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1.
Anticancer Res ; 39(10): 5653-5662, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570463

RESUMO

BACKGROUND/AIM: Factors influencing fulvestrant efficacy may be useful in selecting the optimal treatment regimen for postmenopausal Japanese women with metastatic/recurrent HR-positive, HER2-negative breast cancer. PATIENTS AND METHODS: We retrospectively evaluated progression-free and overall survival (PFS and OS) in 100 fulvestrant-treated patients according to metastatic site. RESULTS: Median PFS was significantly better in patients with non-visceral (bone and regional metastases; 22.8 months) vs. visceral metastasis (lung, liver, and other organs; 8.2 months; p=0.024), although median OS did not differ (p=0.922). Median PFS in patients with lung metastasis (20.8 months) and non-visceral metastasis (22.8 months) were comparable; patients with liver metastasis (6.1 months) and other organ metastases (3.7 months) had worse prognoses. CONCLUSION: Patients with non-visceral metastases had a better prognosis than those with visceral metastases. Fulvestrant induced a longer PFS in patients with non-visceral metastasis, and also in those with lung metastasis without liver or other organ involvement.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Fulvestranto/uso terapêutico , Metástase Neoplásica/prevenção & controle , Recidiva Local de Neoplasia/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica/genética , Metástase Neoplásica/patologia , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Prognóstico , Intervalo Livre de Progressão , Receptor ErbB-2/genética , Receptores de Superfície Celular/genética , Estudos Retrospectivos
2.
Biol Res ; 52(1): 40, 2019 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-31387647

RESUMO

BACKGROUND: There are currently a number of barriers hindering the successful treatment of breast cancer, including the metastatic spread of cancer cells. In looking for new anticancer agents, we reported two novel hydrazide derivatives with anti-cancer activity in human breast cancer cells. The current study aims to explore the therapeutic potential of the most effective one, N'-((5-nitrothiophen-2-yl)methylene)-2-(phenylthio)benzohydrazide (compound B), on metastatic breast cancer, which is resistant to available chemotherapeutics. METHODS: 4T1 mammary carcinoma cells were inoculated into the fat pad mammary of 5-7-week-old female BALB/c mice and then the effective compound was intraperitoneally administered for 4 weeks. Proliferation index and angiogenesis in tumor and lung tissues were examined with immunohistochemistry. In vitro assessments were also carried out to evaluate the effect of the compound on invasion of MDA-MB-231 cells. RESULTS: Our results demonstrated that this effective derivative significantly inhibited invasion of MDA-MB-231 cells in vitro as shown by Matrigel assay and quantitative real-time method for MMP-9 expression after 48 h of treatment. Daily administration of the compound suppressed the growth of primary tumor and its metastasis to lung, which was confirmed by H&E experiment at a dose of 1 mg/kg in a well-known metastatic model of 4T1 breast cancer in syngeneic BALB/c mice. These outcomes were supported by the immunohistochemical examinations of the tumor and lung tissues of mice. Tumors and lungs in mice treated with the effective compound showed a reduced proliferation index and a smaller microvessel density compared to the control. CONCLUSION: This study highlights an anti-metastatic role for a novel hydrazide derivative in both in vitro and in vivo models of breast cancer.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Metástase Neoplásica/prevenção & controle , Animais , Linhagem Celular Tumoral , Feminino , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos BALB C
3.
Cytogenet Genome Res ; 158(4): 205-212, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31434093

RESUMO

EHMT2 (euchromatic histone lysine methyltransferase 2), a histone methyltransferase, has been shown to be involved in multiple human cancers. In this study, we determined mRNA and protein expression of EHMT2 in cervical cancer cells and normal cervical epithelial cells. EHMT2 was inhibited with short hairpin RNA (shEHMT2) in cervical cancer cells. Cell viability, colony proliferation, apoptosis, adhesion, and invasion assays and Western blot were performed to assess the function of EHMT2. As a result, EHMT2 was upregulated in human cervical cancer cells compared to normal cervical epithelial cells. Suppression of EHMT2 expression impairs cell proliferation and induces apoptosis. Furthermore, EHMT2 silencing inhibited cell adhesion and invasion. Finally, knockdown of EHMT2 resulted in a reduction of the expression of the tumorigenic proteins Bcl-2, Mcl-1, and Survivin and in an increase in the expression of the anti-malignant protein E-cadherin. In conclusion, our data suggest that EHMT2 plays a key role in cell proliferation and metastatic capacity in cervical cancer cells and could serve as a potential therapeutic target.


