Farnesyltransferase Inhibitor BMS-214662 Induces Apoptosis in Myeloma Cells through PUMA Up-Regulation, Bax and Bak Activation, and Mcl-1 Elimination
We have studied the mechanism of apoptosis elicited by the farnesyltransferase inhibitor ( R )-7-cyano-2,3,4,5-tetrahydro-1-(1 H -imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thienylsulfonyl)-1 H -1,4-benzodiazepine (BMS-214662) in human myeloma cell lines. Low concentrations of BMS-214662 efficiently...
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| Veröffentlicht in: | Molecular pharmacology 2005-06, Vol.67 (6), p.1991-1998 |
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| creator | Gómez-Benito, María Marzo, Isabel Anel, Alberto Naval, Javier |
| description | We have studied the mechanism of apoptosis elicited by the farnesyltransferase inhibitor ( R )-7-cyano-2,3,4,5-tetrahydro-1-(1 H -imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thienylsulfonyl)-1 H -1,4-benzodiazepine (BMS-214662) in human myeloma cell lines. Low concentrations of BMS-214662 efficiently inhibited protein
farnesylation but did not affect the activation of Akt. BMS-214662 treatment increased levels of the BH3-only protein PUMA;
induced proapoptotic conformational changes of Bax and Bak; reduced Mcl-1 levels; caused mitochondrial transmembrane potential
loss; induced cytochrome c release, caspase activation, apoptosis-inducing factor (AIF) nuclear translocation, and phosphatidylserine exposure; and
allowed the development of apoptotic morphology. Western blot analysis of cell extracts revealed the activation of caspases
2, 3, 8, and 9 upon treatment with BMS-214662. The general caspase inhibitor Z-VAD-fmk significantly prevented BMS-214662âinduced
death in U266 and RPMI 8226 cells but not in NCI-H929 cells. A mixture of selective caspase inhibitors for caspases 9 [ N -benzyloxycarbonyl-Leu-Glu-His-Asp-fluoromethyl ketone (Z-LEHD-fmk)], 3 (Z-DEVD-fmk), and 6 (Z-VEID-fmk) approached the protective
effect of Z-VAD upon cell death. However, Z-VAD-fmk did not prevent BMS-214662âinduced Bax and Bak activation and decrease
of Mcl-1 levels. According to its effect on cell death, Z-VAD-fmk inhibited nuclear translocation of AIF in RPMI 8226 and
U266 but not in NCI-H929 cells. These results suggest that apoptosis triggered by BMS-214662 is initiated by a PUMA/Bax/Bak/Mcl-1âdependent
mechanism. In some cell lines, Bax/Bak activation is not sufficient per se to induce mitochondrial failure and release of
apoptogenic proteins, and so caspases need to be activated to facilitate apoptosis. After ÎΨ m loss, execution of apoptosis was performed in all cases by a cytochrome c -enabled, caspase-9âtriggered, caspase cascade and the nuclear action of AIF. |
| doi_str_mv | 10.1124/mol.104.007021 |
| format | Article |
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farnesylation but did not affect the activation of Akt. BMS-214662 treatment increased levels of the BH3-only protein PUMA;
induced proapoptotic conformational changes of Bax and Bak; reduced Mcl-1 levels; caused mitochondrial transmembrane potential
loss; induced cytochrome c release, caspase activation, apoptosis-inducing factor (AIF) nuclear translocation, and phosphatidylserine exposure; and
allowed the development of apoptotic morphology. Western blot analysis of cell extracts revealed the activation of caspases
2, 3, 8, and 9 upon treatment with BMS-214662. The general caspase inhibitor Z-VAD-fmk significantly prevented BMS-214662âinduced
death in U266 and RPMI 8226 cells but not in NCI-H929 cells. A mixture of selective caspase inhibitors for caspases 9 [ N -benzyloxycarbonyl-Leu-Glu-His-Asp-fluoromethyl ketone (Z-LEHD-fmk)], 3 (Z-DEVD-fmk), and 6 (Z-VEID-fmk) approached the protective
effect of Z-VAD upon cell death. However, Z-VAD-fmk did not prevent BMS-214662âinduced Bax and Bak activation and decrease
of Mcl-1 levels. According to its effect on cell death, Z-VAD-fmk inhibited nuclear translocation of AIF in RPMI 8226 and
U266 but not in NCI-H929 cells. These results suggest that apoptosis triggered by BMS-214662 is initiated by a PUMA/Bax/Bak/Mcl-1âdependent
