Downregulation of survivin and aurora A by histone deacetylase and RAS inhibitors: a new drug combination for cancer therapy.
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.
Biran
Anat
A
Department of Neurobiology, George S Wise Faculty of Life Science, Tel Aviv University, Tel-Aviv, Israel.
Brownstein
Michael
M
Haklai
Ronit
R
Kloog
Yoel
Y
D000970:Antineoplastic Agents / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D064127:Aurora Kinases; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology; D018288:Carcinoma, Small Cell / Q000473:pathology; D002455:Cell Division; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000473:pathology; D015536:Down-Regulation / Q000187:drug effects; D005204:Farnesol / Q000031:analogs & derivatives / Q000627:therapeutic use; D005434:Flow Cytometry; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008175:Lung Neoplasms / Q000473:pathology; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012334:RNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012459:Salicylates / Q000627:therapeutic use; D000077022:Survivin; D014635:Valproic Acid / Q000627:therapeutic use
D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D056572:Histone Deacetylase Inhibitors; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D012334:RNA, Neoplasm; D012459:Salicylates; D000077022:Survivin; C093323:farnesylthiosalicylic acid; D005204:Farnesol; D014635:Valproic Acid; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; D006655:Histone Deacetylases