitro in the treatment of hepatocellular carcinoma HepG2 cell line. Aerial parts of P. undulata plants were collected, used for phytochemical analysis, and assessed for anticancer activity. The antitumor activity was evaluated through studying the cell viability and apoptotic pathway. The gas chromatography-mass spectrometry phytochemical analysis revealed that P. undulata is a promising new source of several known antioxidant and antitumor compounds which could participate in drug development and exploration of alternative strategies to the harmful synthetic antitumor drugs. P. undulata stifled HepG2 cell viability in a concentration-dependent manner. Meanwhile, P. undulata tempted substantial apoptosis in HepG2 cells and enhanced the expression of miR-34a. However, the mRNA expression level of antiapoptotic B-cell lymphoma-2 was markedly decreased by P. undulata treatment. Moreover, P. undulata increased the protein expression of proapoptotic p53 and caspase 3/9 with reducing B-cell lymphoma-2 protein expression level. Thus, P. undulata induced apoptosis in the HepG2 cells by overexpression of miR-34a which regulates p53/B-cell lymphoma-2/caspases signaling pathway. These findings were well appreciated with morphological studies of cells treated with P. undulata. In conclusion, P. undulata could be a probable candidate agent for the initiation of cell apoptosis in HepG2 and thereby can serve as promising therapeutic agent for treatment of hepatocellular carcinoma which should attract further studies.


Assuntos
Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/patologia , Proliferação de Células/efeitos dos fármacos , Neoplasias Hepáticas/patologia , Extratos Vegetais/farmacologia , Pulicaria/química , Carcinoma Hepatocelular/tratamento farmacológico , Células Hep G2 , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Transdução de Sinais
4.
Anticancer Res ; 39(10): 5495-5504, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570443

RESUMO

BACKGROUND/AIM: Most patients with hepatocellular carcinoma (HCC) cannot be treated using traditional therapies. Boron neutron capture therapy (BNCT) may provide a new treatment for HCC. In this study, the therapeutic efficacy and radiobiological effects of boric acid (BA)-mediated BNCT in a VX2 multifocal liver tumor-bearing rabbit model are investigated. MATERIALS AND METHODS: Rabbits were irradiated with neutrons at the Tsing Hua Open Pool Reactor 35 min following an intravenous injection of BA (50 mg 10B/kg BW). The tumor size following BNCT treatment was determined by ultrasonography. The radiobiological effects were identified by histopathological examination. RESULTS: A total of 92.85% of the tumors became undetectable in the rabbits after two fractions of BNCT treatment. The tumor cells were selectively eliminated and the tumor vasculature was collapsed and destroyed after two fractions of BA-mediated BNCT, and no injury to the hepatocytes or blood vessels was observed in the adjacent normal liver regions. CONCLUSION: Liver tumors can be cured by BA-mediated BNCT in the rabbit model of a VX2 multifocal liver tumor. BA-mediated BNCT may be a breakthrough therapy for hepatocellular carcinoma.


Assuntos
Ácidos Bóricos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/radioterapia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/radioterapia , Animais , Vasos Sanguíneos/efeitos dos fármacos , Vasos Sanguíneos/efeitos da radiação , Terapia por Captura de Nêutron de Boro/métodos , Hepatócitos/efeitos dos fármacos , Hepatócitos/efeitos da radiação , Fígado/efeitos dos fármacos , Fígado/efeitos da radiação , Masculino , Coelhos
5.
Anticancer Res ; 39(10): 5695-5701, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570469

