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1.
Pharmacol Res ; 119: 242-250, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28212889

RESUMO

Despite the recent advances in the clinical management of melanoma, there remains a need for new pharmacological approaches to treat this cancer. 2-methoxyestradiol (2ME) is a metabolite of estrogen that has shown anti-tumor effects in many cancer types. In this study we show that 2ME treatment leads to growth inhibition in melanoma cells, an effect associated with entry into senescence, decreased pRb and Cyclin B1 expression, increased p21/Cip1 expression and G2/M cell cycle arrest. 2ME treatment also inhibits melanoma cell growth in colony formation assay, including cell lines with acquired resistance to BRAF and BRAF+MEK inhibitors. We further show that 2ME is effective against melanoma with different BRAF and NRAS mutational status. Moreover, 2ME induced the retraction of cytoplasmic projections in a 3D spheroid model and significantly decreased cell proliferation in a 3D skin reconstruct model. Together our studies bring new insights into the mechanism of action of 2ME allowing melanoma targeted therapy to be further refined. Continued progress in this area is expected to lead to improved anti-cancer treatments and the development of new and more effective clinical analogues.


Assuntos
Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Estradiol/análogos & derivados , Melanoma/tratamento farmacológico , Invasividade Neoplásica/prevenção & controle , Neoplasias Cutâneas/tratamento farmacológico , Pele/efeitos dos fármacos , 2-Metoxiestradiol , Apoptose/efeitos dos fármacos , Ciclo Celular , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Estradiol/farmacologia , Humanos , Melanoma/patologia , Invasividade Neoplásica/patologia , Pele/patologia , Neoplasias Cutâneas/patologia
2.
Br J Cancer ; 112(2): 217-26, 2015 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-25180764

RESUMO

In recent years, melanoma has become a poster-child for the development of oncogene-directed targeted therapies. This approach, which has been exemplified by the development of small-molecule BRAF inhibitors and the BRAF/MEK inhibitor combination for BRAF-mutant melanoma, has brought new hope to patients. Despite these successes, treatment failure seems near inevitable in the majority of cases­even in individuals treated with the BRAF/MEK inhibitor doublet. In the current review, we discuss the future of combination strategies for patients with BRAF-mutant melanoma as well as the emerging therapeutic options for patients with NRAS-mutant and BRAF/NRAS-wild-type melanoma. We also outline some of the newest developments in the in-depth personalisation of therapy that should allow melanoma treatment to continue shaping the field precision cancer medicine.


Assuntos
Proteínas Proto-Oncogênicas B-raf/genética , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Ensaios Clínicos como Assunto , Resistencia a Medicamentos Antineoplásicos/genética , GTP Fosfo-Hidrolases/genética , Humanos , Melanoma/tratamento farmacológico , Melanoma/genética , Proteínas de Membrana/genética , Terapia de Alvo Molecular , Mutação de Sentido Incorreto , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/genética
3.
Br J Cancer ; 102(12): 1724-30, 2010 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-20531415

RESUMO

BACKGROUND: Resistance to BRAF inhibitors is an emerging problem in the melanoma field. Strategies to prevent and overcome resistance are urgently required. METHODS: The dynamics of cell signalling, BrdU incorporation and cell-cycle entry after BRAF inhibition was measured using flow cytometry and western blot. The ability of combined BRAF/MEK inhibition to prevent the emergence of resistance was demonstrated by apoptosis and colony formation assays and in 3D organotypic cell culture. RESULTS: BRAF inhibition led to a rapid recovery of phospho-ERK (pERK) signalling. Although most of the cells remained growth arrested in the presence of drug, a minor population of cells retained their proliferative potential and escaped from BRAF inhibitor therapy. A function for the rebound pERK signalling in therapy escape was demonstrated by the ability of combined BRAF/MEK inhibition to enhance the levels of apoptosis and abrogate the onset of resistance. CONCLUSION: Combined BRAF/MEK inhibition may be one strategy to prevent the emergence of drug resistance in BRAF-V600E-mutated melanomas.