Assuntos
Inativação Gênica , Antígenos de Histocompatibilidade/genética , Histona-Lisina N-Metiltransferase/deficiência , Histona-Lisina N-Metiltransferase/genética , Invasividade Neoplásica/genética , Invasividade Neoplásica/prevenção & controle , Neoplasias do Colo do Útero/enzimologia , Neoplasias do Colo do Útero/patologia , Apoptose/genética , Caderinas/biossíntese , Adesão Celular/genética , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Antígenos de Histocompatibilidade/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Invasividade Neoplásica/patologia , Metástase Neoplásica/genética , Metástase Neoplásica/patologia , Metástase Neoplásica/prevenção & controle , Neoplasias do Colo do Útero/genética
4.
Nat Immunol ; 20(8): 1012-1022, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31263276

RESUMO

The plasma membrane tetraspan molecule MS4A4A is selectively expressed by macrophage-lineage cells, but its function is unknown. Here we report that MS4A4A was restricted to murine and human mononuclear phagocytes and was induced during monocyte-to-macrophage differentiation in the presence of interleukin 4 or dexamethasone. Human MS4A4A was co-expressed with M2/M2-like molecules in subsets of normal tissue-resident macrophages, infiltrating macrophages from inflamed synovium and tumor-associated macrophages. MS4A4A interacted and colocalized with the ß-glucan receptor dectin-1 in lipid rafts. In response to dectin-1 ligands, Ms4a4a-deficient macrophages showed defective signaling and defective production of effector molecules. In experimental models of tumor progression and metastasis, Ms4a4a deficiency in macrophages had no impact on primary tumor growth, but was essential for dectin-1-mediated activation of macrophages and natural killer (NK) cell-mediated metastasis control. Thus, MS4A4A is a tetraspan molecule selectively expressed in macrophages during differentiation and polarization, essential for dectin-1-dependent activation of NK cell-mediated resistance to metastasis.


Assuntos
Células Matadoras Naturais/imunologia , Lectinas Tipo C/metabolismo , Macrófagos/imunologia , Proteínas de Membrana/metabolismo , Metástase Neoplásica/imunologia , Neoplasias/imunologia , Animais , Diferenciação Celular/imunologia , Linhagem da Célula , Dexametasona/farmacologia , Humanos , Interleucina-4/metabolismo , Ativação Linfocitária/imunologia , Ativação de Macrófagos/imunologia , Macrófagos/citologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Metástase Neoplásica/prevenção & controle , Neoplasias/patologia
5.
Eur J Oncol Nurs ; 41: 1-6, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31358241

RESUMO

PURPOSE: This study examined the prognostic associations of pre-treatment quality of life (QoL) with overall survival (OS) and distant metastasis-free survival (DFMS) among patients with head and neck cancer (HNC) who underwent free flap reconstruction. METHODS: A cohort of 127 HNC patients who received free flap reconstruction between November 2010 and June 2014 at a hospital were recruited. Pre-treatment QoL was measured by the University of Washington Quality of Life Questionnaire, which contains six physical domains, including speech, swallowing, appearance, saliva, taste and chewing, as well as the six social-emotional domains of pain, activity, recreation, shoulder, mood, and anxiety. Cox regression analyses were performed. RESULTS: Results showed that pre-treatment QoL was predictive of OS and DMFS. Of the domains, swallowing, chewing, speech, taste, saliva, pain and shoulder were demonstrated to be significant predictors of OS. Additionally, swallowing, chewing, speech, pain and activity were demonstrated making significant contributions to DMFS. CONCLUSION: Our data supported that physical domains of pre-treatment QoL were predictors for OS and DFMS in HNC patients with free-flap reconstruction. Longitudinal studies are warranted to clarify the prognostic abilities of social-emotional domains. Information on pre-treatment QoL should be taken into account to individualize care plan for these patients, and hence prolong their survival.


Assuntos
Retalhos de Tecido Biológico , Neoplasias de Cabeça e Pescoço/cirurgia , Metástase Neoplásica/prevenção & controle , Cuidados Pré-Operatórios/psicologia , Qualidade de Vida/psicologia , Sobrevida/psicologia , Adulto , Idoso , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Procedimentos Cirúrgicos Reconstrutivos , Inquéritos e Questionários
6.
Nature ; 571(7763): 127-131, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31243371

RESUMO

Cancer metastasis is the primary cause of morbidity and mortality, and accounts for up to 95% of cancer-related deaths1. Cancer cells often reprogram their metabolism to efficiently support cell proliferation and survival2,3. However, whether and how those metabolic alterations contribute to the migration of tumour cells remain largely unknown. UDP-glucose 6-dehydrogenase (UGDH) is a key enzyme in the uronic acid pathway, and converts UDP-glucose to UDP-glucuronic acid4. Here we show that, after activation of EGFR, UGDH is phosphorylated at tyrosine 473 in human lung cancer cells. Phosphorylated UGDH interacts with Hu antigen R (HuR) and converts UDP-glucose to UDP-glucuronic acid, which attenuates the UDP-glucose-mediated inhibition of the association of HuR with SNAI1 mRNA and therefore enhances the stability of SNAI1 mRNA. Increased production of SNAIL initiates the epithelial-mesenchymal transition, thus promoting the migration of tumour cells and lung cancer metastasis. In addition, phosphorylation of UGDH at tyrosine 473 correlates with metastatic recurrence and poor prognosis of patients with lung cancer. Our findings reveal a tumour-suppressive role of UDP-glucose in lung cancer metastasis and uncover a mechanism by which UGDH promotes tumour metastasis by increasing the stability of SNAI1 mRNA.