RESUMO

Large tumor size and arterioportal shunt are poor prognostic factors for hepatocellular carcinoma. Lenvatinib is a novel and potent multi-tyrosine kinase inhibitor developed in Japan. A 66-year-old woman with hepatocellular carcinoma and untreated hepatitis C was referred to our hospital. She was judged as unresectable and was treated with four sessions of transarterial chemoembolization; however, the therapeutic effect was unsatisfactory because of major arterioportal shunt. Lenvatinib was sequentially administered for 4 months. Thereafter, we observed tumor shrinkage, complete disappearance of arterioportal shunt, and obvious improvement in liver function. A curative conversion hepatectomy was successfully accomplished. The extremely high levels of tumor markers almost normalized; the pretreatment levels were 1,008,021 ng/ml for alpha-fetoprotein. At 1 year after the primary treatment, the patient has not experienced recurrence. To our knowledge, this is the first case of a patient with initially unresectable hepatocellular carcinoma with arterioportal shunt who underwent conversion hepatectomy after multidisciplinary treatment, including lenvatinib.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/cirurgia , Hepatectomia/métodos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/cirurgia , Compostos de Fenilureia/uso terapêutico , Quinolinas/uso terapêutico , Idoso , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/metabolismo , Quimioembolização Terapêutica/métodos , Feminino , Humanos , Neoplasias Hepáticas/metabolismo , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/cirurgia , alfa-Fetoproteínas/metabolismo
6.
Expert Opin Investig Drugs ; 28(11): 941-949, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31590579

RESUMO

Introduction: Hepatocellular carcinoma (HCC) is the most common primary liver cancer and the burden of disease is increasing globally. Until recently, systemic therapies for HCC were limited and prognosis for advanced disease generally poor.Area covered: This article describes some recent phase I and II clinical trials for the treatment of HCC. We performed a search on Pubmed with keywords hepatocellular carcinoma, phase I clinical trial, phase II clinical trial, and immunotherapy. We also searched https://clinicaltrials.gov and identified relevant trials listed as active. Studies in progress or recently reported were conducted using novel therapies based on targets identified through molecular profiling of tumors or based on insights into immune system dysregulation in HCC. We also identified studies using drugs targeting recently discovered biomarkers such as endoglin or aldo-keto reductase 1c3. The major outcomes were safety and efficacy as measured by response rate, progression-free survival or overall survival.Expert opinion: HCC is a heterogeneous disease resulting from aberrations in intracellular signaling and immune system dysregulation. Thus, a multisystem approach will be required to deliver personalized therapy. Combination therapies are likely to be future options; it is also possible that modulation of the microbiome might form part of future treatment paradigms.


Assuntos
Antineoplásicos/administração & dosagem , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/patologia , Drogas em Investigação/administração & dosagem , Drogas em Investigação/efeitos adversos , Drogas em Investigação/farmacologia , Humanos , Imunoterapia , Neoplasias Hepáticas/patologia , Terapia de Alvo Molecular , Sobrevida
7.
Life Sci ; 236: 116933, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31614146

RESUMO

AIMS: Hepatocellular carcinoma (HCC) pathogenesis involves the interplay of multiple signalling pathways. Notch and Hedgehog (Hh) are two major developmental pathways that act in concert to regulate adult cell repair. CK2α -serine-threonine kinase-down-regulation enhanced apoptotic activity and was proven beneficial for HCC patients. Quercetin is a bioactive flavonoid and has been shown to protect against HCC through its antioxidant activity. This study was carried out to elucidate the antineoplastic effect of quercetin through regulating both Notch and Hh pathways, apoptosis, cell proliferation and CK2α activity. MAIN METHODS: Hepatocellular carcinoma was induced in male Sprague Dawley rats by thioacetamide. Quercetin was administered in both protective and curative doses. Parameters of liver function and oxidative stress were assessed. CK2α, Notch and Hh pathways were evaluated using RT-PCR and ELISA. Apoptosis was investigated by detecting caspase-3, caspase-8 and p53. Proliferative and cell cycle markers as cyclin D1 and Ki-67 were detected immunohistochemically. KEY FINDINGS: Quercetin inhibited CK2α and downregulated mRNA and protein expression of Notch1 and Gli2. Quercetin also suppressed caspase-3 expression but not caspase-8. Quercetin elevated p53 expression whereas proliferative and cell cycle markers cyclin D1 and Ki-67 were downregulated. Markers of hepatic cellular integrity such as AST, ALT, ALP, GGT, albumin and bilirubin were significantly ameliorated. This was confirmed by histological examination. Quercetin also alleviated oxidative stress as shown by SOD, GSH, MDA and NO levels. SIGNIFICANCE: We can conclude that in addition to its antioxidant power, quercetin blocked Notch, Hedgehog, regulated the apoptotic and proliferative pathways and inhibited CK2α in HCC.