Assuntos
Resistencia a Medicamentos Antineoplásicos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Melanoma/tratamento farmacológico , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Humanos , Indóis/farmacologia , Sistema de Sinalização das MAP Quinases , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Mutação , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/farmacologia , Fatores de Tempo
4.
Br J Cancer ; 100(3): 431-5, 2009 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-19156138

RESUMO

The discovery of BRAF mutations in melanoma has not yet translated into clinical success, suggesting that BRAF/MEK inhibitors will need to be combined with other agents. In the current review, we discuss other pathways likely to be important for melanoma progression and suggest possible drug combinations for future clinical testing.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , MAP Quinase Quinase Quinases/antagonistas & inibidores , Melanoma/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Humanos , Camundongos , Inibidores de Proteínas Quinases/farmacologia
5.
Mini Rev Med Chem ; 6(4): 387-93, 2006 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16613575

RESUMO

Novel anti-cancer treatments use knowledge about the underlying biology of the tumor to find suitable molecular targets. The recent years have seen great advances in understanding the biology of melanoma. In the current review we discuss the most promising molecular targets for melanoma and suggest possible strategies for overcoming resistance.


Assuntos
Antineoplásicos/uso terapêutico , Melanoma/tratamento farmacológico , Humanos , Melanoma/enzimologia , Melanoma/genética , Mutação , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo
6.
Oncogene ; 35(10): 1225-35, 2016 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-26073081

RESUMO

The mechanisms by which some melanoma cells adapt to Serine/threonine-protein kinase B-Raf (BRAF) inhibitor therapy are incompletely understood. In the present study, we used mass spectrometry-based phosphoproteomics to determine how BRAF inhibition remodeled the signaling network of melanoma cell lines that were BRAF mutant and PTEN null. Short-term BRAF inhibition was associated with marked changes in fibronectin-based adhesion signaling that were PTEN dependent. These effects were recapitulated through BRAF siRNA knockdown and following treatment with chemotherapeutic drugs. Increased fibronectin expression was also observed in mouse xenograft models as well as specimens from melanoma patients undergoing BRAF inhibitor treatment. Analysis of a melanoma tissue microarray showed loss of PTEN expression to predict for a lower overall survival, with a trend for even lower survival being seen when loss of fibronectin was included in the analysis. Mechanistically, the induction of fibronectin limited the responses of these PTEN-null melanoma cell lines to vemurafenib, with enhanced cytotoxicity observed following the knockdown of either fibronectin or its receptor α5ß1 integrin. This in turn abrogated the cytotoxic response to BRAF inhibition via increased AKT signaling, which prevented the induction of cell death by maintaining the expression of the pro-survival protein Mcl-1. The protection conveyed by the induction of FN expression could be overcome through combined treatment with a BRAF and PI3K inhibitor.


Assuntos
Fibronectinas/metabolismo , Melanoma/patologia , PTEN Fosfo-Hidrolase/deficiência , PTEN Fosfo-Hidrolase/genética , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/genética , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Integrina alfa5beta1/metabolismo , Camundongos , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Proteômica , Proteínas Proto-Oncogênicas B-raf/deficiência , RNA Interferente Pequeno/genética , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Mol Oncol ; 9(7): 1447-1457, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25957812

RESUMO

The median survival for metastatic melanoma is in the realm of 8-16 months and there are few therapies that offer significant improvement in overall survival. One of the recent advances in cancer treatment focuses on epigenetic modifiers to alter the survivability and immunogenicity of cancer cells. Our group and others have previously demonstrated that pan-HDAC inhibitors induce apoptosis, cell cycle arrest and changes in the immunogenicity of melanoma cells. Here we interrogated specific HDACs which may be responsible for this effect. We found that both genetic abrogation and pharmacologic inhibition of HDAC6 decreases in vitro proliferation and induces G1 arrest of melanoma cell lines without inducing apoptosis. Moreover, targeting this molecule led to an important upregulation in the expression of tumor associated antigens and MHC class I, suggesting a potential improvement in the immunogenicity of these cells. Of note, this anti-melanoma activity was operative regardless of mutational status of the cells. These effects translated into a pronounced delay of in vivo melanoma tumor growth which was, at least in part, dependent on intact immunity as evidenced by the restoration of tumor growth after CD4+ and CD8+ depletion. Given our findings, we provide the initial rationale for the further development of selective HDAC6 inhibitors as potential therapeutic anti-melanoma agents.