Assuntos
Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Metástase Neoplásica/genética , Metástase Neoplásica/prevenção & controle , Estabilidade de RNA , Fatores de Transcrição da Família Snail/genética , Uridina Difosfato Glucose/metabolismo , Animais , Linhagem Celular Tumoral , Movimento Celular , Proteína Semelhante a ELAV 1/deficiência , Proteína Semelhante a ELAV 1/genética , Proteína Semelhante a ELAV 1/metabolismo , Transição Epitelial-Mesenquimal , Feminino , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/metabolismo , Camundongos , Camundongos Nus , Fosfotirosina/metabolismo , Prognóstico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Neoplásico/genética , RNA Neoplásico/metabolismo , Fatores de Transcrição da Família Snail/biossíntese , Uridina Difosfato Glucose Desidrogenase/química , Uridina Difosfato Glucose Desidrogenase/genética , Uridina Difosfato Glucose Desidrogenase/metabolismo , Uridina Difosfato Ácido Glucurônico/metabolismo
7.
Scand J Immunol ; 90(2): e12777, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31075180

RESUMO

TAM family members (TYRO3, AXL and MERTK) play essential roles in the resolution of inflammation and in infectious diseases and cancer. AXL, a tyrosine kinase receptor, is commonly overexpressed in several solid tumours and numerous hematopoietic malignancies including acute myeloid leukaemia, acute lymphocytic leukaemia, chronic myeloid leukaemia, chronic lymphocytic leukaemia and multiple myeloma. AXL significantly promotes tumour cell migration, invasion and metastasis, as well as angiogenesis. AXL also plays an important role in inflammation and macrophage ontogeny. Recent studies have revealed that AXL contributes to leukaemic phenotypes through activation of oncogenic signalling pathways that lead to increased cell migration and proliferation. To evaluate the mechanisms underlying the role of AXL signalling in tumour metastasis, we screened a phage display library to generate a novel human monoclonal antibody, named DAXL-88, that recognizes both human and murine AXL. The concentrations of DAXL-88 required for 50% maximal binding to human and murine AXL were 0.118 and 0.164 µg/mL, respectively. Furthermore, DAXL-88 bound to human AXL with high affinity (KD  ~ 370 pM). DAXL-88 blocked the interaction between AXL and its ligand, growth arrest-specific gene 6 (GAS6), with a half maximal inhibitory concentration of 2.16 µg/mL. Moreover, DAXL-88 inhibited AXL/GAS6-dependent cell signalling, which is implicated in cell migration and invasion. In conclusion, the novel anti-AXL DAXL-88 high-affinity antibody blocks the interaction between AXL and GAS6 and inhibits tumour cell migration and invasion induced by GAS6. Thus, DAXL-88 offers promise for the development of targeted therapeutic strategies in solid tumours, leukaemias and other lymphoid neoplasms.


Assuntos
Anticorpos Monoclonais/farmacologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Neoplasias Ovarianas/patologia , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Células A549 , Anticorpos Monoclonais/imunologia , Linhagem Celular Tumoral , Movimento Celular , Feminino , Humanos , Simulação de Acoplamento Molecular , Invasividade Neoplásica/patologia , Invasividade Neoplásica/prevenção & controle , Metástase Neoplásica/prevenção & controle , Ligação Proteica , Proteínas Proto-Oncogênicas/imunologia , Receptores Proteína Tirosina Quinases/imunologia , Transdução de Sinais
8.
Inorg Chem ; 58(8): 4880-4893, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30932487

