Therefore, developing targeted therapy to proteins such as Bcl 2 that prevent death of lymphoma cells is advantageous. Bcl 2 plays an important role in the lymphomagenesis of FL. Bcl 2 was originally discovered in FL as a proto onco gene involved in the t chromosomal translocation. This genetic event Tipifarnib cost is found in more than 85% of FL. It has been shown that transfection of Bcl 2 into B cell lines could increase cell viability and decrease apoptosis of lymphoma cells and additionally, confers Inhibitors,Modulators,Libraries resistance of these cells to chemotherapeutic drugs. Thus, interfer ing with Bcl 2 function is hypothesized to lead to apopto sis of lymphoma cells. Therefore, Bcl 2 is a rational therapeutic target because of its role in regulating the apoptotic pathway.

Structural analysis of the binding clefts in Bcl 2 and Bcl XL using X ray crystallography and NMR spectroscopy showed conserved similarity in the BH1, BH2, and BH3 domains. These domains create a hydrophobic surface pocket Inhibitors,Modulators,Libraries that may represent a binding site for pro apoptotic members of the Bcl 2 family, such as Bax. The het erodimerization of Bcl 2 family proteins is believed to be pivotal to the anti apoptotic function of these proteins. Furthermore, site specific mutagenesis of BH1 and BH2 domains completely abrogrates the anti apoptotic activity of these proteins. These studies suggest that this region could be a promising target for the use of SMIs to induce apoptosis. Previous studies in this lab using the SMI gossypol has shown significant growth inhibition in vitro and tumor growth inhibition in vivo in a diffuse large cell lymphoma Inhibitors,Modulators,Libraries model.

With a structural based screening approach, TW 37 a more potent SMI to Bcl 2, was discovered. Subsequently, we have confirmed that TW 37 has anti lymphoma properties in our diffuse large cell lymphoma Inhibitors,Modulators,Libraries model. More recently, we developed a new non pep tidic SMI, ApoG2, which binds like the previous SMIs but with a considerably lower Ki. ApoG2 is a derivative of gossypol that binds to the Bcl 2 family of proteins in the low nanomolar range with a Ki of 35 and 25 nmol/L for Bcl 2 and Mcl 1, respectively and a Ki of 660 nmol/L for Bcl XL. Therefore, the new SMI, ApoG2, could in the ory inhibit the anti apoptotic function of Bcl 2, Bcl XL and Mcl 1 more efficiently and induce apoptosis in FL cells.

In this study, we evaluated the effect of ApoG2 on growth of malignant lymphoid cells in vitro, its ability to induce apoptosis as well as its anti lymphoma activity in vivo using a SCID mouse xenograft model of FSCCL. Materials and methods Inhibitors,Modulators,Libraries Cell Culture and Reagents The origin of human FL B cell line WSU FSCCL was described previously. The cell line was maintained in RPMI 1640 medium containing 10% heat inactivated fetal bovine serum, 1% L glutamine, 100 U/ml pen icillin G and 100g/ml www.selleckchem.com/products/BAY-73-4506.html streptomycin.