Anti-MAPK3 monoclonal antibody, clone FQS82-77S

Purpose: Genistein belongs to the group of isoflavones, which include powerful anticancer agents. Its antitumor properties have been intensively described in many cancers, but related studies assessing ovarian cancer are scarce. The aim of this study was to develop a new method of the underlying mechanisms of genistein's effects and broaden the perspective of targeted therapies in ovarian carcinoma. Materials and methods: Genistein targets were searched in the DrugBank database. Prediction of drug interactions with targets (including secondary targets) was performed with STRING database. Interaction pairs with overall score above 0.9 were recorded for protein-protein interaction (PPI) network generation based on the Cytoscape software. Genes with intense interconnections were grouped into a module. Then, PPI network modules with significance were assessed using Molecular Complex Detection (MCODE) analysis tool. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was performed for the critical genes. Furthermore, disease targets were searched in Comparative Toxicogenomics Database (CTD). The overlapping targets were studied using a Kaplan-Meier analysis to evaluate ovarian carcinoma survival. Results: A total of 13 direct targets and 372 secondary targets were identified for genistein and further analyzed with the MCODE analysis tool to identify critical genes. The top 72 genes were further assessed with KEGG. Then, the term "ovarian cancer" was searched in CTD, and 123 genes associated only with the marker "T" or "M" were recorded. Next, seven overlapping genes (CDKN1B, PTEN, EGFR, MAPK1, MAPK3, PIK3C, and AKT1) resulting from the intersection of three pathways and 123 genes were obtained from CTD. Elevated CDKN1B amounts showed correlation with overall survival (log-rank P=0.021) according to Kaplan-Meier analysis. Conclusion: The current findings indicated that drug-target-disease network analysis represents a useful tool in gene-phenotype connectivity for genistein in ovarian cancer. Our result also showed that CDKN1B is worthy of further research.

Uterine leiomyomas are benign uterine tumors characterized by extracellular matrix remodeling, increased collagen deposition, and increased smooth muscle cell (SMC) proliferation. The reactive oxygen species (ROS) producing NADPH oxidase complex has been shown to be involved in the signaling pathways of several growth factors, cytokines, and vasoactive agents that stimulate proliferation of a variety of cell types. Our objective was to test the hypothesis that ROS derived from NADPH oxidase is a necessary component of the MAP kinase mitogenic pathway activated by platelet derived growth factor (PDGF) and epidermal growth factor (EGF) in leiomyoma SMCs (LSMCs). Primary cell cultures of LSMCs were used as our experimental model. Our results showed that stimulation of these cells with PDGF or EGF caused a marked increase in intracellular ROS production and that the NADPH oxidase inhibitor, DPI, blocks ROS production. In addition, inhibition of ROS production by NADPH oxidase inhibitors blocked, in a dose-dependent manner, the EGF- and PDGF-induced increase in [3 H] thymidine incorporation by LSMCs. Furthermore, an exogenous source of ROS, hydrogen peroxide, was sufficient to stimulate [3 H] thymidine incorporation in LSMCs but did not affect COL1A2 and COL3A1 mRNA levels. Inhibition of the NADPH oxidase complex decreased PDGF-induced MAPK1/MAPK3 activation, whereas exogenous hydrogen peroxide induced MAPK1/MAPK3 activation. This article is the first report suggesting the presence of the NADPH oxidase system and its importance in mitogenic signaling pathways in LSMCs. The necessity of NADPH oxidase-derived ROS for EGF and PDGF signaling pathways leading to cell proliferation points to another potential therapeutic target for treatment and/or prevention of uterine leiomyomas.