title: Inhibition of glycogen synthase kinase-3 increases the cytotoxicity of enzastaurin.
abstract: Cutaneous T-cell lymphomas (CTCL) represent a spectrum of several distinct non-Hodgkin's lymphomas that are characterized by an invasion of the skin by malignant, clonal lymphocytes. Our laboratory has previously demonstrated that the protein kinase C (PKC) β inhibitor Enzastaurin increases apoptosis in malignant lymphocytes of CTCL. These results directly led to a clinical trial for Enzastaurin in CTCL in which it was well tolerated and showed modest activity. To ascertain a means of improving the efficacy of Enzastaurin, we investigated complementary signaling pathways and identified glycogen synthase kinase-3 (GSK3) as important in survival signaling in CTCL. Enzastaurin combined with GSK3 inhibitors demonstrated an enhancement of cytotoxicity. Treatment with a combination of Enzastaurin and the GSK3 inhibitor AR-A014418 resulted in upregulation of β-catenin total protein and β-catenin-mediated transcription. Inhibition of β-catenin-mediated transcription or small hairpin RNA (shRNA) knockdown of β-catenin decreased the cytotoxic effects of Enzastaurin plus AR-A014418. In addition, treatment with Enzastaurin and AR-A014418 decreased the mRNA levels and surface expression of CD44. shRNA knockdown of β-catenin also restored CD44 surface expression. Our observations provide a rationale for the combined targeting of PKC and GSK3 signaling pathways in CTCL to enhance the therapeutic outcome.
authors.affiliation: Robert H Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA. rovedo@northwestern.edu
authors.forename: Mark A
authors.initials: MA
authors.lastname: Rovedo
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Krett
authors.forename: Steven T
authors.initials: ST
authors.lastname: Rosen
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000502:physiology; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics; D007211:Indoles / Q000494:pharmacology*; D016410:Lymphoma, T-Cell, Cutaneous / Q000188:drug therapy* / Q000473:pathology; D011493:Protein Kinase C / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051820:TCF Transcription Factors / Q000502:physiology; D013844:Thiazoles / Q000494:pharmacology; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology; D051176:beta Catenin / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D007211:Indoles; D047428:Protein Kinase Inhibitors; D051820:TCF Transcription Factors; D013844:Thiazoles; D051176:beta Catenin; C479831:N-(4-methoxybenzyl)-N'-(5-nitro-1,3-thiazol-2-yl)urea; D014508:Urea; D011493:Protein Kinase C; D038362:Glycogen Synthase Kinase 3; C504878:enzastaurin