title: The novel HDAC inhibitor AR-42-induced anti-colon cancer cell activity is associated with ceramide production.
abstract: In the current study, we investigated the potential activity of AR-42, a novel histone deacetylase (HDAC) inhibitor, against colon cancer cells. Our in vitro results showed that AR-42 induced ceramide production, exerted potent anti-proliferative and pro-apoptotic activities in established (SW-620 and HCT-116 lines) and primary human colon cancer cells. Exogenously-added sphingosine 1-phosphate (S1P) suppressed AR-42-induced activity, yet a cell-permeable ceramide (C4) facilitated AR-42-induced cytotoxicity against colon cancer cells. In addition, AR-42-induced ceramide production and anti-colon cancer cell activity were inhibited by the ceramide synthase inhibitor fumonisin B1, but were exacerbated by PDMP, which is a ceramide glucosylation inhibitor. In vivo, oral administration of a single dose of AR-42 dramatically inhibited SW-620 xenograft growth in severe combined immunodeficient (SCID) mice, without inducing overt toxicities. Together, these results show that AR-42 dramatically inhibits colon cancer cell proliferation in vitro and in vivo, and ceramide production might be the key mechanism responsible for its actions.
authors.affiliation: Department of Clinical Laboratory, Tongren Hospital, Shanghai, China.
authors.forename: Weihong
authors.initials: W
authors.lastname: Xu
authors.affiliation: Department of Clinical Laboratory, Tongren Hospital, Shanghai, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Xu
authors.affiliation: Department of Clinical Laboratory, Tongren Hospital, Shanghai, China.
authors.forename: Yiting
authors.initials: Y
authors.lastname: Yao
authors.affiliation: Department of Clinical Laboratory, Tongren Hospital, Shanghai, China.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Yu
authors.affiliation: Department of Administrative, Tongren Hospital, No. 786 Yuyuan Road, Changning District, Shanghai, China. Electronic address: tongrensj163@163.com.
authors.forename: Jie
authors.initials: J
authors.lastname: Shen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002518:Ceramides / Q000096:biosynthesis*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D010654:Phenylbutyrates / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D002518:Ceramides; D056572:Histone Deacetylase Inhibitors; C529674:OSU-HDAC42 compound; D010654:Phenylbutyrates
keywords: AR-42 and ceramide and apoptosis; Colon cancer; HDAC inhibitor