Assuntos
Proliferação de Células/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/efeitos dos fármacos , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Animais , Linhagem Celular Tumoral , Fase G1/efeitos dos fármacos , Desacetilase 6 de Histona , Humanos , Melanoma Experimental/enzimologia , Camundongos , Camundongos Endogâmicos C57BL
8.
Melanoma Res ; 12(3): 187-92, 2002 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12140374

RESUMO

The retinoblastoma protein (pRB), the product of the retinoblastoma gene, is a key regulator of the cell cycle, affecting apoptosis, proliferation and differentiation. Dysregulation of pRB is implicated in the pathogenesis of many cancers, including malignant melanoma. Recently we demonstrated that alpha-melanocyte-stimulating hormone (alpha-MSH)-induced activation of p38 mitogen-activated protein (MAP) kinase leads to differentiation of B16 murine melanoma cells. The current study assesses the ability of alpha-MSH to activate p38 MAP kinase in COLO 853 human melanoma cells and determines whether this is linked to modulation of pRB activity. Treatment of COLO 853 cells with alpha-MSH induced time- and concentration-dependent increases in the phosphorylation of p38 MAP kinase, which corresponded with its ability to induce melanogenesis and inhibit cell growth. SB 203580, a selective inhibitor of p38 MAP kinase, blocked both the alpha-MSH-induced melanogenic response and inhibition of cell growth. Cell cycle analysis using flow cytometry revealed that treatment of COLO 853 cells with alpha-MSH for 72 h led to an increase in the proportion of cells in the G(1) phase and a marked reduction in the amount of phosphorylated pRB. Both of these effects were reversed by pre-treatment of cells with SB 203580. In summary, we have demonstrated for the first time that the alpha-MSH-induced differentiation of COLO 853 human melanoma cells proceeds via a p38 MAP kinase-mediated pathway and is associated with decreased pRB phosphorylation and accumulation of cells in the G(1) phase.


Assuntos
Sistema de Sinalização das MAP Quinases , Melanoma/patologia , Proteínas Quinases Ativadas por Mitógeno/fisiologia , Proteínas de Neoplasias/fisiologia , Processamento de Proteína Pós-Traducional , Proteína do Retinoblastoma/metabolismo , alfa-MSH/farmacologia , Diferenciação Celular/efeitos dos fármacos , Colforsina/farmacologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Fase G1 , Humanos , Imidazóis/farmacologia , Cinética , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Melaninas/biossíntese , Melaninas/metabolismo , Melanoma/enzimologia , Proteína Quinase 3 Ativada por Mitógeno , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Proteínas de Neoplasias/antagonistas & inibidores , Fosforilação , Piridinas/farmacologia , Células Tumorais Cultivadas/efeitos dos fármacos , Células Tumorais Cultivadas/enzimologia , Células Tumorais Cultivadas/metabolismo , Células Tumorais Cultivadas/patologia
9.
Oncogene ; 32(25): 3009-18, 2013 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-23069660

RESUMO

The recent years have seen a significant shift in the expectations for the therapeutic management of disseminated melanoma. The clinical success of BRAF targeted therapy suggests that long-term disease control may one day be a reality for genetically defined subgroups of melanoma patients. Despite this progress, few advances have been made in developing targeted therapeutic strategies for the 50% of patients whose melanomas are BRAF wild-type. The most well-characterized subgroup of BRAF wild-type tumors is the 15-20% of all melanomas that harbor activating NRAS (Neuroblastoma Rat Sarcoma Virus) mutations. Emerging preclinical and clinical evidence suggests that NRAS mutant melanomas have patterns of signal transduction and biological behavior that is distinct from BRAF mutant melanomas. This overview will discuss the unique clinical and prognostic behavior of NRAS mutant melanoma and will summarize the emerging data on how NRAS-driven signaling networks can be translated into novel therapeutic strategies.


Assuntos
GTP Fosfo-Hidrolases/genética , Melanoma/genética , Melanoma/terapia , Proteínas de Membrana/genética , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/terapia , Farnesil-Difosfato Farnesiltransferase/antagonistas & inibidores , Farnesil-Difosfato Farnesiltransferase/metabolismo , Humanos , Melanoma/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Mutação , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Prognóstico , Proteínas Proto-Oncogênicas B-raf/metabolismo , Transdução de Sinais , Neoplasias Cutâneas/metabolismo
10.
Pigment Cell Melanoma Res ; 24(1): e1-15, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21232023

