Sorafenib and HDAC inhibitors synergize with TRAIL to kill tumor cells.

Abstract

The present studies were designed to compare and contrast the abilities of TRAIL (death receptor agonist) and obatoclax (BCL-2 family inhibitor) to enhance sorafenib + HDAC inhibitor toxicity in GI tumor cells. Sorafenib and HDAC inhibitor treatment required expression of CD95 to kill GI tumor cells in vitro and in vivo. In cells lacking CD95 expression, TRAIL treatment, and to a lesser extent obatoclax, enhanced the lethal effects of sorafenib + HDAC inhibitor exposure. In hepatoma cells expressing CD95 a similar data pattern emerged with respect to the actions of TRAIL. Downstream of the death receptor the ability of TRAIL to enhance cell killing correlated with reduced AKT, ERK1/2, p70 S6K, and mTOR activity and enhanced cleavage of pro-caspase 3 and reduced expression of MCL-1 and BCL-XL. Over-expression of BCL-XL or MCL-1 or expression of dominant negative pro-caspase 9 protected cells from drug toxicity. Expression of activated AKT, p70 S6K, mTOR, and to a lesser extent MEK1EE also protected cells that correlated with maintained c-FLIP-s expression, reduced BIM expression, and increased BAD phosphorylation. In vivo sorafenib + HDAC inhibitor toxicity against tumors was increased in a greater than additive fashion by TRAIL. Collectively, our data argue that TRAIL, rather than obatoclax, is the most efficacious agent at promoting sorafenib + HDAC inhibitor lethality.

• Authors: Hossein A Hamed, Yukihiro Yamaguchi, Paul B Fisher, Steven Grant, Paul Dent
• Journal: Journal of cellular physiology (J Cell Physiol) Vol. 228 Issue 10 Pg. 1996-2005 (Oct 2013) ISSN: 1097-4652 [Electronic] United States
• PMID: 23674352 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2013 Wiley Periodicals, Inc.

Chemical References

• BAD protein, human
• CASP8 and FADD-Like Apoptosis Regulating Protein
• CFLAR protein, human
• Histone Deacetylase Inhibitors
• Phenylurea Compounds
• Proto-Oncogene Proteins c-bcl-2
• TNF-Related Apoptosis-Inducing Ligand
• bcl-2-Associated X Protein
• bcl-Associated Death Protein
• fas Receptor
• Niacinamide
• Sorafenib
• MTOR protein, human
• Proto-Oncogene Proteins c-akt
• Ribosomal Protein S6 Kinases, 70-kDa
• TOR Serine-Threonine Kinases
• Caspase 3
• Caspase 9
• Histone Deacetylases

Topics

• Animals
• CASP8 and FADD-Like Apoptosis Regulating Protein (metabolism)
• Carcinoma, Hepatocellular (drug therapy, metabolism)
• Caspase 3 (metabolism)
• Caspase 9 (metabolism)
• Cell Line, Tumor
• Drug Synergism
• Female
• Hep G2 Cells
• Histone Deacetylase Inhibitors (pharmacology)
• Histone Deacetylases (metabolism)
• Humans
• Liver Neoplasms (drug therapy, metabolism)
• Mice
• Mice, Nude
• Niacinamide (analogs & derivatives, pharmacology)
• Phenylurea Compounds (pharmacology)
• Proto-Oncogene Proteins c-akt (metabolism)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Ribosomal Protein S6 Kinases, 70-kDa (metabolism)
• Sorafenib
• TNF-Related Apoptosis-Inducing Ligand (pharmacology)
• TOR Serine-Threonine Kinases (metabolism)
• Xenograft Model Antitumor Assays
• bcl-2-Associated X Protein (metabolism)
• bcl-Associated Death Protein (metabolism)
• fas Receptor (metabolism)