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Oral Oncol ; 81: 100-108, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29884408


Squamous cell carcinoma of the head and neck is a lethal disease with suboptimal survival outcomes and standard therapies with significant comorbidities. Whole exome sequencing data recently revealed an abundance of genetic and expression alterations in a family of enzymes known as protein methyltransferases in a variety of cancer types, including squamous cell carcinoma of the head and neck. These enzymes are mostly known for their chromatin-modifying functions through methylation of various histone substrates, though evidence supports their function also through methylation of non-histone substrates. This review summarizes the current knowledge on the function of protein methyltransferases in squamous cell carcinoma of the head and neck and highlights their promising potential as the next generation of therapeutic targets in this disease.

Mol Cancer Ther ; 8(5): 1148-56, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19435875


Sunitinib is an oral small-molecule multitargeted receptor tyrosine kinase inhibitor that has recently been shown to have clinical benefit as a single agent in renal cell cancer and gastrointestinal stromal tumors, leading to its Food and Drug Administration approval for treatment of these cancers. However, the benefit is short-lived; and for the majority of cancers, sunitinib single-agent clinical activity is low. Therefore, combination strategies with sunitinib are currently in clinical development. The hypoxia-inducible transcription factors, HIF-1 and HIF-2, induce gene programs important for cancer cell growth and angiogenesis. We hypothesized that inhibiting HIF-1 and HIF-2 would further improve tumor response to sunitinib therapy. To test this hypothesis, HIF-1α and HIF-2α genes were disrupted in colon cancer cells. We found that disruption of HIF-1α, HIF-2α, or both HIF-1α and HIF-2α genes led to improved tumor response to sunitinib. For xenografts in which both HIF-1α and HIF-2α genes were disrupted, there was prolonged complete remission with sunitinib treatment in 50% of mice. This enhanced response was mediated by two potential mechanisms. First, tumor angiogenesis and perfusion were almost completely inhibited by sunitinib when both HIF-1α and HIF-2α genes were disrupted. The enhanced inhibitory effect on tumor angiogenesis was mediated by the inhibition of multiple proangiogenic factors, including vascular endothelial growth factor and angiopoietin-like protein 4, and the induction of the antiangiogenic factor, thrombospondin 1. Second, disruption of HIF-1α, HIF-2α, or both HIF-1α and HIF-2α genes directly inhibited tumor cell proliferation. These preclinical findings have clinical implications and suggest novel clinical trials.

Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Neoplasias do Colo/tratamento farmacológico , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Indóis/farmacologia , Pirróis/farmacologia , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Inativação de Genes , Humanos , Indóis/uso terapêutico , Camundongos , Camundongos Nus , Neovascularização Patológica , Pirróis/uso terapêutico , Sunitinibe , Ensaios Antitumorais Modelo de Xenoenxerto
Cancer Res ; 68(6): 1872-80, 2008 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-18339868


Antiangiogenic therapy improves survival in patients with advanced stage cancers. Currently, there are no reliable predictors or markers for tumor vessel response to antiangiogenic therapy. To model effective antiangiogenic therapy, we disrupted the VEGF gene in three representative cancer cell lines. HCT116 xenografts had low proportions of endothelial tubes covered by pericytes that stained with alpha-smooth muscle actin (SMA) antibody. Upon disruption of VEGF, HCT116(VEGF-/-) xenografts had significantly decreased tumor microvessel perfusion compared with their parental counterparts. Furthermore, HCT116(VEGF-/-) xenografts mounted a tumor-reactive response to hypoxia, characterized by the induction of hypoxia-inducible factor-1 (HIF-1) target genes. One highly induced protein was DPP4, a measurable serum protein that has well-described roles in cancer progression. In contrast, LS174T and MKN45 tumor xenografts had high proportion of endothelial tubes that were covered by SMA+ pericytes. Upon disruption of VEGF, LS174T(VEGF-/-) and MKN45(VEGF-/-) xenografts maintained tumor microvessel perfusion. As such, there were no changes in intratumoral hypoxia or HIF-1 alpha induction. Together, these data show that the extent of tumor vessel response to angiogenic inhibition could be correlated with (a) the preexisting coverage of tumor endothelial tubes with SMA+ pericytes and (b) differential tumor induction of HIF-1 target genes. The data further show that DPP4 is a novel marker of HIF-1 induction. Altogether, these preclinical findings suggest novel clinical trials for predicting and monitoring tumor vessel responses to antiangiogenic therapy.

Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Neoplasias/irrigação sanguínea , Neoplasias/terapia , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Adenoviridae/genética , Animais , Hipóxia Celular/genética , Linhagem Celular Tumoral , Dipeptidil Peptidase 4/biossíntese , Dipeptidil Peptidase 4/genética , Endotélio Vascular/patologia , Feminino , Terapia Genética , Células HCT116 , Células HT29 , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/biossíntese , Camundongos , Neoplasias/genética , Neoplasias/metabolismo , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Neovascularização Patológica/terapia , Fator A de Crescimento do Endotélio Vascular/genética , Ensaios Antitumorais Modelo de Xenoenxerto
Mol Cancer ; 7: 24, 2008 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-18325101


BACKGROUND: Cisplatin has been widely used to treat head and neck cancer. One of the clinical limitations with this treatment, however, is that tumors that are initially responsive to cisplatin later acquire resistance. We have recently shown that a subset of head and neck cancer cell lines has a defective Fanconi anemia DNA damage response pathway and this defect correlates to cisplatin sensitivity. We have also shown that the histone deacetylase inhibitor phenylbutyrate sensitize human cells to cisplatin. In this study we explored whether phenylbutyrate may sensitize head and neck cancer cells by interfering with the Fanconi anemia pathway. RESULTS: We found that the phenylbutyrate sensitizes head and neck cancer cell lines to cisplatin. This sensitization by phenylbutyrate correlated to a significant decrease in the formation of cisplatin-induced FANCD2 nuclear foci, which is a functional read out of the Fanconi anemia and BRCA (FA/BRCA) pathway. This abrogation of the FA/BRCA pathway by phenylbutyrate was not due to loss of FANCD2 monoubiquitylation but rather correlated to a phenylbutyrate-mediated reduction in the expression of the BRCA1 protein. Furthermore, we found that cancer cells defective in the FA pathway were also sensitized to cisplatin by phenylbutyrate suggesting that phenylbutyrate targets additional pathways. CONCLUSION: The results from this study suggest that phenylbutyrate may have therapeutic utility as a cisplatin sensitizer in head and neck cancer by inhibiting the FA/BRCA pathway through the down regulation of BRCA1 as well as by an FA/BRCA-independent mechanism.

Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Proteína BRCA1/antagonistas & inibidores , Cisplatino/farmacologia , Proteína do Grupo de Complementação D2 da Anemia de Fanconi/antagonistas & inibidores , Neoplasias de Cabeça e Pescoço/metabolismo , Fenilbutiratos/farmacologia , Proteína BRCA1/metabolismo , Proteína do Grupo de Complementação D2 da Anemia de Fanconi/metabolismo , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Transdução de Sinais/efeitos dos fármacos , Células Tumorais Cultivadas
Cancer Lett ; 253(1): 131-7, 2007 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-17321670


Head and neck cancers are commonly treated with the DNA-damaging agent cisplatin. While many tumors respond well to cisplatin treatment, some do not. The mechanism for this differential sensitivity of head and neck tumors to cisplatin is not understood in detail. In this study, we explored whether the functional status of the Fanconi anemia and BRCA pathway (FA/BRCA) would predict cisplatin sensitivity in head and neck cancer cells. The FA/BRCA pathway is critical for the orchestration of the cellular response to cisplatin and other DNA cross-linking agents. It was found that three out of four cisplatin-sensitive head and neck cancer cell lines showed defective formation of FANCD2 nuclear foci while all four cisplatin-resistant cell lines tested were proficient in FANCD2 foci formation following cisplatin treatment. The defect in FANCD2 foci formation in the cisplatin-sensitive cell lines was not due to defective monoubiquitylation of FANCD2 but appeared to be due to reduced expression or defective function of BRCA1 since expression of exogenous BRCA1 restored the ability of these cells to induce FANCD2 foci following cisplatin treatment and enhanced cisplatin resistance. These results suggest a possible role for BRCA1 in modulating cisplatin sensitivity in head and neck cancer cells.

Proteína BRCA1/metabolismo , Carcinoma de Células Escamosas/metabolismo , Cisplatino/farmacologia , Proteína do Grupo de Complementação D2 da Anemia de Fanconi/metabolismo , Neoplasias de Cabeça e Pescoço/metabolismo , Proteína BRCA1/deficiência , Carcinoma de Células Escamosas/tratamento farmacológico , Linhagem Celular Tumoral , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Ubiquitina/metabolismo