Assuntos
Antioxidantes/farmacologia , Carcinoma Hepatocelular/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Hepáticas/metabolismo , Quercetina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Caseína Quinase II/antagonistas & inibidores , Caseína Quinase II/metabolismo , Proliferação de Células/efeitos dos fármacos , Proteínas Hedgehog/antagonistas & inibidores , Proteínas Hedgehog/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Masculino , Estresse Oxidativo , Ratos , Ratos Sprague-Dawley , Receptores Notch/antagonistas & inibidores , Receptores Notch/metabolismo
8.
Anticancer Res ; 39(9): 4787-4794, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519580

RESUMO

BACKGROUND/AIM: The aim of this study was to investigate the effects of the macrophage colony-stimulating factor (M-CSF) receptor antagonist on hepatic carcinogenesis in mice. MATERIALS AND METHODS: Mice were injected with diethylnitrosamine (DEN) and treated with M-CSF receptor antagonist GW2580 (GW) or a saline vehicle just after (early treated group) or 2 weeks after (late treated group) DEN injection. Animals were sacrificed after 28 weeks and incidence of tumor was assessed. Isolated Kupffer cells were co-cultured with M-CSF in the presence or absence of GW, and the concentration of VEGF was measured. RESULTS: The incidence of tumors was significantly blunted both in the early- and the late-treated groups. In addition, angiogenesis within the tumor was also suppressed in both groups. The concentration of VEGF increased in Kupffer cells treated with M-CSF compared to those cultured without M-CSF. This increase was blunted by GW. CONCLUSION: M-CSF and its receptor could be novel molecular targets for hepatocellular carcinoma.


Assuntos
Anisóis/farmacologia , Transformação Celular Neoplásica/efeitos dos fármacos , Pirimidinas/farmacologia , Receptor de Fator Estimulador de Colônias de Macrófagos/antagonistas & inibidores , Animais , Biomarcadores , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Proliferação de Células/efeitos dos fármacos , Imuno-Histoquímica , Macrófagos do Fígado/efeitos dos fármacos , Macrófagos do Fígado/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Camundongos , Carga Tumoral/efeitos dos fármacos
9.
Anticancer Res ; 39(9): 5149-5156, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519627

RESUMO

BACKGROUND: Factors associated with response to lenvatinib have not been clarified in patients with hepatocellular carcinoma (HCC). PATIENTS AND METHODS: This study retrospectively analyzed 50 patients treated with lenvatinib as first-line therapy between March 2018 and March 2019. Patients were divided into two groups by the Modified Response Evaluation Criteria in Solid Tumours (mRECIST) (responders and non-responders, whose best overall responses were complete (CR)/partial response (PR) and stable (SD)/progressive disease (PD), respectively). Factors associated with response were assessed, including the relative dose intensity 8 weeks after lenvatinib induction (8W-RDI). RESULTS: The best overall responses were 0/22/14/14 of CR/PR/SD/PD. Multivariate analysis revealed that only 8W-RDI was significantly associated with response. The receiver operating characteristic curve for 8W-RDI in differentiating responders from non-responders revealed a cut-off value of 75%. Patients with 8W-RDI ≥75% experienced a higher response rate and longer progression-free survival than patients with 8W-RDI <75%. CONCLUSION: Our results suggest that maintaining an RDI ≥75% during the initial 8 weeks of lenvatinib treatment has a favorable impact on response.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Compostos de Fenilureia/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Quinolinas/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/mortalidade , Feminino , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/mortalidade , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/efeitos adversos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Quinolinas/administração & dosagem , Quinolinas/efeitos adversos , Curva ROC , Estudos Retrospectivos , Resultado do Tratamento
10.
Chem Commun (Camb) ; 55(79): 11944-11947, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31531457