RESUMO

Rhodium(III) anticancer drugs can exert preferential antimetastatic or cytotoxic activities, which are dependent on subtle structural changes. In order to delineate factors affecting the biotransformations and speciation, mer,cis-[RhCl3( S-dmso)2( O-dmso)] (A1) and mer,cis-[RhCl3( S-dmso)2(2N-indazole)] (A2) have been studied by X-ray absorption spectroscopy (XAS). Interactions of these complexes with saline buffer, cell culture media, serum proteins (albumin and apo-transferrin), native and chemically degraded collagen gels, and A549 cells have been studied using linear combination fitting (LCF) and 3D scatter plots of XAS data. Following initial aquation and hydrolysis reactions involving stepwise displacement of Cl- and S-/ O-dmso ligands, the Rh(III) complexes underwent further ligand substitution reactions with biological nucleophiles (e.g., amino acid residues of serum proteins). The reaction of A1 with chemically degraded collagen gel was postulated to be a key reason for its antimetastatic activity. Analyses of the XAS of Rh-treated bulk cells were consistent with structure-reactivity relationships in which the more reactive A1 was predominantly antimetastatic and the less reactive A2 was predominantly cytotoxic, showing relationships parallel to typical Ru(III) anticancer agents, i.e., NAMI-A ([ImH] trans-[RuCl4( S-dmso)( N-imidazole)2], ImH = imidazolium cation) and KP1019/NKP1339 (KP1019, [IndH] trans-[RuCl4(N-indazole)2], IndH = indazolium cation; NKP1339, sodium trans-[RuCl4(2N-indazole)2]), respectively.


Assuntos
Antineoplásicos/farmacologia , Dimetil Sulfóxido/química , Dimetil Sulfóxido/farmacologia , Metástase Neoplásica/prevenção & controle , Ródio/química , Ródio/farmacologia , Espectroscopia por Absorção de Raios X/métodos , Células A549 , Proteínas Sanguíneas/química , Meios de Cultura , Meios de Cultura Livres de Soro , Humanos , Relação Estrutura-Atividade
9.
J Enzyme Inhib Med Chem ; 34(1): 909-926, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30957641

RESUMO

Overexpression of heat shock protein 90 (Hsp90) is common in various types of cancer. In cutaneous melanoma, a cancer with one of the high levels of Hsp90 overexpression, such expression was correlated with a panel of protein kinases, thus offering an opportunity to identify Hsp90-based multi-kinase inhibitors for novel cancer therapies. Towards this goal, we utilized a 2,4-dihydroxy-5-isopropylbenzate-based Hsp90 inhibitor scaffold and thieno[2,3-d]pyrimidine-based kinase inhibitor scaffold to develop a Hsp90-inhibiting compound library. Our inhibitory compound named 8m inhibited Hsp90 and PI3Kα with an IC50 value of 38.6 nM and 48.4 nM, respectively; it displayed improved cellular activity which could effectively induce cell cycle arrest and apoptosis in melanoma cells and lead to the inhibition of cell proliferation, colony formation, migration and invasion. Our results demonstrated 8m to be a promising lead compound for further therapeutic potential assessment of Hsp90/PI3Kα dual inhibitors in melanoma targeted therapy.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Desenho de Drogas , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Melanoma/tratamento farmacológico , Proteínas Nucleares/antagonistas & inibidores , Neoplasias Cutâneas/tratamento farmacológico , Fatores de Transcrição/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cromatografia Gasosa , Inibidores Enzimáticos/síntese química , Feminino , Humanos , Concentração Inibidora 50 , Melanoma/enzimologia , Melanoma/metabolismo , Melanoma/patologia , Camundongos , Camundongos Endogâmicos C57BL , Invasividade Neoplásica/prevenção & controle , Metástase Neoplásica/prevenção & controle , Espectroscopia de Prótons por Ressonância Magnética , Neoplasias Cutâneas/enzimologia , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Biosci Biotechnol Biochem ; 83(9): 1729-1739, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31010399

RESUMO

Lupeol, one of the common components from the fruits and natural foods, has been reported to exert antitumor activities in many human cancer cell lines; however, its effects on osteosarcoma cell metastasis were not elucidated. In the present study, lupeol at 10-25 µM induced cell morphological changes and decreased total viable cell number in U-2 OS cells. Lupeol (5-15 µM) suppressed cell mobility, migration, and invasion by wound healing and transwell chamber assays, respectively. Lupeol inhibited the activities of MMP-2 and -9 in U-2 OS cells by gelatin zymography assay. Lupeol significantly decreased PI3K, pAKT, ß-catenin, and increased GSK3ß. Furthermore, lupeol decreased the expressions of Ras, p-Raf-1, p-p38, and ß-catenin. Lupeol also decreased uPA, MMP-2, MMP-9, and N-cadherin but increased VE-cadherin in U-2 OS cells. Based on these observations, we suggest that lupeol can be used in anti-metastasis of human osteosarcoma cells in the future.