mechanism. In some cell lines, Bax/Bak activation is not sufficient per se to induce mitochondrial failure and release of
apoptogenic proteins, and so caspases need to be activated to facilitate apoptosis. After ÎΨ m loss, execution of apoptosis was performed in all cases by a cytochrome c -enabled, caspase-9âtriggered, caspase cascade and the nuclear action of AIF.</description><identifier>ISSN: 0026-895X</identifier><identifier>EISSN: 1521-0111</identifier><identifier>DOI: 10.1124/mol.104.007021</identifier><identifier>PMID: 15738311</identifier><language>eng</language><publisher>United States: American Society for Pharmacology and Experimental Therapeutics</publisher><subject>Alkyl and Aryl Transferases - antagonists & inhibitors ; Alkyl and Aryl Transferases - metabolism ; Apoptosis - drug effects ; Apoptosis - physiology ; Apoptosis Regulatory Proteins ; bcl-2 Homologous Antagonist-Killer Protein ; bcl-2-Associated X Protein ; Benzodiazepines - pharmacology ; Cell Line, Tumor ; Dose-Response Relationship, Drug ; Enzyme Inhibitors - pharmacology ; Farnesyltranstransferase ; Humans ; Imidazoles - pharmacology ; Membrane Proteins - biosynthesis ; Membrane Proteins - genetics ; Multiple Myeloma - enzymology ; Multiple Myeloma - pathology ; Myeloid Cell Leukemia Sequence 1 Protein ; Neoplasm Proteins - antagonists & inhibitors ; Neoplasm Proteins - biosynthesis ; Neoplasm Proteins - genetics ; Proto-Oncogene Proteins - biosynthesis ; Proto-Oncogene Proteins - genetics ; Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors ; Proto-Oncogene Proteins c-bcl-2 - biosynthesis ; Proto-Oncogene Proteins c-bcl-2 - genetics ; Tumor Suppressor Protein p53 - biosynthesis ; Tumor Suppressor Protein p53 - genetics ; Up-Regulation - drug effects ; Up-Regulation - physiology</subject><ispartof>Molecular pharmacology, 2005-06, Vol.67 (6), p.1991-1998</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c270t-a8208dcf9a16f614cf07fe01c8e3932375a044e3acd6f306bc343692f9dcf41b3</citedby><cites>FETCH-LOGICAL-c270t-a8208dcf9a16f614cf07fe01c8e3932375a044e3acd6f306bc343692f9dcf41b3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15738311$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Gómez-Benito, María</creatorcontrib><creatorcontrib>Marzo, Isabel</creatorcontrib><creatorcontrib>Anel, Alberto</creatorcontrib><creatorcontrib>Naval, Javier</creatorcontrib><title>Farnesyltransferase Inhibitor BMS-214662 Induces Apoptosis in Myeloma Cells through PUMA Up-Regulation, Bax and Bak Activation, and Mcl-1 Elimination</title><title>Molecular pharmacology</title><addtitle>Mol Pharmacol</addtitle><description>We have studied the mechanism of apoptosis elicited by the farnesyltransferase inhibitor ( R )-7-cyano-2,3,4,5-tetrahydro-1-(1 H -imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thienylsulfonyl)-1 H -1,4-benzodiazepine (BMS-214662) in human myeloma cell lines. Low concentrations of BMS-214662 efficiently inhibited protein
farnesylation but did not affect the activation of Akt. BMS-214662 treatment increased levels of the BH3-only protein PUMA;
induced proapoptotic conformational changes of Bax and Bak; reduced Mcl-1 levels; caused mitochondrial transmembrane potential
loss; induced cytochrome c release, caspase activation, apoptosis-inducing factor (AIF) nuclear translocation, and phosphatidylserine exposure; and
allowed the development of apoptotic morphology. Western blot analysis of cell extracts revealed the activation of caspases
2, 3, 8, and 9 upon treatment with BMS-214662. The general caspase inhibitor Z-VAD-fmk significantly prevented BMS-214662âinduced
death in U266 and RPMI 8226 cells but not in NCI-H929 cells. A mixture of selective caspase inhibitors for caspases 9 [ N -benzyloxycarbonyl-Leu-Glu-His-Asp-fluoromethyl ketone (Z-LEHD-fmk)], 3 (Z-DEVD-fmk), and 6 (Z-VEID-fmk) approached the protective
effect of Z-VAD upon cell death. However, Z-VAD-fmk did not prevent BMS-214662âinduced Bax and Bak activation and decrease
of Mcl-1 levels. According to its effect on cell death, Z-VAD-fmk inhibited nuclear translocation of AIF in RPMI 8226 and
U266 but not in NCI-H929 cells. These results suggest that apoptosis triggered by BMS-214662 is initiated by a PUMA/Bax/Bak/Mcl-1âdependent
