title: Blockade of the ERK pathway enhances the therapeutic efficacy of the histone deacetylase inhibitor MS-275 in human tumor xenograft models.
abstract: The ERK pathway is up-regulated in various human cancers and represents a prime target for mechanism-based approaches to cancer treatment. Specific blockade of the ERK pathway alone induces mostly cytostatic rather than pro-apoptotic effects, however, resulting in a limited therapeutic efficacy of the ERK kinase (MEK) inhibitors. We previously showed that MEK inhibitors markedly enhance the ability of histone deacetylase (HDAC) inhibitors to induce apoptosis in tumor cells with constitutive ERK pathway activation in vitro. To evaluate the therapeutic efficacy of such drug combinations, we administered the MEK inhibitor PD184352 or AZD6244 together with the HDAC inhibitor MS-275 in nude mice harboring HT-29 or H1650 xenografts. Co-administration of the MEK inhibitor markedly sensitized the human xenografts to MS-275 cytotoxicity. A dose of MS-275 that alone showed only moderate cytotoxicity thus suppressed the growth of tumor xenografts almost completely as well as induced a marked reduction in tumor cellularity when administered with PD184352 or AZD6244. The combination of the two types of inhibitor also induced marked oxidative stress, which appeared to result in DNA damage and massive cell death, specifically in the tumor xenografts. The enhanced therapeutic efficacy of the drug combination was achieved by a relatively transient blockade of the ERK pathway. Administration of both MEK and HDAC inhibitors represents a promising chemotherapeutic strategy with improved safety for cancer patients.
authors.affiliation: Laboratory of Cell Regulation, Department of Pharmaceutical Sciences, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8521, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Sakamoto
authors.forename: Kei-ichi
authors.initials: K
authors.lastname: Ozaki
authors.forename: Kohsuke
authors.initials: K
authors.lastname: Fujio
authors.forename: Shu-hei
authors.initials: SH
authors.lastname: Kajikawa
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Uesato
authors.forename: Kazushi
authors.initials: K
authors.lastname: Watanabe
authors.forename: Susumu
authors.initials: S
authors.lastname: Tanimura
authors.forename: Takehiko
authors.initials: T
authors.lastname: Koji
authors.forename: Michiaki
authors.initials: M
authors.lastname: Kohno
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis; D001549:Benzamides / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology; D004357:Drug Synergism; D005260:Female; D019073:HT29 Cells; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D020287:In Situ Nick-End Labeling; D020935:MAP Kinase Signaling System; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors; D018384:Oxidative Stress; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays
chemical_list: C120227:2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide; C517975:AZD 6244; D001549:Benzamides; D001562:Benzimidazoles; D056572:Histone Deacetylase Inhibitors; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C118739:entinostat; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1