Assuntos
Neoplasias Ósseas/patologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Invasividade Neoplásica/prevenção & controle , Metástase Neoplásica/prevenção & controle , Osteossarcoma/patologia , Triterpenos Pentacíclicos/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Neoplasias Ósseas/enzimologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Metaloproteinases da Matriz/metabolismo , Osteossarcoma/enzimologia
11.
Food Chem Toxicol ; 127: 19-30, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30844437

RESUMO

Hesperidin is a flavonoid which occurs in citrus fruits. Hesperidin was gamma-irradiated at doses of 0, 30, 70, and 150 kGy. Gamma irradiation induced a decreased hesperidin peak, and a new radiolytic peak that gradually increased up to 150 kGy. The new radiolytic peak was fractionated, and the fractionated hesperidin derivative was used for subsequent experiments. Hesperidin gamma-irradiated at 150 kGy was toxic toward B16BL6 cells, but not toward bone marrow-derived macrophages. This cytotoxicity was exerted via induction of apoptosis, as reflected by the high population of double-positive cells, increased sub-G1 phase cells, depolarization of matrix metalloproteinase, production of reactive oxygen species, weakness of cell adhesion, changes in cell morphology, and inhibition of B16BL6 cell migration. Furthermore, 150 kGy gamma-irradiated hesperidin decreased the expression of Bcl-2 and pro-caspases-3 and -9, increased the expression of Bax and cytosolic cytochrome c, and increased the cleavage of poly ADP ribose polymerase. In vitro mechanistic study revealed that 150 kGy gamma-irradiated hesperidin achieved significantly greater inhibition of lung metastasis and growth of melanoma B16BL6 cells in C57BL/6 mice than non-irradiated intact hesperidin did. These results suggest that the structural modification of hesperidin induced by gamma irradiation could facilitate the development of anti-cancer drugs.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Raios gama , Hesperidina/farmacologia , Melanoma Experimental/patologia , Metástase Neoplásica/prevenção & controle , Animais , Linhagem Celular Tumoral , Relação Dose-Resposta à Radiação , Hesperidina/química , Hesperidina/efeitos da radiação , Masculino , Metaloproteinases da Matriz/metabolismo , Melanoma Experimental/enzimologia , Melanoma Experimental/metabolismo , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/efeitos da radiação , Estrutura Molecular , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade
12.
Cell Biochem Funct ; 37(3): 128-138, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30883849

RESUMO

Xanthoangelol (XAG), a prenylated chalcone isolated from the Japanese herb Angelica keiskei Koidzumi, has been reported to exhibit antineoplastic properties. However, the specific anti-tumor activity of XAG in human hepatocellular carcinoma (HCC), and the relevant mechanisms are not known. Herein, we evaluated the effect of XAG against HCC in vitro and in vivo. Although XAG treatment did not significantly reduce the viability of the Hep3B and Huh7 cell lines, it suppressed cell migration, invasion, and EMT. This anti-metastatic effect of XAG was due to induction of autophagy, because treatment with the autophagy inhibitor 3-methyadenine (3-MA) or knockdown of the pro-autophagy Beclin-1 effectively abrogated the XAG-induced suppression of metastasis. Mechanistically, XAG induced autophagy via activation of the AMPK/mTOR signaling pathway, and XAG treatment dramatically increased the expression of p-AMPK while decreasing p-mTOR expression. In addition, blocking AMPK/mTOR axis with compound C abrogated the autophagy-mediated inhibition of metastasis. The murine model of HCC metastasis also showed that XAG effectively reduced the number of metastatic pulmonary nodules. Taken together, our results revealed that autophagy via the activation of AMPK/mTOR pathway is essential for the anti-metastatic effect of XAG against HCC. These findings not only contribute to our understanding of the anti-tumor activity of XAG but also provide a basis for its clinical application in HCC. Before this study, evidence of XAG on HCC was purely anecdotal; present study provides the first comprehensive assessments of XAG on HCC metastasis and investigates its underlying mechanism. Results suggest that XAG exerts anti-metastatic properties against HCC through inducing autophagy which is mediated by the activation of AMPK/mTOR signaling pathway. This research extends our knowledge about the antineoplastic properties of XAG and suggests that induction autophagy may represent future treatment strategies for metastatic HCC.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Autofagia/efeitos dos fármacos , Carcinoma Hepatocelular/patologia , Chalcona/análogos & derivados , Neoplasias Hepáticas/patologia , Metástase Neoplásica/prevenção & controle , Angelica/química , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Chalcona/química , Chalcona/isolamento & purificação , Chalcona/farmacologia , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Metástase Neoplásica/tratamento farmacológico , Metástase Neoplásica/patologia , Relação Estrutura-Atividade , Células Tumorais Cultivadas
13.
Acta Biochim Biophys Sin (Shanghai) ; 51(3): 263-276, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30883650

RESUMO

Metastasis is the main reason for high recurrence and poor survival of hepatocellular carcinoma (HCC). The molecular mechanism underlying HCC metastasis remains unclear. In this study, we found that argininosuccinate synthase 1 (ASS1) expression was significantly decreased and down-regulation of ASS1 was closely correlated with poor prognosis in HCC patients. DNA methylation led to the down-regulation of ASS1 in HCC. Stable silencing of ASS1 promoted migration and invasion of HCC cells, whereas overexpression of ASS1-inhibited metastasis of HCC cells in vivo and in vitro. We also revealed that ASS1-knockdown increased the phosphorylation level of S727STAT3, which contributed to HCC metastasis by up-regulation of inhibitor of differentiation 1 (ID1). These findings indicate that ASS1 inhibits HCC metastasis and may serve as a target for HCC diagnosis and treatment.


