BCL-2 Family Inhibitors Enhance Histone Deacetylase Inhibitor and Sorafenib Lethality via Autophagy and Overcome Blockade of the Extrinsic Pathway to Facilitate KillingS
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 c...
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| Veröffentlicht in: | Molecular pharmacology 2009-05, Vol.76 (2), p.327-341 |
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| creator | Martin, Aditi Pandya Park, Margaret A. Mitchell, Clint Walker, Teneille Rahmani, Mohamed Thorburn, Andrew Häussinger, Dieter Reinehr, Roland Grant, Steven Dent, Paul |
| description | 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)]-4
H
-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. |
| doi_str_mv | 10.1124/mol.109.056309 |
| format | Article |
| fullrecord | <record><control><sourceid>pubmedcentral</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_2713125</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>pubmedcentral_primary_oai_pubmedcentral_nih_gov_2713125</sourcerecordid><originalsourceid>FETCH-pubmedcentral_primary_oai_pubmedcentral_nih_gov_27131253</originalsourceid><addsrcrecordid>eNqljs1KAzEURoMotv5sXd8XmJrMdGpnI9jaUlFQqAt3w21621zNJCVJq_NIvqVFBHHt6lucw-ET4kLJnlJ5_7Lxtqdk1ZPloJDVgeiqMleZVEodiq6U-SAbVuVLR5zE-Cql6pdDeSw6quoPCyXLrvgcjR-yHKbYsG3hzhlecPIhwsQZdJpgxjF5R3BLqCm1FiP9aoBuCXMfcEWOF_BAyaDl1MKOEW62yW8Mrttv63FHQfuGYGS9fsMlgV9BMgSTjxTYRdbwhMm8YwvJ7_9o3ocwEdyztezW8zNxtEIb6fxnT8X1dPI8nmWb7aKhpSaXAtp6E7jB0NYeuf5LHJt67Xd1fqUKlZfFvwNfrhF-PQ</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>BCL-2 Family Inhibitors Enhance Histone Deacetylase Inhibitor and Sorafenib Lethality via Autophagy and Overcome Blockade of the Extrinsic Pathway to Facilitate KillingS</title><source>EZB-FREE-00999 freely available EZB journals</source><source>Alma/SFX Local Collection</source><source>Free Full-Text Journals in Chemistry</source><creator>Martin, Aditi Pandya ; Park, Margaret A. ; Mitchell, Clint ; Walker, Teneille ; Rahmani, Mohamed ; Thorburn, Andrew ; Häussinger, Dieter ; Reinehr, Roland ; Grant, Steven ; Dent, Paul</creator><creatorcontrib>Martin, Aditi Pandya ; Park, Margaret A. ; Mitchell, Clint ; Walker, Teneille ; Rahmani, Mohamed ; Thorburn, Andrew ; Häussinger, Dieter ; Reinehr, Roland ; Grant, Steven ; Dent, Paul</creatorcontrib><description>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)]-4
H
-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.</description><identifier>ISSN: 0026-895X</identifier><identifier>EISSN: 1521-0111</identifier><identifier>DOI: 10.1124/mol.109.056309</identifier><identifier>PMID: 19483105</identifier><language>eng</language><publisher>American Society for Pharmacology and Experimental Therapeutics</publisher><ispartof>Molecular pharmacology, 2009-05, Vol.76 (2), p.327-341</ispartof><rights>Copyright © 2009, The American Society for Pharmacology and Experimental Therapeutics</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,315,781,785,886,27929,27930</link.rule.ids></links><search><creatorcontrib>Martin, Aditi Pandya</creatorcontrib><creatorcontrib>Park, Margaret A.</creatorcontrib><creatorcontrib>Mitchell, Clint</creatorcontrib><creatorcontrib>Walker, Teneille</creatorcontrib><creatorcontrib>Rahmani, Mohamed</creatorcontrib><creatorcontrib>Thorburn, Andrew</creatorcontrib><creatorcontrib>Häussinger, Dieter</creatorcontrib><creatorcontrib>Reinehr, Roland</creatorcontrib><creatorcontrib>Grant, Steven</creatorcontrib><creatorcontrib>Dent, Paul</creatorcontrib><title>BCL-2 Family Inhibitors Enhance Histone Deacetylase Inhibitor and Sorafenib Lethality via Autophagy and Overcome Blockade of the Extrinsic Pathway to Facilitate KillingS</title><title>Molecular pharmacology</title><description>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)]-4
