title: Proteome analyses of the growth inhibitory effects of NCH-51, a novel histone deacetylase inhibitor, on lymphoid malignant cells.
abstract: Recent reports showing successful inhibition of cancer and leukemia cell growth using histone deacetylase inhibitor (HDACi) compounds have highlighted the potential use of HDACi as anti-cancer agents. However, high incidence of toxicity and low stability in vivo were observed with hydroxamic acid-based HDACi such as suberoylanilide hydroxamic acid (SAHA), thus limiting its clinical applicability. In this study, we found that a novel non-hydroxamate HDACi NCH-51 could inhibit the cell growth of a variety of lymphoid malignant cells through apoptosis induction, more effectively than SAHA. Activation of caspase-3, -8 and -9, but not -7 was detected after the treatment with NCH-51. Gene expression profiles showed that NCH-51 and SAHA similarly upregulated p21 and downregulated anti-apoptotic molecules including survivin, bcl-w and c-FLIP. Proteome analysis using two-dimensional electrophoresis revealed that NCH-51 upregulated anti-oxidant molecules including peroxiredoxin 1 and 2 and glutathione S-transferase at the protein level. Interestingly, NCH-51 induced reactive oxygen species (ROS) after 8 h whereas SAHA continuously declined ROS. Pretreatment with an antioxidant, N-acetyl-L-cysteine, abolished the cytotoxicity of NCH-51. These findings suggest that NCH-51 exhibits cytotoxicity by sustaining ROS at the higher level greater than SAHA. This study indicates the therapeutic efficacy of NCH-51 and novel insights for anti-HDAC therapy.
authors: Department of Molecular and Cellular Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors: T
authors: T
authors: Sanda
authors: T
authors: T
authors: Okamoto
authors: Y
authors: Y
authors: Uchida
authors: H
authors: H
authors: Nakagawa
authors: S
authors: S
authors: Iida
authors: S
authors: S
authors: Kayukawa
authors: T
authors: T
authors: Suzuki
authors: T
authors: T
authors: Oshizawa
authors: T
authors: T
authors: Suzuki
authors: N
authors: N
authors: Miyata
authors: R
authors: R
authors: Ueda
mesh_terms: D000975:Antioxidants / Q000737:chemistry; D017209:Apoptosis; D002453:Cell Cycle; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D007938:Leukemia / Q000188:drug therapy*; D008223:Lymphoma / Q000188:drug therapy*; D054464:Peroxiredoxins; D020543:Proteome; D040901:Proteomics / Q000379:methods*; D017382:Reactive Oxygen Species; D013438:Sulfhydryl Compounds / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; C524831:NCH-51 compound; D020543:Proteome; D017382:Reactive Oxygen Species; D013438:Sulfhydryl Compounds; D054464:Peroxiredoxins