Drug development targeting the glycogen synthase kinase-3beta (GSK-3beta)-mediated signal transduction pathway: inhibitors of the Wnt/beta-catenin signaling pathway as novel anticancer drugs.
Accumulating evidence suggests that the Wnt/beta-catenin signaling pathway is often involved in oncogenesis and cancer development. Accordingly, a novel anticancer drug can be developed using inhibitors of this pathway. However, at present, there is no selective inhibitor of this pathway available as a therapeutic agent. Although all the components of the Wnt/beta-catenin signaling pathway can be a target for drug development, glycogen synthase kinase-3beta (GSK-3beta), in particular, may be a good target because GSK-3beta is an essential component of the pathway, and activation of this kinase results in the inhibition of the Wnt signaling pathway. We found that the differentiation-inducing factors (DIFs), putative morphogens for Dictyostelium discoideum, inhibit the Wnt/beta-catenin signaling pathway via the activation of GSK-3beta, resulting in the cell-cycle arrest of human cancer cell lines. In this review, we summarize our recent findings on the antiproliferative effect of DIFs and show the possibility for development of a novel anticancer drug from DIFs and their derivatives.
Takahashi-Yanaga
Fumi
F
Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, Japan. yanaga@clipharm.med.kyushu-u.ac.jp
Sasaguri
Toshiyuki
T
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D019938:Cyclin D1 / Q000378:metabolism / Q000502:physiology; D016503:Drug Delivery Systems; D038362:Glycogen Synthase Kinase 3 / Q000187:drug effects / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006588:Hexanones / Q000494:pharmacology*; D006801:Humans; D006843:Hydrocarbons, Chlorinated / Q000494:pharmacology*; D051379:Mice; D015398:Signal Transduction; D051153:Wnt Proteins / Q000037:antagonists & inhibitors*; D051176:beta Catenin / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; C490570:Differentiation-inducing factor-1, Dictyostelium; D006588:Hexanones; D006843:Hydrocarbons, Chlorinated; D051153:Wnt Proteins; D051176:beta Catenin; D019938:Cyclin D1; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3