Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 4 de 4
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
ACS Cent Sci ; 5(7): 1170-1178, 2019 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-31403069

RESUMO

The natural product neocarzilin A (NCA) was discovered decades ago, and despite its potent cytotoxic effects no mode of action studies have been performed up to date. Synthesis of neocarzilins A, B, and C and a stereoisomer of NCA provided insights into structural preferences as well as access to probes for functional studies. NCA turned out to be the most active member and was not only effective against cell proliferation but also migration, a novel and so far overlooked activity. To decipher the molecular mode of action, we applied chemical proteomics for target discovery and revealed that NCA targets cancer cell migration via irreversible binding to the largely uncharacterized synaptic vesicle membrane protein VAT-1. A corresponding knockout of the protein confirmed the phenotype, and pull-down studies showed the interaction with an intricate network of key migration mediators such as Talin-1. Overall, we introduce VAT-1 as a promising novel target for the development of selective migration inhibitors with the perspective to limit toxicity in the absence of antiproliferative effects.

2.
Cell Death Dis ; 10(4): 302, 2019 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-30944311

RESUMO

Severe side effects often restrict clinical application of the widely used chemotherapeutic drug doxorubicin. In order to decrease required substance concentrations, new concepts for successful combination therapy are needed. Since doxorubicin causes DNA damage, combination with compounds that modulate DNA repair could be a promising strategy. Very recently, a role of nuclear actin for DNA damage repair has been proposed, making actin a potential target for cancer therapy in combination with DNA-damaging therapeutics. This is of special interest, since actin-binding compounds have not yet found their way into clinics. We find that low-dose combination treatment of doxorubicin with the actin polymerizer chondramide B (ChB) synergistically inhibits tumor growth in vivo. On the cellular level we demonstrate that actin binders inhibit distinctive double strand break (DSB) repair pathways. Actin manipulation impairs the recruitment of replication factor A (RPA) to the site of damage, a process crucial for homologous recombination. In addition, actin binders reduce autophosphorylation of DNA-dependent protein kinase (DNA-PK) during nonhomologous end joining. Our findings substantiate a direct involvement of actin in nuclear DSB repair pathways, and propose actin as a therapeutic target for combination therapy with DNA-damaging agents such as doxorubicin.


Assuntos
Actinas/antagonistas & inibidores , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proteínas de Bactérias/uso terapêutico , Dano ao DNA/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Depsipeptídeos/uso terapêutico , Doxorrubicina/uso terapêutico , Actinas/metabolismo , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Proteínas de Bactérias/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Morte Celular/efeitos dos fármacos , Reparo do DNA por Junção de Extremidades/efeitos dos fármacos , Proteína Quinase Ativada por DNA/metabolismo , Depsipeptídeos/farmacologia , Doxorrubicina/farmacologia , Células HeLa , Humanos , Autoantígeno Ku/genética , Autoantígeno Ku/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos SCID , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/patologia , Fosforilação , Recombinação Genética/efeitos dos fármacos , Proteína de Replicação A/genética , Proteína de Replicação A/metabolismo , Tiazolidinas/farmacologia , Tiazolidinas/uso terapêutico , Transplante Heterólogo
3.
Hepatology ; 69(1): 376-393, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30033593

RESUMO

Therapeutic options for patients with advanced-stage hepatocellular carcinoma (HCC) are very limited. The only approved first-line treatment is the multi-tyrosine kinase inhibitor sorafenib, which shows low response rates and severe side effects. In particular, the compensatory activation of growth factor receptors leads to chemoresistance and limits the clinical impact of sorafenib. However, combination approaches to improve sorafenib have failed. Here we investigate the inhibition of cyclin-dependent kinase 5 (Cdk5) as a promising combination strategy to improve sorafenib response in HCC. Combination of sorafenib with Cdk5 inhibition (genetic knockdown by short hairpin RNA or CRISPR/Cas9 and pharmacologic inhibition) synergistically impaired HCC progression in vitro and in vivo by inhibiting both tumor cell proliferation and migration. Importantly, these effects were mediated by a mechanism for Cdk5: A liquid chromatography-tandem mass spectrometry-based proteomic approach revealed that Cdk5 inhibition interferes with intracellular trafficking, a process crucial for cellular homeostasis and growth factor receptor signaling. Cdk5 inhibition resulted in an accumulation of enlarged vesicles and respective cargos in the perinuclear region, considerably impairing the extent and quality of growth factor receptor signaling. Thereby, Cdk5 inhibition offers a comprehensive approach to globally disturb growth factor receptor signaling that is superior to specific inhibition of individual growth factor receptors. Conclusion: Cdk5 inhibition represents an effective approach to improve sorafenib response and to prevent sorafenib treatment escape in HCC. Notably, Cdk5 is an addressable target frequently overexpressed in HCC, and with Dinaciclib, a clinically tested Cdk5 inhibitor is readily available. Thus, our study provides evidence for clinically evaluating the combination of sorafenib and Dinaciclib to improve the therapeutic situation for patients with advanced-stage HCC.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Quinase 5 Dependente de Ciclina/antagonistas & inibidores , Neoplasias Hepáticas/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Sorafenibe/uso terapêutico , Animais , Feminino , Humanos , Camundongos , Resultado do Tratamento , Células Tumorais Cultivadas
4.
Cancer Res ; 77(6): 1427-1438, 2017 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-28108508

RESUMO

Metastatic invasion is the major cause of cancer-related deaths. In this study, we introduce two-pore channels (TPC), a recently described class of NAADP- and PI(3,5)P2-sensitive Ca2+-permeable cation channels in the endolysosomal system of cells, as candidate targets for the treatment of invasive cancers. Inhibition of the channel abrogated migration of metastatic cancer cells in vitro Silencing or pharmacologic inhibition of the two-pore channel TPC2 reduced lung metastasis of mammary mouse cancer cells. Disrupting TPC function halted trafficking of ß1-integrin, leading to its accumulation in EEA1-positive early endosomes. As a consequence, invasive cancer cells were no longer able to form leading edges, which are required for adequate migration. Our findings link TPC to cancer cell migration and provide a preclinical proof of concept for their candidacy as targets to treat metastatic cancers. Cancer Res; 77(6); 1427-38. ©2017 AACR.


Assuntos
Canais de Cálcio/química , Cálcio/metabolismo , Movimento Celular/efeitos dos fármacos , Neoplasias Pulmonares/secundário , Neoplasias Mamárias Animais/patologia , NADP/análogos & derivados , Animais , Apoptose/efeitos dos fármacos , Benzilisoquinolinas/farmacologia , Canais de Cálcio/genética , Canais de Cálcio/metabolismo , Carbolinas/farmacologia , Adesão Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Endossomos/metabolismo , Feminino , Neoplasias Pulmonares/metabolismo , Lisossomos/metabolismo , Neoplasias Mamárias Animais/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , NADP/antagonistas & inibidores , Invasividade Neoplásica , Piperazinas/farmacologia , Células Tumorais Cultivadas
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...