RESUMO
PURPOSE: The KIT inhibitor, imatinib, has shown promising efficacy in patients with KIT-mutated melanoma; however, acquisition of resistance to imatinib occurs rapidly in the majority of patients. The mechanisms of acquired resistance to imatinib in melanoma remain unclear. METHODS: We analyzed biopsy samples from paired baseline and post-treatment tumor lesions in one patient with KIT-mutated melanoma who had had an initial objective tumor regression in response to imatinib treatment followed by disease progression 8 months later. RESULTS: Targeted deep sequencing from post-treatment biopsy samples detected an additional mutation in CTNNB1 (S33C) with original KIT L576P mutation. We examined the functional role of the additional CTNNB1 S33C mutation in resistance to imatinib indirectly using the Ba/F3 cell model. Ba/F3 cell lines transfected with both the L576P KIT mutation and the CTNNB1 S33C mutation demonstrated no growth inhibition despite imatinib treatment, whereas growth inhibition was observed in the Ba/F3 cell line transfected with the L576 KIT mutation alone. CONCLUSIONS: We report the first identification of the emergence of a CTNNB1 mutation that can confer acquired resistance to imatinib. Further investigation into the causes of acquired resistance to imatinib will be essential to improve the prognosis for patients with KIT-mutated melanoma.
Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Mesilato de Imatinib/farmacologia , Neoplasias Pulmonares/genética , Melanoma/genética , Mutação , Neoplasias Cutâneas/genética , beta Catenina/genética , Proliferação de Células/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Masculino , Melanoma/tratamento farmacológico , Melanoma/patologia , Pessoa de Meia-Idade , Prognóstico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-kit , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/secundário , Células Tumorais CultivadasRESUMO
INTRODUCTION: Growing evidence indicates that norepinephrine promotes cancer growth and metastasis whereas ß-blockers decrease these risks. This study aimed to examine the clinical impact of ß-blockers and other hypertensive drugs on disease recurrence and survival in patients with head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS: This study analyzed a cohort of 1274 consecutive patients who received definitive treatments for previously untreated HNSCC at our tertiary referral center between January 2001 and December 2012. Antihypertensive use was considered positive if patients were on medication from HNSCC diagnosis to at least 1 year after treatment initiation. Cox proportional hazard models were utilized to determine associations between antihypertensive drugs and recurrence, survival, and second primary cancer (SPC) occurrence. RESULTS: Hypertension itself was not a significant variable of recurrence and survival and no antihypertensive drug use affected SPC occurrence (all P > 0.1). After controlling for clinical factors, calcium-channel blocker use remained an independent variable for index cancer recurrence, and ß-blocker use was significantly associated with poor cancer-specific mortality, competing mortality, and all-cause mortality (all P < 0.05). ß-blocker use significantly affected competing and all-cause mortalities in normotensive patients, and calcium-channel blocker use affected index cancer recurrence in normotensive patients (all P < 0.05). CONCLUSIONS: Our data show that ß-blocker use is associated with decreased survival and calcium-channel blockers is associated with increased cancer recurrence in patients of HNSCC.
Assuntos
Antagonistas Adrenérgicos beta/efeitos adversos , Anti-Hipertensivos/efeitos adversos , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Recidiva Local de Neoplasia/mortalidade , Segunda Neoplasia Primária/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/mortalidade , Estudos de Coortes , Feminino , Seguimentos , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/induzido quimicamente , Recidiva Local de Neoplasia/diagnóstico , Segunda Neoplasia Primária/induzido quimicamente , Segunda Neoplasia Primária/diagnóstico , Prognóstico , Fatores de Risco , Taxa de Sobrevida , Adulto JovemRESUMO
Glycopentalone isolated from Glycosmis pentaphylla (family Rutaceae) has cytotoxic and apoptosis inducing effects in various human cancer cell lines; however, its mode of action is not known. Therefore, target fishing of glycopentalone using a combined approach of inverse docking and reverse pharmacophore mapping approach was used to identify potential targets of glycopentalone, and gain insight into its binding modes against the selected molecular targets, viz., CDK-2, CDK-6, Topoisomerase I, Bcl-2, VEGFR-2, Telomere:G-quadruplex and Topoisomerase II. These targets were chosen based on their key roles in the progression of cancer via regulation of cell cycle and DNA replication. Molecular docking analysis revealed that glycopentalone displayed binding energies ranging from -6.38 to -8.35 kcal/mol and inhibition constants ranging from 0.758 to 20.90 µM. Further, the binding affinities of glycopentalone to the targets were in the order: Telomere:G-quadruplex > VEGFR-2 > CDK-6 > CDK-2 > Topoisomerase II > Topoisomerase I > Bcl-2. Binding mode analysis revealed critical hydrogen bonds as well as hydrophobic interactions with the targets. The targets were validated by reverse pharmacophore mapping of glycopentalone against a set of 2241 known human target proteins which revealed CDK-2 and VEGFR-2 as the most favorable targets. The glycopentalone was well mapped to CDK-2 and VEGFR-2 which involve six pharmacophore features (two hydrophobic centers and four hydrogen bond acceptors) and nine pharmacophore features (five hydrophobic, two hydrogen bond acceptors and two hydrogen bond donors), respectively. The present computational approach may aid in rational identification of targets for small molecules against large set of candidate macromolecules before bioassays validation.
