title: Targeting the extracellular signal-regulated kinase pathway in cancer therapy.
abstract: The extracellular signal-regulated kinase (ERK) pathway is a major determinant in the control of diverse cellular processes such as proliferation, survival, and motility. This pathway is often upregulated in human cancers and as such represents an attractive target for mechanism-based approaches to cancer treatment. However, specific blockade of the ERK pathway alone induces mostly cytostatic rather than proapoptotic effects, resulting in limited therapeutic efficacy. Blockade of the constitutively activated ERK pathway by an ERK kinase (MEK) inhibitor sensitizes tumor cells to apoptotic cell death induced by several cytotoxic anticancer agents including microtubule-destabilizing agents and histone deacetylase inhibitors, not only in vitro but also in tumor zenografts in vivo. Thus, low concentrations of these anticancer drugs that by themselves show little cytotoxicity effectively kill tumor cells in which the ERK pathway is constitutively activated when co-administrated with a MEK inhibitor. The combination of a cytostatic signaling pathway inhibitor (MEK inhibitors) and conventional anticancer drugs (microtubule-destabilizing agents or histone deacetylase inhibitors) provides an excellent basis for the development of safer anticancer chemotherapies with enhanced efficacy through lowering the required dose of the latter cytotoxic drugs.
authors: Laboratory of Cell Regulation, Department of Pharmaceutical Sciences, Graduate School of Biomedical Sciences, Nagasaki University, Japan. kohnom@nagasaki-u.ac.jp
authors: Michiaki
authors: M
authors: Kohno
authors: Susumu
authors: S
authors: Tanimura
authors: Kei-ichi
authors: K
authors: Ozaki
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors*; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D050257:Tubulin Modulators / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D047428:Protein Kinase Inhibitors; D050257:Tubulin Modulators; D048049:Extracellular Signal-Regulated MAP Kinases