Assuntos
Argininossuccinato Sintase/fisiologia , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Fator de Transcrição STAT3/antagonistas & inibidores , Animais , Argininossuccinato Sintase/antagonistas & inibidores , Argininossuccinato Sintase/genética , Carcinoma Hepatocelular/enzimologia , Linhagem Celular Tumoral , Movimento Celular , Metilação de DNA , Humanos , Proteína 1 Inibidora de Diferenciação/genética , Neoplasias Hepáticas/enzimologia , Camundongos , Invasividade Neoplásica , Metástase Neoplásica/prevenção & controle , Fator de Transcrição STAT3/fisiologia , Transdução de Sinais/fisiologia
14.
Proc Natl Acad Sci U S A ; 116(13): 6292-6297, 2019 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-30862734

RESUMO

Inflammation in the tumor microenvironment is a strong promoter of tumor growth. Substantial epidemiologic evidence suggests that aspirin, which suppresses inflammation, reduces the risk of cancer. The mechanism by which aspirin inhibits cancer has remained unclear, and toxicity has limited its clinical use. Aspirin not only blocks the biosynthesis of prostaglandins, but also stimulates the endogenous production of anti-inflammatory and proresolving mediators termed aspirin-triggered specialized proresolving mediators (AT-SPMs), such as aspirin-triggered resolvins (AT-RvDs) and lipoxins (AT-LXs). Using genetic and pharmacologic manipulation of a proresolving receptor, we demonstrate that AT-RvDs mediate the antitumor activity of aspirin. Moreover, treatment of mice with AT-RvDs (e.g., AT-RvD1 and AT-RvD3) or AT-LXA4 inhibited primary tumor growth by enhancing macrophage phagocytosis of tumor cell debris and counter-regulating macrophage-secreted proinflammatory cytokines, including migration inhibitory factor, plasminogen activator inhibitor-1, and C-C motif chemokine ligand 2/monocyte chemoattractant protein 1. Thus, the pro-resolution activity of AT-resolvins and AT-lipoxins may explain some of aspirin's broad anticancer activity. These AT-SPMs are active at considerably lower concentrations than aspirin, and thus may provide a nontoxic approach to harnessing aspirin's anticancer activity.


Assuntos
Antineoplásicos/farmacologia , Aspirina/farmacologia , Neoplasias/tratamento farmacológico , Neoplasias/prevenção & controle , Animais , Aspirina/administração & dosagem , Quimiocina CCL2/metabolismo , Quimiocinas/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Ácidos Docosa-Hexaenoicos/metabolismo , Eicosanoides/metabolismo , Ácidos Graxos Insaturados/metabolismo , Feminino , Inflamação/tratamento farmacológico , Lipoxinas/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Metabolômica , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Proteínas Associadas aos Microtúbulos/metabolismo , Metástase Neoplásica/tratamento farmacológico , Metástase Neoplásica/prevenção & controle , Proteínas do Tecido Nervoso/metabolismo , Fagocitose/efeitos dos fármacos , Inativadores de Plasminogênio/metabolismo , Prostaglandinas/metabolismo
15.
J Med Food ; 22(5): 451-459, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30897013

RESUMO

To examine the anti-metastatic activities of polysaccharides in broccoli, purified polysaccharides (BCE-I, -II, and -III) were isolated by fractionation of broccoli enzyme extracts and subsequent ethanol precipitation. BCE-I mainly consisted of galactose and arabinose, whereas BCE-II mainly consisted of galacturonic acid and rhamnose, and BCE-III mainly consisted of rhamnose and galactose. Of the three fractions, stimulation of murine peritoneal macrophages by BCE-I showed the greatest enhancement of tumor necrosis factor-α, interleukin (IL)-12, and IL-6 secretion. In addition, intravenous (i.v.) administration of BCE-I enhanced the lethal activity of natural killer (NK) cells on YAC-1 tumor cells significantly and dose-dependently in an ex vivo experiment of NK cell activity. In an experimental model using lung metastasis of Colon26-M3.1 carcinoma cells, prophylactic i.v. and oral administration of BCE-I significantly and dose-dependently inhibited lung metastatic activity. Furthermore, the inhibitory activity of BCE-1 on lung metastasis partially disappeared when NK cell function was removed through treatment of rabbit anti-asialo GM1. These results indicated that BCE-I has potent antitumor metastatic activity, and that its anti-metastatic activity has relevance to the stimulation of NK and other immune cells.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Brassica/química , Neoplasias do Colo/imunologia , Imunidade Inata/efeitos dos fármacos , Neoplasias Pulmonares/prevenção & controle , Pectinas/farmacologia , Extratos Vegetais/farmacologia , Polissacarídeos/farmacologia , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Neoplasias do Colo/patologia , Feminino , Humanos , Interleucina-12/genética , Interleucina-12/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/secundário , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Metástase Neoplásica/imunologia , Metástase Neoplásica/prevenção & controle , Pectinas/química , Pectinas/isolamento & purificação , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Polissacarídeos/química , Polissacarídeos/isolamento & purificação
16.
Nutrients ; 11(2)2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30781353

