Journal de génétique et de thérapie génique

The Effects of p110 Synthetic Inhibitors in Mouse Neutrophils and Macrophages

Samira Khaliq

Phosphatidylinositol 3-Kinases (PI3Ks) are a family of lipid kinases that synthesize PtdIns(3,4,5)P3, and in doing so, relay signals from external cues, regulating multiple signaling pathways such as cell proliferation,growth, survival, motility, and metabolism. Hyperactivation of PI3K signaling cascades is one among the foremost  common events in human cancers. Tremendous efforts are dedicated to the event of effective PI3K inhibitors for cancer therapy. Initial PI3K-directed drugs in clinical trials, consisting largely of non-isoform-selective pan-PI3K inhibitors, haven't yielded exciting results. However, recent preclinical studies have demonstrated that different PI3K isoforms play divergent roles in cellular signaling and cancer, suggesting that inhibitors targeting individual isoforms may be able to achieve greater therapeutic efficacy. Isoform-selective inhibitors are now emerging in the clinic, and have had promising success. ClassI PI3K catalytic isoforms share a conserved domain structure. They utilize the same lipid substrates and generate the same lipid products. Despite their similarities, accumulating evidence indicates these isoforms have distinct roles in mediating PI3K signaling in physiological and oncogenic contexts.PI3K has been reported to be either pro- or anti-inflammatory in several model systems. We hypothesized that this might flow from to different activities of the p110 and isoforms of PI3K.