Lead Optimization of COX-2 Inhibitor Nimesulide Analogs to Overcome Aromatase Inhibitor Resistance in Breast Cancer Cells

A series of COX-2 selective inhibitor nimesulide derivatives were synthesized. Their anti-cell proliferation activities were evaluated with a long-term estrogen deprived MCF-7aro (LTEDaro) breast cancer cell line, which is the biological model of aromatase inhibitor resistance for hormone-dependent breast cancer. Compared to nimesulide which inhibited LTEDaro cell proliferation with an IC50 at 170.30 μM, several new compounds showed IC50 close to 1.0 μM

A COX-2 Inhibitor Nimesulide Analog Selectively Induces Apoptosis in Her2 Overexpressing Breast Cancer Cells via Cytochrome C Dependent Mechanisms

Epidemiological and animal model studies have suggested that non-steroidal anti-inflammatory drugs (NSAIDs) can act as chemopreventive agents. The cyclooxygenase-2 (COX-2) inhibitor nimesulide shows anti-cancer effect in different type of cancers. In the current study, five breast carcinoma cell lines were used to explore the anti-cancer mechanisms of a nimesulide derivative compound 76. The compound dose dependently suppressed SKBR-3, BT474 and MDA-MB-453 breast cancer cell proliferation with IC50 of 0.9 μM, 2.2 μM and 4.0 μM, respectively. However, it needs much higher concentrations to inhibit MCF-7 and MDA-MB-231 breast cancer cell growth with IC50 at 22.1 μM and 19.6 μM, respectively. Further investigation reveals that compound 76 induced apoptosis in SKBR-3 and BT474 cells. Since these cells are Her2 overexpressing cells, the Her2 intracellular signaling pathways were examined after the treatment. There was no significant changing of kinase activity. However, the cytochrome c release assay indicated that the apoptosis induced by the compound was mediated by the mitochondria. These results suggest that compound 76 selectively induce apoptosis in Her2 overexpressing breast cancer cells through the mitochondria, and could be used as a lead to design more potent derivatives

A COX-2 Inhibitor Nimesulide Analog Selectively Induces Apoptosis in Her2 Overexpressing Breast Cancer Cells via Cytochrome C Dependent Mechanisms

Epidemiological and animal model studies have suggested that non-steroidal anti-inflammatory drugs (NSAIDs) can act as chemopreventive agents. The cyclooxygenase-2 (COX-2) inhibitor nimesulide shows anti-cancer effect in different type of cancers. In the current study, five breast carcinoma cell lines were used to explore the anti-cancer mechanisms of a nimesulide derivative compound 76. The compound dose dependently suppressed SKBR-3, BT474 and MDA-MB-453 breast cancer cell proliferation with IC50 of 0.9 μM, 2.2 μM and 4.0 μM, respectively. However, it needs much higher concentrations to inhibit MCF-7 and MDA-MB-231 breast cancer cell growth with IC50 at 22.1 μM and 19.6 μM, respectively. Further investigation reveals that compound 76 induced apoptosis in SKBR-3 and BT474 cells. Since these cells are Her2 overexpressing cells, the Her2 intracellular signaling pathways were examined after the treatment. There was no significant changing of kinase activity. However, the cytochrome c release assay indicated that the apoptosis induced by the compound was mediated by the mitochondria. These results suggest that compound 76 selectively induce apoptosis in Her2 overexpressing breast cancer cells through the mitochondria, and could be used as a lead to design more potent derivatives

Enabling System-Level Modeling of Variation-Induced Faults in Networks-on-Chip

Process Variation (PV) is increasingly threatening the reliability of Networks-on-Chips. Thus, various resilient router designs have been recently proposed and evaluated. However, these evaluations assume random fault distributions, which result in 52%--81% inaccuracy. We propose an accurate circuit-level fault-modeling tool, which can be plugged into any system-level NoC simulator, quantify the system-level impact of PV-induced faults at runtime, pinpoint fault-prone router components that should be protected, and accurately evaluate alternative resilient multi-core designs.GigaScale Systems Research CenterFocus Center Research Program. Focus Center for Circuit & System Solutions. Semiconductor Research Corporation. Interconnect Focus Cente

Growth Factor Signaling Enhances Aromatase Activity of Breast Cancer Cells Via Post-Transcriptional Mechanisms