RESUMO

Curcumae radix is the dry root of Curcuma longa L. (turmeric) that can be used either as a spice or traditional medicine. The aim of this study was to investigate the survival benefits and the anti-metastatic activity of curcumae radix extract (CRE) in MCF7 cells and in MMTV-PyMT transgenic mice-a mouse model of breast cancer metastasis. In vitro wound scratch assay revealed that CRE treatment inhibited cell motility and cell migration in a dose-dependent manner. To investigate the effect of CRE in breast cancer metastasis, MMTV-PyMT transgenic female virgin mice were used and randomly divided into two groups. For survival curve analysis, CRE was administered in a dose of 50 mg/kg to 8⁻20-week-old mice. Interestingly, CRE treatment significantly increased the median and prolonged survival of MMTV-PyMT mice. Furthermore, CRE treatment decreased tumor burden and inhibited cell proliferation in primary breast tumor, and also suppressed mammary tumor-derived lung metastasis. The size of the lung metastases substantially decreased in the CRE-treated group compared with the ones in the control group. Curcumae radix extract showed anti-metastatic activity through regulating the expression of metastasis markers including C-C Chemokine Receptor Type 7, Matrix Metalloproteinase 9 and the proto-oncogenes c-fos and c-jun. We demonstrated that these metastatic regulators were decreased when CCR7 expression was suppressed in MCF7 cells transfected with CCR7 siRNA. The results of this study show that curcumae radix exerts antitumor and anti-metastatic activities, and we suggest that curcumae radix might be a potential supplement for the treatment and prevention of breast cancer metastasis.


Assuntos
Antineoplásicos/farmacologia , Curcuma , Neoplasias Pulmonares/prevenção & controle , Neoplasias Mamárias Experimentais/tratamento farmacológico , Metástase Neoplásica/prevenção & controle , Extratos Vegetais/farmacologia , Receptores CCR7/efeitos dos fármacos , Animais , Feminino , Genes fos/efeitos dos fármacos , Genes jun/efeitos dos fármacos , Neoplasias Pulmonares/secundário , Neoplasias Mamárias Experimentais/patologia , Metaloproteinase 9 da Matriz/efeitos dos fármacos , Camundongos , Camundongos Transgênicos , Raízes de Plantas , Receptores CCR7/biossíntese
18.
Mar Drugs ; 17(2)2019 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-30781633

RESUMO

Perinereis aibuhitensis peptide (PAP) is a decapeptide (Ile-Glu-Pro-Gly-Thr-Val-Gly-Met-Met-Phe, IEPGTVGMMF) with anticancer activity that was purified from an enzymatic hydrolysate of Perinereis aibuhitensis. In the present study, the anticancer effect of PAP on H1299 cell proliferation was investigated. Our results showed that PAP promoted apoptosis and inhibited the proliferation of H1299 cells in a time- and dose-dependent manner. When the PAP concentration reached 0.92 mM, more than 95% of treated cells died after 72 h of treatment. Changes in cell morphology were further analyzed using an inverted microscope and AO/EB staining and flow cytometry was adopted for detecting apoptosis and cell cycle phase. The results showed that the early and late apoptosis rates of H1299 cells increased significantly after treatment with PAP and the total apoptosis rate was significantly higher than that of the control group. Moreover, after treatment with PAP, the number of cells in the S phase of cells was significantly reduced and the ability for the cells to proliferate was also reduced. H1299 cells were arrested in the G2/M phase and cell cycle progression was inhibited. Furthermore, the results of western blotting showed that nm23-H1 and vascular endothelial growth factor (VEGF) protein levels decreased in a dose-dependent manner, while the pro-apoptotic protein and anti-apoptotic protein ratios and the level of apoptosis-related caspase protein increased in a dose-dependent manner. In conclusion, our results indicated that PAP, as a natural marine bioactive substance, inhibited proliferation and induced apoptosis of human lung cancer H1299 cells. PAP is likely to be exploited as the functional food or adjuvant that may be used for prevention or treatment of human non-small cell lung cancer in the future.