RESUMO

A novel hexanuclear copper(ii)-based complex, [Cu6(tpbb)2(NO3)12] (1), was synthesized, which shows potent cytotoxicity to hepatoma carcinoma cells by inducing apoptosis and apoptosis-related processes. Furthermore, mechanistic investigations based on proteomes revealed that the induced apoptosis was mediated by acting on several targets and multiple pathways in a pleiotropic way.


Assuntos
Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/tratamento farmacológico , Complexos de Coordenação/química , Cobre/química , Neoplasias Hepáticas/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/farmacologia , Dano ao DNA/efeitos dos fármacos , Desenho de Drogas , Humanos , Ligantes , Neoplasias Hepáticas/patologia , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade
11.
Life Sci ; 235: 116817, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31476309

RESUMO

AIMS: In the tumor microenvironment, dysregulated immune cells could promote tumor progression, invasion and metastasis, by establishing a symbiotic relationship with cancer cells. A pivotal role is played by monocyte recruitment and induction of tumor-associated macrophages (TAMs), which provide immunosuppression and tumorigenesis. The effect of nemorosone, an antiproliferative phytocomponent present in Cuban Propolis, on TAM-induced tumor progression remains to be elucidated. Here we investigated the symbiotic relationship between monocytic leukemia THP-1 and hepatocellular carcinoma HepG2 cells, and the role of nemorosone in preventing TAM-induced tumor growth. MAIN METHODS: Macrophage differentiation induced by HepG2-conditioned medium was assessed by flow cytometry, analysis of secreted molecules and cytokine expression. The effect of nemorosone and/or conditioned THP-1-medium on HepG2 proliferation was evaluated by MTT assay, colony formation, cells cycle and migration assays. KEY FINDINGS: HepG2 cells induced THP-1 recruitment and differentiation to macrophages. When compared with control THP-1 cells, differentiated THP-1 showed a significant increase of the matrix metalloproteinases MMP-2 and MMP-9 expression (P < 0.01), and slightly induced HepG2 cells growth. This effect was counteracted by nemorosone, which also significantly inhibited colony formation (P < 0.01) and migratory capacity of HepG2 cells, driving a high percentage of cells (80%) to the G0/G1 phase. SIGNIFICANCE: HepG2-conditioned medium is a suitable model for THP-1 modulation and differentiation. Moreover, nemorosone significantly inhibits the proliferation of HepG2 cells, both in presence and absence of the soluble factors secreted by TAMs. Further studies are needed to elucidate the role of this natural compound in the HCC-TAM relationship.


Assuntos
Benzofenonas/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias Hepáticas/tratamento farmacológico , Monócitos/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Diferenciação Celular/efeitos dos fármacos , Meios de Cultivo Condicionados/farmacologia , Células Hep G2 , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Monócitos/citologia , Monócitos/metabolismo , Células THP-1
12.
Oncology ; 97(4): 206-210, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31390629

RESUMO

Lenvatinib (LEN) is a multikinase inhibitor with antiangiogenic properties recently approved in radioactive iodine-refractory differentiated thyroid cancer, hepatocellular carcinoma, and renal cell carcinoma in combination with everolimus. LEN-treated patients frequently have adverse events (AEs) that generally require such dose modifications, including drug discontinuation. Hypertension, diarrhea, weight loss, proteinuria, fatigue, and palmar-plantar erythrodysesthesia are reported among the most frequent AEs, often leading to discontinuations or dose modifications. This paper reports a case series focusing on the role of the immediate multidisciplinary approach to manage AEs.


