Remote loading of preencapsulated drugs into stealth liposomes.

Loading drugs into carriers such as liposomes can increase the therapeutic ratio by reducing drug concentrations in normal tissues and raising their concentrations in tumors. Although this strategy has proven advantageous in certain circumstances, many drugs are highly hydrophobic and nonionizable and cannot be loaded into liposomes through conventional means. We hypothesized that such drugs could be actively loaded into liposomes by encapsulating them into specially designed cyclodextrins. To test this hypothesis, two hydrophobic drugs that had failed phase II clinical trials because of excess toxicity at deliverable doses were evaluated. In both cases, the drugs could be remotely loaded into liposomes after their encapsulation (preloading) into cyclodextrins and administered to mice at higher doses and with greater efficacy than possible with the free drugs.

[Docking-based virtual screening of MEK1 inhibitors from Chinese herbs].

The hyperphosphorylation of MEK1(mitogen-activated protein kinase kinase 1) is one of the causesfor melanoma. It is important to discover a potential medicine for melanoma through virtual screening of chemical composition of Chinese material medica on MEK1. In this study, a docking pocket model and Flex Search model were built by using a MEK1 crystal structure, the similarity between connector conformation and gametophyte conformation in the crystal structure was 0.784.There was a linear relationship between total score and pIC50on MEK1 inhibitors, with R²=0.937, which further indicated the reliability of the virtual screening model.The search library of traditional Chinese medicine database on the Lipinski's rule was docked with the pocket model, and then 50 compounds with a totalscore of more than 7.0 were obtained by the Flex model. In this paper, top 10 active ingredients in screening results showed atotal score of more than that of positive medicines. It is expected to further research the inhibition of MEK1 and melanoma.

Cardiac concentric hypertrophy promoted by activated Met receptor is mitigated in vivo by inhibition of Erk1,2 signalling with Pimasertib.

Cardiac hypertrophy is a major risk factor for heart failure. Hence, its attenuation represents an important clinical goal. Erk1,2 signalling is pivotal in the cardiac response to stress, suggesting that its inhibition may be a good strategy to revert heart hypertrophy. In this work, we unveiled the events associated with cardiac hypertrophy by means of a transgenic model expressing activated Met receptor. c-Met proto-oncogene encodes for the tyrosine kinase receptor of Hepatocyte growth factor and is a strong inducer of Ras-Raf-Mek-Erk1,2 pathway. We showed that three weeks after the induction of activated Met, the heart presents a remarkable concentric hypertrophy, with no signs of congestive failure and preserved contractility. Cardiac enlargement is accompanied by upregulation of growth-regulating transcription factors, natriuretic peptides, cytoskeletal proteins, and Extracellular Matrix remodelling factors (Timp1 and Pai1). At a later stage, cardiac hypertrophic remodelling results into heart failure with preserved systolic function. Prevention trial by suppressing activated Met showed that cardiac hypertrophy is reversible, and progression to heart failure is prevented. Notably, treatment with Pimasertib, Mek1 inhibitor, attenuates cardiac hypertrophy and remodelling. Our results suggest that modulation of Erk1.2 signalling may constitute a new therapeutic approach for treating cardiac hypertrophies.

MEK1 Inhibitor Combined with Irradiation Reduces Migration of Breast Cancer Cells Including miR-221 and ZEB1 EMT Marker Expression.

The miR-221 expression is dependent on the oncogenic RAS-RAF-MEK pathway activation and influences epithelial-to-mesenchymal transition (EMT). The Cancer Genome Atlas (TCGA) database analysis showed high gene significance for ZEB1 with EMT module analysis and miR-221 overexpression within the triple-negative breast cancer (TNBC) and HER2+ subgroups when compared to luminal A/B subgroups. EMT marker expression analysis after MEK1 (TAK-733) inhibitor treatment and irradiation was combined with miR-221 and ZEB1 expression analysis. The interaction of miR-221 overexpression with irradiation and its influence on migration, proliferation, colony formation and subsequent EMT target activation were investigated. The results revealed that MEK1 inhibitor treatment combined with irradiation could decrease the migratory potential of breast cancer cells including reduction of miR-221 and corresponding downstream ZEB1 (EMT) marker expression. The clonogenic survival assays revealed that miR-221 overexpressing SKBR3 cells were more radioresistant when compared to the control. Remarkably, the effect of miR-221 overexpression on migration in highly proliferative and highly HER2-positive SKBR3 cells remained constant even upon 8 Gy irradiation. Further, in naturally miR-221-overexpressing MDA-MB-231 cells, the proliferation and migration significantly decrease after miR-221 knockdown. This leads to the assumption that radiation alone is not reducing migration capacity of miR-221-overexpressing cells and that additional factors play an important role in this context. The miR-221/ZEB1 activity is efficiently targeted upon MEK1 inhibitor (TAK-733) treatment and when combined with irradiation treatment, significant reduction in migration of breast cancer cells was shown.

Docking-based virtual screening of MEK1 inhibitors from Chinese herbs / 中国中药杂志

The hyperphosphorylation of MEK1(mitogen-activated protein kinase kinase 1) is one of the causesfor melanoma. It is important to discover a potential medicine for melanoma through virtual screening of chemical composition of Chinese material medica on MEK1. In this study, a docking pocket model and Flex Search model were built by using a MEK1 crystal structure, the similarity between connector conformation and gametophyte conformation in the crystal structure was 0.784.There was a linear relationship between total score and pIC₅₀on MEK1 inhibitors, with R²=0.937, which further indicated the reliability of the virtual screening model.The search library of traditional Chinese medicine database on the Lipinski's rule was docked with the pocket model, and then 50 compounds with a totalscore of more than 7.0 were obtained by the Flex model. In this paper, top 10 active ingredients in screening results showed atotal score of more than that of positive medicines. It is expected to further research the inhibition of MEK1 and melanoma.