Assuntos
Antineoplásicos/farmacologia , Oligopeptídeos/farmacologia , Poliquetos/química , Sequência de Aminoácidos , Animais , Antineoplásicos/isolamento & purificação , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Caspases/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Metástase Neoplásica/prevenção & controle , Oligopeptídeos/isolamento & purificação , Fator A de Crescimento do Endotélio Vascular/biossíntese
19.
Phytomedicine ; 56: 194-206, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30668340

RESUMO

BACKGROUND: Cisplatin (CP) is a chemotherapeutic drug for treating melanoma that also causes adverse side effects in cancer patients. PURPOSE: This study investigated the bioefficacy of a phytoagent deoxyelephantopin (DET) in inhibiting B16 melanoma cell activity, its synergism with CP against metastatic melanoma, and its capability to attenuate CP side effects in animals. METHODS: DET and CP bioactivities were assessed by MTT assay, isobologram analysis, time-lapse microscopy, migration and invasion assays, flow cytometry and western blotting. In vivo bioluminescence imaging was used to detect lung metastasis of B16 cells carrying COX-2 reporter gene in syngeneic mice. H&E staining and immunohistochemistry were used to evaluate the compound/drug efficacy and CP side effects. Nephrotoxicity caused by CP treatment in mice was evaluated by UPLC/ESI-QTOF MS - based metabolomics and haematometry. RESULT: DET, alone or in combination with cisplatin, inhibited B16 cell proliferation, migration, and invasion, and induced cell-cycle arrested at the G2/M phase and de-regulated cell-cycle mediators in cancer cells. In a murine B16COX-Luc metastatic allograft model, CP2 (2  mg/kg) treatment inhibited B16 lung metastasis accompanied by severe body weight loss, renal damage and inflammation, and haematological toxicity. DET10 and CP cotreatment (DET10 + CP1) or sequential treatment (CP2→DET10) significantly inhibited formation of pulmonary melanoma foci and reduced renal damage. DET pretreatment (Pre-DET10) or CP2→DET10 treatment had the longest survival (52  vs. 37 days for tumor control mice). CP treatment caused abnormally accumulated urea cycle metabolites and serotonin metabolite hippuric acid in renal tissues that were not seen with DET alone or in combination with CP. CONCLUSION: The CP and DET combination may be an effective intervention for melanoma with reduced side effects.


Assuntos
Antineoplásicos/farmacologia , Cisplatino/farmacologia , Lactonas/farmacologia , Neoplasias Pulmonares/prevenção & controle , Melanoma Experimental/tratamento farmacológico , Compostos Fitoquímicos/farmacologia , Sesquiterpenos/farmacologia , Animais , Antineoplásicos/efeitos adversos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cisplatino/efeitos adversos , Modelos Animais de Doenças , Sinergismo Farmacológico , Quimioterapia Combinada , Feminino , Humanos , Neoplasias Pulmonares/secundário , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Invasividade Neoplásica/prevenção & controle , Metástase Neoplásica/prevenção & controle
20.
Phytother Res ; 33(3): 798-807, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30653763

RESUMO

Tumor metastasis is still the leading cause of melanoma mortality. Luteolin, a natural flavonoid, is found in fruits, vegetables, and medicinal herbs. The pharmacological action and mechanism of luteolin on the metastasis of melanoma remain elusive. In this study, we investigated the effect of luteolin on A375 and B16-F10 cell viability, migration, invasion, adhesion, and tube formation of human umbilical vein endothelial cells. Epithelial-mesenchymal transition (EMT) markers and pivotal molecules in HIF-1α/VEGF signaling expression were analysed using western blot assays or quantitative real-time polymerase chain reaction. Results showed that luteolin inhibits cellular proliferation in A375 and B16-F10 melanoma cells in a time-dependent and concentration-dependent manner. Luteolin significantly inhibited the migratory, invasive, adhesive, and tube-forming potential of highly metastatic A375 and B16-F10 melanoma cells or human umbilical vein endothelial cells at sub-IC50 concentrations, where no significant cytotoxicity was observed. Luteolin effectively suppressed EMT by increased E-cadherin and decreased N-cadherin and vimentin expression both in mRNA and protein levels. Further, luteolin exerted its anti-metastasis activity through decreasing the p-Akt, HIF-1α, VEGF-A, p-VEGFR-2, MMP-2, and MMP-9 proteins expression. Overall, our findings first time suggests that HIF-1α/VEGF signaling-mediated EMT and angiogenesis is critically involved in anti-metastasis effect of luteolin as a potential therapeutic candidate for melanoma.


Assuntos
Inibidores da Angiogênese/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Subunidade alfa do Fator 1 Induzível por Hipóxia/fisiologia , Luteolina/farmacologia , Melanoma/tratamento farmacológico , Transdução de Sinais/fisiologia , Fator A de Crescimento do Endotélio Vascular/fisiologia , Animais , Linhagem Celular Tumoral , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Melanoma/secundário , Metástase Neoplásica/prevenção & controle
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