Assuntos
Compostos de Fenilureia/uso terapêutico , Quinolinas/uso terapêutico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/radioterapia , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/radioterapia , Terapia Combinada/métodos , Progressão da Doença , Intervalo Livre de Doença , Everolimo/uso terapêutico , Feminino , Humanos , Radioisótopos do Iodo/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/radioterapia , Masculino , Inibidores de Proteínas Quinases/uso terapêutico , Neoplasias da Glândula Tireoide/radioterapia , Resultado do Tratamento
13.
J Biomed Nanotechnol ; 15(9): 1881-1896, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31387676

RESUMO

The clinical treatment of hepatocellular carcinoma has been hindered due to the drug resistance and heterogeneity of tumor cells. A new therapy strategy combined chemo drugs and molecular-targeted drugs is considered to be promising for conquering these challenges. However, the different pharmacokinetic profiles, hydrophobicity and systemic toxicity of these drugs may still cause serious challenges to the clinical applications of this combination therapy. In this study, smart sorafenib (SF) and doxorubicin (DOX)-loaded nanodroplets (SF/DOX-NDs) were fabricated to solve the above issues. The liquid-to-gas phase transition of SF/DOX-NDs could function as a cavitation nucleus to boost drug release and increase cellular uptake after exposure to therapeutic ultrasound (TUS) irradiation. Additionally, this strategy has a therapeutic effect to induce apoptosis and inhibit the proliferation, migration, and invasion of hepatoma cells. Furthermore, the intense cavitation of SF/DOX-NDs at the tumor site could disrupt microvessels, which is beneficial for tissue-penetrating drug delivery inside tumors. Consequently, tumor angiogenesis was reduced, and tumor growth was remarkably inhibited by SF/DOX-NDs. These results indicated that combination therapy using SF/DOX-NDs may offer a promising approach to achieve effective HCC therapy with low side effects.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Hepatocelular , Neoplasias Hepáticas , Carcinoma Hepatocelular/tratamento farmacológico , Doxorrubicina , Sistemas de Liberação de Medicamentos , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Sorafenibe
14.
J Microbiol Biotechnol ; 29(8): 1281-1287, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31370114

RESUMO

Nattokinase (NK, E.C. 3.4.21.62) is a serine protease produced by Bacillus subtilis natto that shows promise for the treatment of thrombotic disease. In this study, we assessed the effects of NK on the development of hepatocellular carcinoma (HCC), a principal malignancy of the liver that causes morbidity and mortality worldwide. Crude extracts of NK (NCE) were isolated from fermentation medium by centrifugation and separated into three fractions (<10 K, 100~30 K and >30K). Orthotopic HCC mouse models were established and NCE was administered by oral gavage. H&E staining was performed to examine the pathology of HCC livers. Immunohistochemistry and immunofluorescence were used to evaluate FOXM1, CD31, CD44 and vimentin expression in the liver. Compared to PBS groups, NCE increased the survival rates of HCC-bearing mice to 31% and decreased ascites. Low-intensity ultrasound imaging showed that the hypoechoic mass area was lower in NCE-treated mice and that tumor growth significantly decreased. IHC staining showed that the expression of FOXM1 was inhibited by NCE treatment. Immunofluorescence results revealed lower levels of CD31, CD44 and vimentin in the NCE groups. Taken together, these data demonstrate that NCE from Bacillus subtilis natto improves survival and inhibits tumor growth in HCC mice.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Misturas Complexas/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Subtilisinas/farmacologia , Animais , Bacillus subtilis/enzimologia , Carcinoma Hepatocelular/patologia , Misturas Complexas/isolamento & purificação , Modelos Animais de Doenças , Fermentação , Fibrinolíticos/farmacologia , Proteína Forkhead Box M1/análise , Receptores de Hialuronatos/análise , Fígado/metabolismo , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Endogâmicos C57BL , Molécula-1 de Adesão Celular Endotelial a Plaquetas/análise , Subtilisinas/isolamento & purificação , Vimentina/análise
15.
Eur J Med Chem ; 179: 515-526, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31276896

