Document Detail


Downregulation of survivin and aurora A by histone deacetylase and RAS inhibitors: a new drug combination for cancer therapy.
MedLine Citation:
PMID:  20473860     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Histone deacetylase (HDAC) inhibitors, such as valproic acid (VPA), constitute a novel class of anticancer agents that cause an increase in acetylated histones and thus restore the expression of dormant tumor-suppressor and other genes related to cell differentiation, cell-cycle arrest or apoptosis of tumor cells. The Ras inhibitor farnesylthiosalicylic acid (FTS, salirasib) attenuates cancer cell proliferation in vitro and in vivo and, under certain circumstances, induces cell death. FTS by itself does not induce differentiation or complete growth arrest. The abovementioned activity of VPA as a differentiation agent suggested that it might be worth investigating its possible therapeutic potential in synergistic combination with FTS. Here, we examined whether the combined application of VPA and FTS could synergistically inhibit the proliferation of cancer cells that express oncogenic K-Ras (A549 nonsmall-cell lung carcinoma cells), DLD1 (colon carcinoma cells) or chronically active wild-type K-Ras and constitutively active B-Raf (ARO, thyroid carcinoma cells). The results showed that combined treatment with VPA and FTS synergistically reduces proliferation in all of these cancer cell lines by downregulating Ras and blocking the expression of Survivin and Aurora A. These alterations, which were most pronounced following the combined treatment, led to a mitotic crisis, as reflected by mislocalization of the chromosomal passenger complex. Our findings thus demonstrate that combination therapy with VPA and FTS might offer a promising therapeutic approach to the treatment of epithelial tumors.
Authors:
Anat Biran; Michael Brownstein; Ronit Haklai; Yoel Kloog
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  International journal of cancer. Journal international du cancer     Volume:  128     ISSN:  1097-0215     ISO Abbreviation:  Int. J. Cancer     Publication Date:  2011 Feb 
Date Detail:
Created Date:  2010-11-29     Completed Date:  2011-01-14     Revised Date:  2011-07-11    
Medline Journal Info:
Nlm Unique ID:  0042124     Medline TA:  Int J Cancer     Country:  United States    
Other Details:
Languages:  eng     Pagination:  691-701     Citation Subset:  IM    
Affiliation:
Department of Neurobiology, George S Wise Faculty of Life Science, Tel Aviv University, Tel-Aviv, Israel.
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents / therapeutic use
Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
Blotting, Western
Carcinoma, Non-Small-Cell Lung / pathology
Carcinoma, Small Cell / pathology
Cell Division
Cell Line, Tumor
Colonic Neoplasms / pathology
Down-Regulation / drug effects
Farnesol / analogs & derivatives,  therapeutic use
Flow Cytometry
Histone Deacetylase Inhibitors / therapeutic use
Histone Deacetylases / genetics,  metabolism
Humans
Lung Neoplasms / pathology
Microtubule-Associated Proteins / genetics*
Protein-Serine-Threonine Kinases / genetics*
RNA, Neoplasm / genetics,  isolation & purification
Reverse Transcriptase Polymerase Chain Reaction
Salicylic Acids / therapeutic use
Valproic Acid / therapeutic use
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/BIRC5 protein, human; 0/Histone Deacetylase Inhibitors; 0/Microtubule-Associated Proteins; 0/RNA, Neoplasm; 0/Salicylic Acids; 0/farnesylthiosalicylic acid; 4602-84-0/Farnesol; 99-66-1/Valproic Acid; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.11.1/aurora kinase; EC 3.5.1.98/Histone Deacetylases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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