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.
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Authors | Weihong Xu, Bin Xu, Yiting Yao, Xiaoling Yu, Jie Shen |
Journal | Biochemical and biophysical research communications
(Biochem Biophys Res Commun)
Vol. 463
Issue 4
Pg. 545-50
(Aug 07 2015)
ISSN: 1090-2104 [Electronic] United States |
PMID | 26026677
(Publication Type: Journal Article)
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Copyright | Copyright © 2015 Elsevier Inc. All rights reserved. |
Chemical References |
- Ceramides
- Histone Deacetylase Inhibitors
- OSU-HDAC42 compound
- Phenylbutyrates
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Topics |
- Animals
- Apoptosis
(drug effects)
- Cell Line, Tumor
- Cell Proliferation
(drug effects)
- Ceramides
(biosynthesis)
- Colonic Neoplasms
(drug therapy, enzymology, metabolism)
- Histone Deacetylase Inhibitors
(pharmacology, therapeutic use)
- Humans
- Male
- Mice
- Mice, SCID
- Phenylbutyrates
(pharmacology, therapeutic use)
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