Document Detail

Sorafenib and vorinostat kill colon cancer cells by CD95-dependent and -independent mechanisms.
MedLine Citation:
PMID:  19483104     Owner:  NLM     Status:  MEDLINE    
We examined the interaction between the multikinase inhibitor sorafenib and histone deacetylase inhibitors. Sorafenib and vorinostat synergized (sorafenib + vorinostat) to kill HCT116 and SW480 cells. In SW480 cells, sorafenib + vorinostat increased CD95 plasma membrane levels and promoted death-inducing signal complex (DISC) formation, and drug toxicity was blocked by knockdown of CD95 or overexpression of cellular FLICE-like inhibitory protein (c-FLIP-s). In SW620 cells that are patient-matched to SW480 cells, sorafenib + vorinostat toxicity was significantly lower, which correlated with a lack of CD95 activation and lower expression of ceramide synthase 6 (LASS6). Overexpression of LASS6 in SW620 cells enhanced drug-induced CD95 activation and enhanced tumor cell killing, whereas knockdown of LASS6 in SW480 cells suppressed CD95 activation. Knocking down LASS6 expression also suppressed CD95 activation in hepatoma, pancreatic, and ovarian cancer cells. In HCT116 cells, sorafenib + vorinostat treatment caused DISC formation without reducing c-FLIP-s expression and did not increase CD95 plasma membrane levels; sorafenib + vorinostat exposure killed HCT116 cells via an intrinsic pathway/caspase 9-dependent mechanism. In HCT116 cells, knockdown of CD95 enhanced sorafenib + vorinostat lethality, which correlated with less drug-induced CD95-dependent autophagy. Sorafenib + vorinostat treatment activated the c-Jun NH(2)-terminal kinase pathway, which was causal in promoting dissociation of Beclin1 from BCL-2, and in promoting autophagy. Knockdown of Beclin1 expression blocked autophagy and enhanced drug toxicity. Our data demonstrate that treatment of colon cancer cells with sorafenib + vorinostat activates CD95 via de novo ceramide synthesis that promotes viability via autophagy or degrades survival via either the extrinsic or intrinsic pathways.
Teneille Walker; Clint Mitchell; Margaret A Park; Adly Yacoub; Martin Graf; Mohamed Rahmani; Peter J Houghton; Christina Voelkel-Johnson; Steven Grant; Paul Dent
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2009-05-29
Journal Detail:
Title:  Molecular pharmacology     Volume:  76     ISSN:  1521-0111     ISO Abbreviation:  Mol. Pharmacol.     Publication Date:  2009 Aug 
Date Detail:
Created Date:  2009-07-21     Completed Date:  2009-08-17     Revised Date:  2013-11-21    
Medline Journal Info:
Nlm Unique ID:  0035623     Medline TA:  Mol Pharmacol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  342-55     Citation Subset:  IM    
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MeSH Terms
Antigens, CD / metabolism*
Antineoplastic Agents / toxicity*
Apoptosis Regulatory Proteins / metabolism
Autophagy / drug effects
Benzenesulfonates / toxicity*
CASP8 and FADD-Like Apoptosis Regulating Protein / metabolism
Caspase 9 / metabolism
Cell Line, Tumor
Colonic Neoplasms / metabolism*
Drug Synergism
Enzyme Activation / drug effects
HCT116 Cells
Hydroxamic Acids / toxicity*
JNK Mitogen-Activated Protein Kinases / metabolism
Membrane Proteins / metabolism
Niacinamide / analogs & derivatives
Oxidoreductases / metabolism
Phenylurea Compounds
Pyridines / toxicity*
Grant Support
P01-CA104177/CA/NCI NIH HHS; R01 CA093738-08/CA/NCI NIH HHS; R01 DK052825/DK/NIDDK NIH HHS; R01-CA108520/CA/NCI NIH HHS; R01-CA63753/CA/NCI NIH HHS; R01-CA77141/CA/NCI NIH HHS; R01-CA93738/CA/NCI NIH HHS; R01-DK52825/DK/NIDDK NIH HHS
Reg. No./Substance:
0/Antigens, CD; 0/Antineoplastic Agents; 0/Apoptosis Regulatory Proteins; 0/BECN1 protein, human; 0/Benzenesulfonates; 0/CASP8 and FADD-Like Apoptosis Regulating Protein; 0/Hydroxamic Acids; 0/Membrane Proteins; 0/Phenylurea Compounds; 0/Pyridines; 0/sorafenib; 149647-78-9/vorinostat; 25X51I8RD4/Niacinamide; EC 1.-/Oxidoreductases; EC 1.3.1.-/dihydroceramide desaturase; EC Mitogen-Activated Protein Kinases; EC 3.4.22.-/Caspase 9

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