It has been demonstrated that growth factors produced by breast cancer cells stimulate aromatase expression in both breast cancer and adjacent adipose fibroblasts and stromal cells. However, whether these growth factors affect aromatase activity by other mechanisms still remain unclear. In the current study, MCF-7aro and T47Daro aromatase transfected breast carcinoma cells were used to explore the mechanisms of post-transcriptional regulation of aromatase activity by growth factor pathways. Our study reveals that PI3K/Akt and MAPK inhibitors suppressed aromatase activity in MCF-7aro cells. However, PI3K/Akt pathway inhibitors stimulated aromatase activity in T47Daro cells. This is due to enhanced MAPK phosphorylation as compensation after the PI3K/Akt pathway has been blocked. IGF-1 treatment increased aromatase activity in both breast cancer cell lines. In addition, LTEDaro cells (long-term estrogen deprived MCF-7aro cells) which have enhanced MAPK activity, show higher aromatase activity compared to parental MCF-7aro cells, but the aromatase protein level remains the same. These results suggest that aromatase activity could be enhanced by growth factor signaling pathways via post-transcriptional mechanisms

Gene expression in early and progression phases of autosomal dominant polycystic kidney disease

<p>Abstract</p> <p>Background</p> <p>Little is known about the genes involved in the initial cyst formation and disease progression in autosomal dominant polycystic kidney disease (ADPKD); however, such knowledge is necessary to explore therapeutic avenues for this common inherited kidney disease.</p> <p>Findings</p> <p>To uncover the genetic determinants and molecular mechanisms of ADPKD, we analyzed 4-point time-series DNA microarrays from <it>Pkd1</it>^{<it>L</it>3/<it>L</it>3}mice to generate high resolution gene expression profiles at different stages of disease progression. We found different characteristic gene expression signatures in the kidneys of <it>Pkd1</it>^{<it>L</it>3/<it>L</it>3}mice compared to age-matched controls during the initial phase of the disease. By postnatal week 1, the <it>Pkd1</it>^{<it>L</it>3/<it>L</it>3}kidney already had a distinctive gene expression pattern different from the corresponding normal controls.</p> <p>Conclusion</p> <p>The genes differentially expressed, either induced or repressed, in ADPKD are important in immune defense, cell structure and motility, cellular proliferation, apoptosis and metabolic processes, and include members of three pathways (Wnt, Notch, and BMP) involved in morphogenetic signaling. Further analysis of the gene expression profiles from the early stage of cystogenesis to end stage disease identified a possible gene network involved in the pathogenesis of ADPKD.</p

Molecular Profiling of Prevention Strategies Using Rodent Models of Colorectal Cancer

Colorectal cancer (CRC) is the third most lethal cancer worldwide, caused by both genetic and environmental exposures, with underlying mechanisms that dovetail genetic, epigenetic, metabolomic, and gut microbiome influences. Adenomatous polyposis coli (Apc) is a tumor suppressor and a negative regulator of Wnt/b-catenin signaling, found mutated in over 70% of CRC cases. The current dissertation used two rodent models, one genetic and one environmental, in the context of cancer prevention to study the etiology of CRC and provide preclinical mechanistic insights. The environmental model incorporated a cooked meat derived mutagen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), to mediate multi-organ carcinogenesis in the rat. The study focused on microRNA (miRNA) profiling in the PhIP model. miRNAs are stable negative regulators of gene targets, and play important roles in cancer and pluripotency. Rat tumor profiles and human pan-cancer datasets defined a miRNA signature of PhIP-induced multi-organ tumorigenesis. The miR-21^high/miR-126^low/miR-29c^low/miR-215^low/miR-145^low signature was associated with poor survival and reduced Klf4 levels, being predictive of possible environmental exposure and paradigm-shifting from ‘genotoxic’ to epigenetic regulation of dietary heterocyclic amines. A genetic angle was provided by the Apc-mutant polyposis in rat colon (Pirc) model, which harbors a large number of polyps in the colon, and recapitulates human familial adenomatous polyposis (FAP). The second study employed sequencing technology for mRNA, miRNA and 16S rRNA to assess the crosstalk between host, gut microbiota, and a cancer preventive diet in the Pirc model. Dietary spinach reduced tumor outcomes significantly in the Pirc model, and reversed host genetic effects on microbiota. mRNA and miRNA analyses revealed the importance of an inflammatory response in Pirc tumorigenesis, and implicated specific miRNA-mRNA associations, such as miR-145/Serpine1 and miR-34a/Klf4. The third study utilized untargeted metabolomics to investigate metabolic changes in the Pirc model along with the prevention effects of dietary spinach. The preliminary results indicated purine and lipid metabolism are important for tumorigenesis and prevention of colorectal cancer. Current technologies are providing new insights at the molecular level, incorporating ‘big data’ with genetic and phenotypic read-outs, to identify underlying leads associated with a designed dietary prevention strategy, which might help to mitigate the worldwide burden of CRC