The discovery of an abnormal choline phospholipid Calcitriol mechanism metabolism as the hallmark of BC and other cancers stimulated investigations on the pos sible role of phosphatidylcholine cycle enzymes Inhibitors,Modulators,Libraries as potential indicators of tumor response and novel therapy targets. Biochemical, genomic, and proteomic assays showed upregulation of choline kinase in BC and in epithelial ovarian cancer cell lines. RNA interference mediated ChoK knockdown has been reported to exert anti proliferative effects and induce cell differentiation in BC cells. We recently showed potent increases of both ChoK and PtdCho specific phospholipase C activities in EOC cells compared with non tumoral counterparts. PC PLC isoforms responsible for PtdCho hydro lysis into phosphocholine and diacylglycerol have been isolated but not yet cloned from mammalian sources.

Inhibitors,Modulators,Libraries However, accruing evidence points to multiple implications of this enzyme in cell signaling through mitogen activated protein kinase and onco gene activated protein kinase pathways, programmed Inhibitors,Modulators,Libraries cell death, activation of immune cells, and stem cell dif ferentiation. Further more, we reported direct evidence on PC PLC activation and changes in subcellular localization of this enzyme in cancer and non tumoral receptor activated mammalian cells. In particular, selective PC PLC accumulation was detected on the plasma mem brane of EOC cells, human epidermal growth factor receptor 2 overexpressing BC cells, mito gen stimulated fibroblasts, and cytokine activated human natural killer cells.

The competitive PC PLC inhibitor tricyclodecan 9 yl potassium Inhibitors,Modulators,Libraries xanthate used at the dose of 50 ug mL blocked EOC cell proliferation and prevented these cells from entering the S phase under growth factor sti mulation. Moreover, PC PLC was found to associ ate with the HER2 receptor Inhibitors,Modulators,Libraries in raft domains of the plasma membrane of HER2 overexpressing BC cells. In these cells, D609 induced PC PLC inhibition resulted in HER2 receptor downregulation, together with that of its heterodimers with cognate members of the epidermal growth factor receptor family, by interfer ing with receptor internalization, degradation, and recy cling. Overall, this body of evidence little suggests the existence of regulatory links between PC PLC activity, membrane receptor expression, and cancer cell proliferation. On the other hand, at much higher doses, D609 not only inhibited cell proliferation but also reduced cell viability, eventually inducing apoptosis in the metastatic cell line MDA MB 435. These effects were attributed to intracellular ceramide accumulation, as a result of D609 induced inhibition of sphingomyelin synthase and activation of de novo ceramide synthesis.