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The histone-deacetylase inhibitor MS-275 and the CDK-inhibitor CYC-202 promote anti-tumor effects in hepatoma cell lines.

Abstract
Effective therapies for advanced stages of hepatocellular carcinoma (HCC) have yet to be developed. We investigated how far a combination of the HDAC inhibitor MS-275 and the CDK inhibitor CYC-202 synergizes to inhibit proliferation and promotes apoptosis of hepatoma cells in vitro. Human hepatoma cell lines Hep3B and HepG2 as well as primary human foreskin fibroblasts as non-malignant controls were cultured under standardized conditions and incubated with increasing concentrations of CYC-202 and MS-275 as single agents and in combination. After 24 to 72 h, apoptosis was analyzed by flow cytometry (propidium iodide, JC-1) and by immunocytochemistry for cytokeratin 18 fragmentation. DNA synthesis was assessed using bromodeoxyuridine incorporation. Protein was separated for Western blotting against p21, bax and bcl-2 and fluorimetric activity assays against caspase 3 and 8. The results showed that the combination of CYC-202 and MS-275 leads to better pro-apoptotic effects than the employment of single substances. Apoptosis was induced via the mitochondrial pathway as evidenced by a shift in the bax/bcl-2 ratio and breakdown of mitochondrial transmembrane potentials. Caspase assays revealed a strong induction of caspase 3 but not of the extrinsic initiator caspase 8. In conclusion, combination therapy with the biomodulators MS-275 and CYC-202 is a promising treatment option for HCC.
AuthorsSusanne Gahr, Gisela Peter, Thadäus Till Wissniowski, Eckhart G Hahn, Christoph Herold, Matthias Ocker
JournalOncology reports (Oncol Rep) Vol. 20 Issue 5 Pg. 1249-56 (Nov 2008) ISSN: 1021-335X [Print] Greece
PMID18949429 (Publication Type: Journal Article)
Chemical References
  • Antineoplastic Agents
  • Benzamides
  • Enzyme Inhibitors
  • Purines
  • Pyridines
  • Roscovitine
  • entinostat
  • Caspase 3
  • Caspase 8
Topics
  • Antineoplastic Agents (pharmacology)
  • Apoptosis (drug effects)
  • Benzamides (pharmacology)
  • Blotting, Western
  • Carcinoma, Hepatocellular (metabolism)
  • Caspase 3 (drug effects)
  • Caspase 8 (drug effects)
  • Cell Line, Tumor
  • Enzyme Inhibitors (pharmacology)
  • Flow Cytometry
  • Humans
  • Immunohistochemistry
  • Liver Neoplasms (metabolism)
  • Purines (pharmacology)
  • Pyridines (pharmacology)
  • Roscovitine

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