NDLI: C6-ceramide synergistically potentiates the anti-tumor effects of histone deacetylase inhibitors via AKT dephosphorylation and -tubulin hyperacetylation both in vitro and in vivo.

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C6-ceramide synergistically potentiates the anti-tumor effects of histone deacetylase inhibitors via AKT dephosphorylation and -tubulin hyperacetylation both in vitro and in vivo.

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Year: 2010 Volume: 1

C6-ceramide synergistically potentiates the anti-tumor effects of histone deacetylase inhibitors via AKT dephosphorylation and -tubulin hyperacetylation both in vitro and in vivo.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Zhu, Q-y Wang, Z. Ji, C. Cheng, L. Yang, Y-l Ren, J. Jin, Y-h Wang, Q-j Gu, X-j Bi, Z-g Hu, G. Yang, Y.
Description	Author Affiliation: Zhu QY ( Department of Physiology, China Pharmaceutical University, Nanjing, PR China.)
Abstract	Histone deacetylase inhibitors (HDACIs) have shown promising anti-tumor effects for a variety of malignancies, however, many tumors are reportedly resistant to them. In this study, we made a novel discovery that co-administration of HDACIs (Trichostatin A (TSA) and others) and exogenous cell-permeable short-chain ceramide (C6) results in striking increase in cancer cell death and apoptosis in multiple cancer cells. These events are associated with perturbations in diverse cell signaling pathways, including inactivation of Akt/mTOR and increase in -tubulin acetylation (both in vivo and in vitro). TSA interacts in a highly synergistic manner with C6-ceramide to disrupt HDAC6/protein phosphatase 1 (PP1)/tubulin complex, to induce -tubulin hyperacetylation, and to release and activate PP1, which then leads to AKT dephosphorylation and eventually causes cancer cell death. Interestingly, TSA itself results in short-term ceramide accumulation, which as a result of metabolic (glycosylation) removal, does not result in evident increase of cancer cell death. However, adding C6-ceramide led to a very pronounced increase in ceramide level and marked increase in cell death. Importantly, the effective synergistic anti-tumor activity of TSA plus C6-ceramide is also seen in in vivo mice xenograft pancreatic and ovarian cancer models, indicating that this regimen (HDACI plus C6-ceramide) may represent a more effective form of therapy against pancreatic and ovarian carcinoma.
File Format	HTM / HTML
e-ISSN	20414889
DOI	10.1038/cddis.2010.96
Journal	Cell Death and Disease
Volume Number	2
Language	English
Publisher	Nature Publishing Group
Publisher Date	2011-01-27
Publisher Place	Great Britain (UK)
Access Restriction	Open
Subject Keyword	Research Support, Non-u.s. Gov't Phosphorylation Gene Expression Regulation, Neoplastic Neoplasms Tubulin Ceramides Genetics Acetylation Oncogene Protein V-akt Drug Therapy Antineoplastic Agents Histone Deacetylases Pharmacology Administration & Dosage Metabolism Drug Effects Hydroxamic Acids Physiopathology Drug Synergism Discipline Cell Biology Animals Mice, Nude Histone Deacetylase Inhibitors Mice Apoptosis
Content Type	Text
Resource Type	Article

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