Emmanuelle Meuillet

Emmanuelle Meuillet, PhD, has developed a novel Akt inhibitor which structure is based on its similarity with the substrate for PdtIns-3-Kinase, i.e. phosphatidyl-myo-inositol-phosphate. In collaboration with Dr. E. Mash (University of Arizona, analogues such as the D-3-Deoxy-phosphatidyl-myoinositol (3-DPI) and the D-3-Deoxy-phosphatidyl-myoiinositol ether lipid (3-DPIEL) were synthesized and tested for their ability to bind the pleckstrin homology domain of Akt and thus inhibit the kinase activity in vitro and in vivo.

 

The discovery of the possible interaction and regulation of the PdtIns-3-Kinase/Akt/PTEN pathway by a small redox protein, thioredoxin is of great relevance in cancer research. Dr. Meuillet’s lab has recently demonstrated a direct interaction between thioredoxin and the tumor suppressor, PTEN. This project is extensively researched in her lab as it represents her primary funding source at this moment (NIH-RO1 funded for 4 years). One way to study the interaction of these proteins on a genetic level was to use small organism systems such as Drosophila. Using such a system, she has shown a genetic and phenotypic interaction between the tumor suppressor PTEN and the redox protein Thioredoxin-1 in collaboration with Dr. Brabant M. (Director of the Small Organism Facility Core, Arizona Cancer Center). Finally, one way to modulate the interaction between PTEN and thioredoxin exists via the regulation of the thioredoxin reductase activity, using seleno-compounds. Thus, Dr. Meuillet is also studying the importance of sodium selenite and selenomethionine in cancer prevention. This funded project is in collaboration with Dr. Mark Nelson (Department of Pathology, NIH-RO1, funded for 5 year, Co-PI). Several seleno-compounds have been shown to possess chemopreventive effects in various types of cancers, such as colon and prostate cancers. Again this project may the use of small organism systems such as Drosophila.

 

Future research plans include bridging the gap between understanding the role of lipids and exploring signal transduction pathways mainly in diabetes and cancer. Interest exists in investigating how lipids, carbohydrates and kinases interact in normal and abnormal conditions as well as establishing relationships to diets, diseases and prevention. These specific interactions between protein and lipids can be studied at several levels: molecularly by investigating structurally these possible interactions, biochemical by analyzing membrane microdomains in normal and abnormal conditions and finally genetically by exploring gene expression. The investigation of selective inhibition or activation of oncogenes by lipids through the analysis of gene expression-modulation by specific nutrients, or via the molecular study of the occurrence of such interactions may lead to the development of new areas in cancer chemo-prevention, diabetes treatment as well as cancer treatment.

 