RESUMO

The 2010 7th International Melanoma Congress sponsored by the Society for Melanoma Research and held in Sydney, Australia, was held together with the International Melanoma and Skin Cancer Centers group and the International Melanoma Pathology Study Group. As a consequence, there were over 900 registrants that included a wide range of clinicians (surgeons, medical oncologists, dermatologists) specialising in the management of melanoma as well as scientists and students carrying out laboratory-based research in melanoma. There was a general consensus that this grouping of clinicians, pathologists and scientists was mutually advantageous and plans are afoot to continue this grouping in future meetings. The meeting was dominated by the advances being made in treatment of melanoma with selective BRAF inhibitors but interest in epithelial mesenchymal transition and phenotypic changes in melanoma was apparent in many of the talks. The authors have attempted to capture many of the new developments in melanoma research but apologize to those speakers and poster presenters who had equally important findings not captured in these summaries.


Assuntos
Congressos como Assunto , Melanoma/patologia , Animais , Ensaios Clínicos como Assunto , Modelos Animais de Doenças , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Imunoterapia , Melanoma/tratamento farmacológico , Melanoma/genética , Melanoma/terapia , Camundongos , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , New South Wales , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/metabolismo , Peixe-Zebra/genética
11.
Oncogene ; 28(1): 85-94, 2009 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-18794803

RESUMO

Here, we identify a panel of melanoma lines with non-V600E mutations in BRAF. These G469E- and D594G-mutated melanomas were found to exhibit constitutive levels of phospho-extracellular signal-regulated kinase (pERK) and low levels of phospho-mitogen-activated protein kinase/ERK kinase (pMEK) and were resistant to MEK inhibition. Upon treatment with the CRAF inhibitor sorafenib, these lines underwent apoptosis and associated with mitochondrial depolarization and relocalization of apoptosis-inducing factor, whereas the BRAF-V600E-mutated melanomas did not. Studies have shown low-activity mutants of BRAF (G469E/D594G) instead signal through CRAF. Unlike BRAF, CRAF directly regulates apoptosis through mitochondrial localization where it binds to Bcl-2 and phosphorylates BAD. The CRAF inhibitor sorafenib was found to induce a time-dependent reduction in both BAD phosphorylation and Bcl-2 expression in the D594G/G469E lines only. Knockdown of CRAF using a lentiviral shRNA suppressed both Bcl-2 expression and induced apoptosis in the D594G melanoma line but not in a V600E-mutated line. Finally, we showed in a series of xenograft studies that sorafenib was more potent at reducing the growth of tumors with the D594G mutation than those with the V600E mutation. In summary, we have identified a group of melanomas with low-activity BRAF mutations that are reliant upon CRAF-mediated survival activity.


Assuntos
Apoptose , Resistencia a Medicamentos Antineoplásicos/genética , Melanoma/enzimologia , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-raf/antagonistas & inibidores , Apoptose/genética , Benzenossulfonatos/farmacologia , Linhagem Celular Tumoral , Técnicas de Silenciamento de Genes , Ácido Glutâmico/genética , Ácido Glutâmico/metabolismo , Humanos , Melanoma/genética , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Mutação , Niacinamida/análogos & derivados , Compostos de Fenilureia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-raf/genética , Piridinas/farmacologia , RNA Interferente Pequeno/genética , Transdução de Sinais , Sorafenibe , Valina/genética , Valina/metabolismo
13.
Br J Cancer ; 96(3): 445-9, 2007 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-17245336

RESUMO

The loss of tumour phospho-extracellular responsive kinase (pERK) positivity is the major treatment biomarker for mitogen-activated protein kinase/extracellular responsive kinase (MEK) inhibitors. Here, we demonstrate that there is a poor correlation between pERK inhibition and the anti-proliferative effects of MEK inhibitors in melanoma cells. We suggest that Ki67 is a better biomarker for future clinical studies.


Assuntos
Biomarcadores Tumorais/análise , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , MAP Quinases Reguladas por Sinal Extracelular/análise , Antígeno Ki-67/análise , Melanoma/tratamento farmacológico , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Butadienos/análise , Linhagem Celular Tumoral , Proliferação de Células , Fase G1 , Humanos , Melanoma/patologia , Mutação , Nitrilas/análise , Inibidores de Fosfoinositídeo-3 Quinase , Fosforilação , Proteínas Proto-Oncogênicas B-raf/genética
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