RESUMO
In a fluorescence polarization screen for the MYC-MAX interaction, we have identified a novel small-molecule inhibitor of MYC, KJ-Pyr-9, from a Kröhnke pyridine library. The Kd of KJ-Pyr-9 for MYC in vitro is 6.5 ± 1.0 nM, as determined by backscattering interferometry; KJ-Pyr-9 also interferes with MYC-MAX complex formation in the cell, as shown in a protein fragment complementation assay. KJ-Pyr-9 specifically inhibits MYC-induced oncogenic transformation in cell culture; it has no or only weak effects on the oncogenic activity of several unrelated oncoproteins. KJ-Pyr-9 preferentially interferes with the proliferation of MYC-overexpressing human and avian cells and specifically reduces the MYC-driven transcriptional signature. In vivo, KJ-Pyr-9 effectively blocks the growth of a xenotransplant of MYC-amplified human cancer cells.
Assuntos
Antineoplásicos/farmacologia , Proteínas Proto-Oncogênicas c-myc/antagonistas & inibidores , Piridinas/farmacologia , Pirimidinas/farmacologia , Animais , Antineoplásicos/química , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/antagonistas & inibidores , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/química , Proliferação de Células/efeitos dos fármacos , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Células Cultivadas , Embrião de Galinha , Avaliação Pré-Clínica de Medicamentos , Feminino , Polarização de Fluorescência , Genes myc , Humanos , Interferometria , Camundongos , Camundongos Nus , Complexos Multiproteicos/antagonistas & inibidores , Complexos Multiproteicos/química , Domínios e Motivos de Interação entre Proteínas/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-myc/química , Piridinas/química , Pirimidinas/química , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The aim of this study was to examine the potential of self-nanoemulsifying drug delivery systems (SNEDDS) on the uptake of the lipophilic and poorly water soluble phenothiazines thioridazine and chlorpromazine with the isolated plasma derived chylomicron (CM) ex vivo model. The multi-component delivery systems were optimized by evaluating their ability to self-emulsify when introduced to an aqueous medium under gentle agitation. The uptake of phenothiazines by isolated plasma derived chylomicrons was investigated with short chain triglyceride (SCT) SNEDDS, medium chain triglyceride (MCT) SNEDDS, and long chain triglyceride (LCT) SNEDDS. SNEDDS were also evaluated for their stabilities, dispersibilities, percentage transmittances and by particle size analyses. For thioridazine a 5.6-fold and for chlorpromazine a 3.7-fold higher CM uptake could be observed using a LCT-SNEDDS formulation compared to the drugs without formulation. In contrast, ex vivo uptake by isolated CM was not significantly increased by SNEDDS formulations based on MCT and SCT. Compared with isolated CM, the CM sizes were increased 2.5-fold in LCT-SNEDDS, whereas in MCT-SNEDDS or SCT-SNEDDS only a small, non-significant (P<0.05) increase in CM size was observed. These results show that distinct SNEDDS formulations containing phenothiazines are efficiently uptaken by plasma derived chylomicrons ex vivo.
Assuntos
Quilomícrons/química , Sistemas de Liberação de Medicamentos , Emulsões/química , Excipientes/química , Nanopartículas/química , Fenotiazinas/química , Adsorção/fisiologia , Antipsicóticos/química , Antipsicóticos/metabolismo , Clorpromazina/química , Clorpromazina/metabolismo , Quilomícrons/metabolismo , Portadores de Fármacos , Composição de Medicamentos , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Estabilidade de Medicamentos , Emulsificantes , Emulsões/metabolismo , Excipientes/metabolismo , Modelos Químicos , Fenotiazinas/metabolismo , Polissorbatos/química , Refratometria , Solubilidade , Triglicerídeos/química , Triglicerídeos/metabolismoRESUMO
A recent study of plants that accumulate selenium from soils illustrates how plant defenses can be sequestered and presumably exploited defensively by herbivores that have co-evolved selenium resistance.