Assuntos
Antineoplásicos Fitogênicos/química , Propano/análogos & derivados , Pirróis/química , Sítios de Ligação , Quinase 2 Dependente de Ciclina/química , Quinase 6 Dependente de Ciclina/química , Humanos , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Simulação de Acoplamento Molecular , Propano/química , Ligação Proteica , Rutaceae/química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/químicaRESUMO
Peroxisome proliferator activator receptor-gamma (PPARγ) is a ligand-activated transcriptional factor involved in the carcinogenesis of various cancers. Insulin-like growth factor-binding protein-3 (IGFBP-3) is a tumor suppressor gene that has anti-apoptotic activity. The purpose of this study was to investigate the anticancer mechanism of PPARγ with respect to IGFBP-3. PPARγ was overexpressed in SNU-668 gastric cancer cells using an adenovirus gene transfer system. The cells in which PPARγ was overexpressed exhibited growth inhibition, induction of apoptosis, and a significant increase in IGFBP-3 expression. We investigated the underlying molecular mechanisms of PPARγ in SNU-668 cells using an IGFBP-3 promoter/luciferase reporter system. Luciferase activity was increased up to 15-fold in PPARγ transfected cells, suggesting that PPARγ may directly interact with IGFBP-3 promoter to induce its expression. Deletion analysis of the IGFBP-3 promoter showed that luciferase activity was markedly reduced in cells without putative p53-binding sites (-Δ1755, -Δ1795). This suggests that the critical PPARγ-response region is located within the p53-binding region of the IGFBP-3 promoter. We further demonstrated an increase in PPARγ-induced luciferase activity even in cells treated with siRNA to silence p53 expression. Taken together, these data suggest that PPARγ exhibits its anticancer effect by increasing IGFBP-3 expression, and that IGFBP-3 is a significant tumor suppressor.
Assuntos
Adulto , Feminino , Humanos , Masculino , Asma/induzido quimicamente , Genes MHC Classe I/genética , Genes MHC da Classe II/genética , Isocianatos/toxicidade , Doenças Profissionais/induzido quimicamente , Exposição Ocupacional/efeitos adversos , Asma/genética , Variação Genética , Genótipo , Doenças Profissionais/genética , Polimorfismo de Nucleotídeo Único , RiscoRESUMO
Peroxisome proliferator activator receptor-gamma (PPARγ) is a ligand-activated transcriptional factor involved in the carcinogenesis of various cancers. Insulin-like growth factor-binding protein-3 (IGFBP-3) is a tumor suppressor gene that has anti-apoptotic activity. The purpose of this study was to investigate the anticancer mechanism of PPARγ with respect to IGFBP-3. PPARγ was overexpressed in SNU-668 gastric cancer cells using an adenovirus gene transfer system. The cells in which PPARγ was overexpressed exhibited growth inhibition, induction of apoptosis, and a significant increase in IGFBP-3 expression. We investigated the underlying molecular mechanisms of PPARγ in SNU-668 cells using an IGFBP-3 promoter/luciferase reporter system. Luciferase activity was increased up to 15-fold in PPARγ transfected cells, suggesting that PPARγ may directly interact with IGFBP-3 promoter to induce its expression. Deletion analysis of the IGFBP-3 promoter showed that luciferase activity was markedly reduced in cells without putative p53-binding sites (-Δ1755, -Δ1795). This suggests that the critical PPARγ-response region is located within the p53-binding region of the IGFBP-3 promoter. We further demonstrated an increase in PPARγ-induced luciferase activity even in cells treated with siRNA to silence p53 expression. Taken together, these data suggest that PPARγ exhibits its anticancer effect by increasing IGFBP-3 expression, and that IGFBP-3 is a significant tumor suppressor.
Assuntos
Apoptose/efeitos dos fármacos , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , PPAR gama/metabolismo , Neoplasias Gástricas/patologia , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , PPAR gama/genética , Transdução de Sinais , Neoplasias Gástricas/metabolismo , Ativação Transcricional , Regulação para CimaRESUMO
The phylogeny of a phylogenetically poorly known family, Phytolaccaceae sensu lato (s.l.), was constructed for resolving conflicts concerning taxonomic delimitations. Cladistic analyses were made based on 44 sequences of the internal transcribed spacer of nuclear ribosomal DNA from 11 families (Aizoaceae, Basellaceae, Didiereaceae, Molluginaceae, Nyctaginaceae, Phytolaccaceae s.l., Polygonaceae, Portulacaceae, Sarcobataceae, Tamaricaceae, and Nepenthaceae) of the order Caryophyllales. The maximum parsimony tree from the analysis resolved a monophyletic group of the order Caryophyllales; however, the members, Agdestis, Anisomeria, Gallesia, Gisekia, Hilleria, Ledenbergia, Microtea, Monococcus, Petiveria, Phytolacca, Rivinia, Schindleria, Seguieria, Stegnosperma, and Trichostigma, which belong to the family Phytolaccaceae s.l., did not cluster under a single clade, demonstrating that Phytolaccaceae is polyphyletic.
Assuntos
DNA Espaçador Ribossômico/genética , Phytolaccaceae/genética , Núcleo Celular , DNA de Plantas/genética , Genes de Plantas , Tipagem de Sequências Multilocus , Filogenia , Phytolaccaceae/classificaçãoRESUMO
The internal transcribed spacer regions of nuclear ribosomal DNA, trnL and trnL-F chloroplast genes of Cardamine amaraeformis Nakai (Brassicaceae) were sequenced and analyzed with the sequences of related Cardamine sp available in GenBank to detect the pattern of C. amaraeformis evolutionary differentiation. C. amaraeformis, which is endemic to South Korea, formed a clade with Cardamine pedata (69 bootstrap support) in all trees resulting from combined sequence data analyses of internal transcribed spacer, trnL and trnL-F genes. The phylogenetic analysis also clearly revealed that C. amaraeformis is distinct from the morphologically similar Cardamine scutata.