RESUMO

Nineteen organoselenides were synthesized and tested for their intrinsic cytotoxicity in hepatocellular carcinoma (HepG2) and breast adenocarcinoma (MCF-7) cell lines and their corresponding selective cytotoxicity (SI) was estimated using normal lung fibroblast (WI-38) cells. Most of the organic selenides exhibited good anticancer activity, and this was more pronounced in HepG2 cells. Interestingly, the naphthoquinone- (5), thiazol- (12), and the azo-based (13) organic selenides demonstrated promising SI (up to 76). Furthermore, the amine 4c, naphthoquinone 5, and azo-based 13 and 15 organic selenides were able to down-regulate the expression of Bcl-2 and up-regulate the expression levels of IL-2, IL-6 and CD40 in HepG2 cells compared to untreated cells. Moreover, most of the synthesized candidates manifested good free radical-scavenging and GPx-like activities comparable to vitamin C and ebselen. The obtained results suggested that some of the presented organoselenium candidates have promising anti-HepG2 and antioxidant activities.


Assuntos
Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Neoplasias da Mama/tratamento farmacológico , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Compostos Organosselênicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antioxidantes/síntese química , Antioxidantes/química , Compostos de Bifenilo/antagonistas & inibidores , Compostos de Bifenilo/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Células Hep G2 , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Células MCF-7 , Estrutura Molecular , Compostos Organosselênicos/síntese química , Compostos Organosselênicos/química , Picratos/antagonistas & inibidores , Picratos/metabolismo , Relação Estrutura-Atividade
16.
Drugs ; 79(12): 1355-1361, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31313098

RESUMO

Camrelizumab (AiRuiKa™), a programmed cell death 1 (PD-1) inhibitor being developed by Jiangsu Hengrui Medicine Co. Ltd, recently received conditional approval in China for the treatment of relapsed or refractory classical Hodgkin lymphoma. The drug is also being investigated as a treatment for various other malignancies, including B cell lymphoma, oesophageal squamous cell carcinoma, gastric/gastroesophageal junction cancer, hepatocellular carcinoma, nasopharyngeal cancer and non-squamous, non-small cell lung cancer. This article summarizes the milestones in the development of camrelizumab leading to this first approval for classical Hodgkin lymphoma.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Doença de Hodgkin/tratamento farmacológico , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma de Células Escamosas/tratamento farmacológico , China , Aprovação de Drogas , Neoplasias Esofágicas/tratamento farmacológico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Linfoma de Células B/tratamento farmacológico , Neoplasias Nasofaríngeas/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias Gástricas/tratamento farmacológico
17.
Biol Res ; 52(1): 34, 2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-31277690

RESUMO

BACKGROUND: Psoralen is a coumarin-like and coumarin-related benzofuran glycoside, which is a commonly used traditional Chinese medicine to treat patients with kidney and spleen-yang deficiency symptom. Psoralen has been reported to show estrogen-like activity, antioxidant activity, osteoblastic proliferation accelerating activity, antitumor effects and antibacterial activity. However, the antitumor mechanism of psoralen is not fully understood. This study aimed to investigate the therapeutic efficacy of psoralen in human hepatoma cell line SMMC7721 and the mechanism of antitumor effects. RESULTS: Psoralen inhibited proliferation of SMMC7721 in a dose- and time-dependent manner, and promoted apoptosis. Further, psoralen activated the ER stress signal pathway, including the expansion of endoplasmic reticulum, increasing the mRNA levels of GRP78, DDIT3, ATF4, XBP1, GADD34 and the protein levels of GDF15, GRP78, IRE1α, XBP-1s in a time-dependent manner. Psoralen induces cell cycle arrest at G1 phase by enhancing CyclinD1 and reducing CyclinE1 expression. Moreover, TUDC couldn't inhibit the psoralen-induced ER stress in SMMC7721 cells. CONCLUSIONS: Psoralen can inhibit the proliferation of SMMC7721 cells and induce ER stress response to induce cell apoptosis, suggesting that psoralen may represent a novel therapeutic option for the prevention and treatment hepatocellular carcinoma.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Ficusina/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Ficusina/química , Ficusina/uso terapêutico , Humanos , Neoplasias Hepáticas/patologia , Proteínas Serina-Treonina Quinases/farmacologia , Transdução de Sinais/efeitos dos fármacos
18.
Oncology ; 97(5): 277-285, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31307035