Monitoring The Development Of Xenograft Triple Negative Breast Cancer Models Using Diffusion Weighted Magnetic Resonance Imaging. Source: Experimental Biology And Medicine (Maywood, N.J.)
December 14th, 2012 PMID: 23239438 Emmanuelle Meuillet Mark Pagel
Evaluations of tumor growth rates and molecular biomarkers are traditionally used to assess new mouse models of human breast cancers. This study investigated the utility of diffusion weighted (DW)-magnetic resonance imaging (MRI) for evaluating cellular proliferation of new tumor models of triple-negative breast cancer, which may augment traditional analysis methods. Eleven human breast cancer cell lines were used to develop xenograft tumors in severe combined immunodeficient mice, with two of these cell lines exhibiting sufficient growth to be serially passaged. DW-MRI was performed to measure the distributions of the apparent diffusion coefficient (ADC) in these two tumor xenograft models, which showed a correlation with tumor growth rates and doubling times during each passage. The distributions of the ADC values were also correlated with expression of Ki67, a biomarker of cell proliferation, and hypoxia inducible factor (HIF)-1α and vascular endothelial growth factor receptor-2 (VEGFR2), which are essential proteins involved in regulating aerobic glycolysis and angiogenesis that support tumor cell proliferation. Although phosphatase and tensin homolog (PTEN) levels were different between the two xenograft models, AKT levels did not differ nor did they correlate with tumor growth. This last result demonstrates the complexity of signaling protein pathways and the difficulty in interpreting the effects of protein expression on tumor cell proliferation. In contrast, DW-MRI may be a more direct assessment of tumor growth and cancer cell proliferation.<br /><br />
Synthesis And Biological Activity Of Aminophthalazines And Aminopyridazines As Novel Inhibitors Of Pge(2) Production In Cells. Source: Bioorganic & Medicinal Chemistry Letters
November 21st, 2012 PMID: 23237838 Christopher Hulme Emmanuelle Meuillet
This Letter reports the synthesis and biological evaluation of a collection of aminophthalazines as a novel class of compounds capable of reducing production of PGE(2) in HCA-7 human adenocarcinoma cells. A total of 28 analogs were synthesized, assayed for PGE(2) reduction, and selected active compounds were evaluated for inhibitory activity against COX-2 in a cell free assay. Compound 2xxiv (R(1)=H, R(2)=p-CH(3)O) exhibited the most potent activity in cells (EC(50)=0.02μM) and minimal inhibition of COX-2 activity (3% at 5μM). Furthermore, the anti-tumor activity of analog 2vii was analyzed in xenograft mouse models exhibiting good anti-cancer activity.<br /><br />
The Matrix Protein Ccn1/Cyr61 Is Required For α(V) β(5) Mediated Cancer Cell Migration. Source: Cell Biochemistry And Function
June 13th, 2012 PMID: 22692860 Emmanuelle Meuillet
CYR61 is one of the six proteins of the CCN family of proteins known to play diverse roles in angiogenesis, cellular proliferation, survival, migration and wound healing. However, the specific function of CYR61 in cancer is unclear, and the literature remains controversial. We used quantitative real-time PCR to establish the expression profile of CYR61 and integrin α(V) β(5) in three non-small cell lung cancer, five colorectal cancer, one breast cancer and one oesophageal squamous carcinoma cell lines. We showed that the levels of CYR61 were significantly increased in oesophageal squamous carcinoma cell line along with the enhanced levels of α(V) β(5) integrin. Further, we investigated whether tumour cell-secreted CYR61 can facilitate cell migration by interacting with the α(V) β(5) integrin. Using tumour cell lines with low, intermediate and high CYR61 expression and their isogenic variants as a cellular model, we determined that integrin α(V) β(5) expressed on these tumour cells is required for cell migration. Moreover, we showed that the modulation of expression levels of CYR61 in these cancer cells affected their capacity for migration. These results represent an advance to the understanding of the role of CYR61 and α(v) β(5) integrin as proteins that cooperate to mediate cancer cell migration. Copyright © 2012 John Wiley & Sons, Ltd.<br /><br />
Synthesis And Biological Activity Of 2 Aminothiazoles As Novel Inhibitors Of Pge2 Production In Cells. Source: Bioorganic & Medicinal Chemistry Letters
March 28th, 2012 PMID: 22516282 Emmanuelle Meuillet
This Letter presents the synthesis and biological evaluation of a collection of 2-aminothiazoles as a novel class of compounds with the capability to reduce the production of PGE(2) in HCA-7 human adenocarcinoma cells. A total of 36 analogs were synthesized and assayed for PGE(2) reduction, and those with potent cellular activity were counter screened for inhibitory activity against COX-2 in a cell free assay. In general, analogs bearing a 4-phenoxyphenyl substituent in the R(2) position were highly active in cells while maintaining negligible COX-2 inhibition. Specifically, compound 5l (R(1)=Me, R(2)=4-OPh-Ph, R(3)=CH(OH)Me) exhibited the most potent cellular PGE(2) reducing activity of the entire series (EC(50)=90 nM) with an IC(50) value for COX-2 inhibition of >5 μM in vitro. Furthermore, the anti-tumor activity of analog 1a was analyzed in xenograft mouse models exhibiting promising anti-cancer activity.<br /><br />
Identification And Development Of M Pges 1 Inhibitors: Where We Are At? Source: Future Medicinal Chemistry
October 25th, 2011 PMID: 22023034 Emmanuelle Meuillet
Microsomal prostaglandin E synthase-1 (mPGES-1) is the terminal synthase responsible for the synthesis of the pro-tumorigenic prostaglandin E(2) (PGE(2)). mPGES-1 is overexpressed in a wide variety of cancers. Since its discovery in 1997 by Bengt Samuelsson and collaborators, the enzyme has been the object of over 200 peer-reviewed articles. Although today mPGES-1 is considered a validated and promising therapeutic target for anticancer drug discovery, challenges in inhibitor design and selectivity are such that up to this date there are only a few published records of small-molecule inhibitors targeting the enzyme and exhibiting some in vivo anticancer activity. This review summarizes the structures, and the in vitro and in vivo activities of these novel mPGES-1 inhibitors. Challenges that have been encountered are also discussed.<br /><br />
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