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PMID: 19483105 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

BCL-2 family inhibitors enhance histone deacetylase inhibitor and sorafenib lethality via autophagy and overcome blockade of the extrinsic pathway to facilitate killing.

Molecular pharmacology ·Vol. 76 ·No. 2 ·2009-08-00 ·Pages 327-41

Martin AP, Park MA, Mitchell C, Walker T, Rahmani M, Thorburn A, Häussinger D, Reinehr R, Grant S, Dent P

Abstract

We examined whether the multikinase inhibitor sorafenib and histone deacetylase inhibitors (HDACI) interact to kill pancreatic carcinoma cells and determined the impact of inhibiting BCL-2 family function on sorafenib and HDACI lethality. The lethality of sorafenib was enhanced in pancreatic tumor cells in a synergistic fashion by pharmacologically achievable concentrations of the HDACIs vorinostat or sodium valproate. Overexpression of cellular FLICE-like inhibitory protein (c-FLIP-s) or knockdown of CD95 suppressed the lethality of the sorafenib/HDACI combination (sorafenib + HDACI). In immunohistochemical analyses or using expression of fluorescence-tagged proteins, treatment with sorafenib and vorinostat together (sorafenib + vorinostat) promoted colocalization of CD95 with caspase 8 and CD95 association with the endoplasmic reticulum markers calnexin, ATG5, and Grp78/BiP. In cells lacking CD95 expression or in cells expressing c-FLIP-s, the lethality of sorafenib + HDACI exposure was abolished and was restored when cells were coexposed to BCL-2 family inhibitors [ethyl [2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)]-4H-chromene-3-carboxylate (HA14-1), obatoclax (GX15-070)]. Knockdown of BCL-2, BCL-XL, and MCL-1 recapitulated the effects of GX15-070 treatment. Knockdown of BAX and BAK modestly reduced sorafenib + HDACI lethality but abolished the effects of GX15-070 treatment. Sorafenib + HDACI exposure generated a CD95- and Beclin1-dependent protective form of autophagy, whereas GX15-070 treatment generated a Beclin1-dependent toxic form of autophagy. The potentiation of sorafenib + HDACI killing by GX15-070 was suppressed by knockdown of Beclin1 or of BAX + BAK. Our data demonstrate that pancreatic tumor cells are susceptible to sorafenib + HDACI lethality and that in tumor cells unable to signal death from CD95, use of a BCL-2 family antagonist facilitates sorafenib + HDACI killing via autophagy and the intrinsic pathway.

MeSH Terms
Adenoviridae/genetics Antineoplastic Agents/pharmacology Autophagy/drug effects Benzenesulfonates/pharmacology CASP8 and FADD-Like Apoptosis Regulating Protein/metabolism Cell Line, Transformed Cell Line, Tumor Cell Survival/drug effects Drug Synergism Endoplasmic Reticulum Chaperone BiP Enzyme Inhibitors/metabolism Histone Deacetylase Inhibitors Humans Immunohistochemistry Niacinamide/analogs & derivatives Phenylurea Compounds Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors Pyridines/pharmacology RNA, Small Interfering/metabolism Sorafenib Transfection fas Receptor/metabolism
Chemicals
Antineoplastic Agents Benzenesulfonates CASP8 and FADD-Like Apoptosis Regulating Protein Endoplasmic Reticulum Chaperone BiP Enzyme Inhibitors HSPA5 protein, human Histone Deacetylase Inhibitors Phenylurea Compounds Proto-Oncogene Proteins c-bcl-2 Pyridines RNA, Small Interfering fas Receptor Niacinamide Sorafenib
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Martin Aditi Pandya
Department of Biochemistry and Molecular Biology, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298-0035, USA.
Park Margaret A
Mitchell Clint
Walker Teneille
Rahmani Mohamed
Thorburn Andrew
Häussinger Dieter
Reinehr Roland
Grant Steven
Dent Paul
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Article Info
Journal
Molecular pharmacology
Abbr.
Mol Pharmacol
ISSN
1521-0111
DOI
10.1124/mol.109.056309
Published
2009-08-00
Epub
2009-00-29
Pages
327-41
Language
English
Region
United States
NLM ID
0035623
PMCID
PMC2713125
Subset
IM
Grants
NCI NIH HHS · R01-CA77141 · United States
NCI NIH HHS · R01-CA63753 · United States
NIDDK NIH HHS · R01-DK52825 · United States
NCI NIH HHS · R01 CA093738 · United States
NIDDK NIH HHS · R01 DK052825 · United States
NCI NIH HHS · R01-CA93738 · United States
NCI NIH HHS · P01-CA104177 · United States
NCI NIH HHS · R01-CA108520 · United States
External Links
PubMed source DOI: 10.1124/mol.109.056309 PMC Full Text View journal details
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