RESUMO

BACKGROUND/AIM: We evaluated clinical factors related to improved prognosis of unresectable hepatocellular carcinoma patients (u-HCC), who were treated with tyrosine kinase inhibitor (TKI) sequential therapy, including lenvatinib (LEN). MATERIALS/METHODS: We enrolled 84 u-HCC cases treated with TKIs including LEN from March 2018 to January 2019 (median age 71 years, 63 males, Child-Pugh score (CPS) 5/6/7 = 62/21/1, tumor-node-metastasis stage of Liver Cancer Study Group of Japan 6th (TNM-LCSGJ) II/III/IVa/IVb = 12/30/5/37, Barcelona Clinic Liver Cancer stage B/C = 33:51). Clinical findings at introduction of the initial TKI were retrospectively evaluated. RESULTS: The median albumin-bilirubin (ALBI) score at introduction of the initial TKI (sorafenib [SOR]/LEN = 80/4) was -2.56, and the past number of transarterial catheter chemoembolization was 3 (IQR: 2-5) (second-line: regorafenib [REG]/LEN/SOR = 31/49/4, third-line: LEN/REG = 31:1). The total period of administration with TKIs showed a good relationship with overall survival (OS) (r = 0.946, 95% confidence interval [CI]: 0.918-0.965, p < 0.001). The prognosis of the entire cohort was good (estimated median survival time: 46.4 months, 1-/2-/3-year OS rate [OSR] = 87.7/63.0/57.2%). A modified-ALBI grade (mALBI) of 2b (ALBI score >-2.27) was the only significant factor at the start of the initial TKI for poor prognosis (hazard ratio 2.319, 95% CI: 1.064-5.052, p = 0.034), while CPS (≥6) was not. Although there was no significant difference in TNM-LCSGJ (p = 0.213), the prognosis of patients with mALBI 1/2a (n = 66) showed better prognosis as compared to those with mALBI 2b (n = 18) (1-year/2-year/3-year OSR = 89.1/69.8/66% vs. 82.4/47.1/23.5%, p = 0.029). CONCLUSION: Good hepatic function (mALBI 1/2a) at introduction of the initial TKI is a requirement for improved prognosis of u-HCC undergoing TKI sequential therapy.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Compostos de Fenilureia/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Quinolinas/uso terapêutico , Idoso , Bilirrubina/sangue , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Feminino , Humanos , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Masculino , Prognóstico , Albumina Sérica/análise
20.
Eur J Med Chem ; 179: 916-935, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31306818

RESUMO

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors. Traditional chemotherapy drugs are hard to reach a satisfactory therapeutic effect since advanced HCC is highly chemo-resistant. Sorafenib is an oral multikinase inhibitor that can suppress tumor cell proliferation, angiogenesis and induce cancer cell apoptosis. However, the poor solubility, rapid metabolism and low bioavailability of sorafenib greatly restricted its further clinical application. During the past decade, numerous sorafenib derivatives have been designed and synthesized to overcome its disadvantages and improve its clinical performance. This article focuses on the therapeutic effects and mechanisms of various sorafenib derivatives with modifications on the N-methylpicolinamide group, urea group, central aromatic ring or others. More importantly, this review summarizes the current status of the structure-activity relationship (SAR) of reported sorafenib derivatives, which can provide some detailed information of future directions for further structural modifications of sorafenib to discovery new anti-tumor drugs with improved clinical performance.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Sorafenibe/farmacologia , Animais , Antineoplásicos/química , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Proliferação de Células/efeitos dos fármacos , Química Farmacêutica , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Sorafenibe/química
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