H
-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.</description><issn>0026-895X</issn><issn>1521-0111</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><recordid>eNqljs1KAzEURoMotv5sXd8XmJrMdGpnI9jaUlFQqAt3w21621zNJCVJq_NIvqVFBHHt6lucw-ET4kLJnlJ5_7Lxtqdk1ZPloJDVgeiqMleZVEodiq6U-SAbVuVLR5zE-Cql6pdDeSw6quoPCyXLrvgcjR-yHKbYsG3hzhlecPIhwsQZdJpgxjF5R3BLqCm1FiP9aoBuCXMfcEWOF_BAyaDl1MKOEW62yW8Mrttv63FHQfuGYGS9fsMlgV9BMgSTjxTYRdbwhMm8YwvJ7_9o3ocwEdyztezW8zNxtEIb6fxnT8X1dPI8nmWb7aKhpSaXAtp6E7jB0NYeuf5LHJt67Xd1fqUKlZfFvwNfrhF-PQ</recordid><startdate>20090529</startdate><enddate>20090529</enddate><creator>Martin, Aditi Pandya</creator><creator>Park, Margaret A.</creator><creator>Mitchell, Clint</creator><creator>Walker, Teneille</creator><creator>Rahmani, Mohamed</creator><creator>Thorburn, Andrew</creator><creator>Häussinger, Dieter</creator><creator>Reinehr, Roland</creator><creator>Grant, Steven</creator><creator>Dent, Paul</creator><general>American Society for Pharmacology and Experimental Therapeutics</general><scope>5PM</scope></search><sort><creationdate>20090529</creationdate><title>BCL-2 Family Inhibitors Enhance Histone Deacetylase Inhibitor and Sorafenib Lethality via Autophagy and Overcome Blockade of the Extrinsic Pathway to Facilitate KillingS</title><author>Martin, Aditi Pandya ; Park, Margaret A. ; Mitchell, Clint ; Walker, Teneille ; Rahmani, Mohamed ; Thorburn, Andrew ; Häussinger, Dieter ; Reinehr, Roland ; Grant, Steven ; Dent, Paul</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-pubmedcentral_primary_oai_pubmedcentral_nih_gov_27131253</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Martin, Aditi Pandya</creatorcontrib><creatorcontrib>Park, Margaret A.</creatorcontrib><creatorcontrib>Mitchell, Clint</creatorcontrib><creatorcontrib>Walker, Teneille</creatorcontrib><creatorcontrib>Rahmani, Mohamed</creatorcontrib><creatorcontrib>Thorburn, Andrew</creatorcontrib><creatorcontrib>Häussinger, Dieter</creatorcontrib><creatorcontrib>Reinehr, Roland</creatorcontrib><creatorcontrib>Grant, Steven</creatorcontrib><creatorcontrib>Dent, Paul</creatorcontrib><collection>PubMed Central (Full Participant titles)</collection><jtitle>Molecular pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Martin, Aditi Pandya</au><au>Park, Margaret A.</au><au>Mitchell, Clint</au><au>Walker, Teneille</au><au>Rahmani, Mohamed</au><au>Thorburn, Andrew</au><au>Häussinger, Dieter</au><au>Reinehr, Roland</au><au>Grant, Steven</au><au>Dent, Paul</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>BCL-2 Family Inhibitors Enhance Histone Deacetylase Inhibitor and Sorafenib Lethality via Autophagy and Overcome Blockade of the Extrinsic Pathway to Facilitate KillingS</atitle><jtitle>Molecular pharmacology</jtitle><date>2009-05-29</date><risdate>2009</risdate><volume>76</volume><issue>2</issue><spage>327</spage><epage>341</epage><pages>327-341</pages><issn>0026-895X</issn><eissn>1521-0111</eissn><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)]-4
H
-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.</abstract><pub>American Society for Pharmacology and Experimental Therapeutics</pub><pmid>19483105</pmid><doi>10.1124/mol.109.056309</doi></addata></record> |
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| language | eng |
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| source | EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection; Free Full-Text Journals in Chemistry |
| title | BCL-2 Family Inhibitors Enhance Histone Deacetylase Inhibitor and Sorafenib Lethality via Autophagy and Overcome Blockade of the Extrinsic Pathway to Facilitate KillingS |
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