mechanism. In some cell lines, Bax/Bak activation is not sufficient per se to induce mitochondrial failure and release of
apoptogenic proteins, and so caspases need to be activated to facilitate apoptosis. After ÎΨ m loss, execution of apoptosis was performed in all cases by a cytochrome c -enabled, caspase-9âtriggered, caspase cascade and the nuclear action of AIF.</description><subject>Alkyl and Aryl Transferases - antagonists & inhibitors</subject><subject>Alkyl and Aryl Transferases - metabolism</subject><subject>Apoptosis - drug effects</subject><subject>Apoptosis - physiology</subject><subject>Apoptosis Regulatory Proteins</subject><subject>bcl-2 Homologous Antagonist-Killer Protein</subject><subject>bcl-2-Associated X Protein</subject><subject>Benzodiazepines - pharmacology</subject><subject>Cell Line, Tumor</subject><subject>Dose-Response Relationship, Drug</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Farnesyltranstransferase</subject><subject>Humans</subject><subject>Imidazoles - pharmacology</subject><subject>Membrane Proteins - biosynthesis</subject><subject>Membrane Proteins - genetics</subject><subject>Multiple Myeloma - enzymology</subject><subject>Multiple Myeloma - pathology</subject><subject>Myeloid Cell Leukemia Sequence 1 Protein</subject><subject>Neoplasm Proteins - antagonists & inhibitors</subject><subject>Neoplasm Proteins - biosynthesis</subject><subject>Neoplasm Proteins - genetics</subject><subject>Proto-Oncogene Proteins - biosynthesis</subject><subject>Proto-Oncogene Proteins - genetics</subject><subject>Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors</subject><subject>Proto-Oncogene Proteins c-bcl-2 - biosynthesis</subject><subject>Proto-Oncogene Proteins c-bcl-2 - genetics</subject><subject>Tumor Suppressor Protein p53 - biosynthesis</subject><subject>Tumor Suppressor Protein p53 - genetics</subject><subject>Up-Regulation - drug effects</subject><subject>Up-Regulation - physiology</subject><issn>0026-895X</issn><issn>1521-0111</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2005</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFUcFu1DAUtBCILoUrR-QTJ7L42Y6THLerFip1RVVYiZvldeyNwYmDnbTsh_C_uOxKPXKap9HMvPc0CL0FsgSg_GMf_BIIXxJSEQrP0AJKCgUBgOdoQQgVRd2U38_Qq5R-EAK8rMlLdAZlxWoGsEB_rlQcTDr4KaohWRNVMvh66NzOTSHii83XggIXgmaynbVJeDWGcQrJJewGvDkYH3qF18b7hKcuhnnf4dvtZoW3Y3Fn9rNXkwvDB3yhfmM1tBl_4pWe3P2Jf-Q22heAL73r3fCPfo1eWOWTeXPCc7S9uvy2_lzcfPl0vV7dFJpWZCpUTUndatsoEFYA15ZU1hDQtWENo6wqFeHcMKVbYRkRO804Ew21TTZx2LFz9P6YO8bwazZpkr1LOv-iBhPmJEVVM87L5r9CaCra8Epk4fIo1DGkFI2VY3S9igcJRD42JnNjeeby2Fg2vDslz7vetE_yU0VPqzu37x5cNHLsVOyVDj7sD_lEKfL6BthfhASemw</recordid><startdate>20050601</startdate><enddate>20050601</enddate><creator>Gómez-Benito, María</creator><creator>Marzo, Isabel</creator><creator>Anel, Alberto</creator><creator>Naval, Javier</creator><general>American Society for Pharmacology and Experimental Therapeutics</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7T5</scope><scope>H94</scope><scope>7X8</scope></search><sort><creationdate>20050601</creationdate><title>Farnesyltransferase Inhibitor BMS-214662 Induces Apoptosis in Myeloma Cells through PUMA Up-Regulation, Bax and Bak Activation, and Mcl-1 Elimination</title><author>Gómez-Benito, María ; Marzo, Isabel ; Anel, Alberto ; Naval, Javier</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c270t-a8208dcf9a16f614cf07fe01c8e3932375a044e3acd6f306bc343692f9dcf41b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2005</creationdate><topic>Alkyl and Aryl Transferases - antagonists & inhibitors</topic><topic>Alkyl and Aryl Transferases - metabolism</topic><topic>Apoptosis - drug effects</topic><topic>Apoptosis - physiology</topic><topic>Apoptosis Regulatory Proteins</topic><topic>bcl-2 Homologous Antagonist-Killer Protein</topic><topic>bcl-2-Associated X Protein</topic><topic>Benzodiazepines - pharmacology</topic><topic>Cell Line, Tumor</topic><topic>Dose-Response Relationship, Drug</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Farnesyltranstransferase</topic><topic>Humans</topic><topic>Imidazoles - pharmacology</topic><topic>Membrane Proteins - biosynthesis</topic><topic>Membrane Proteins - genetics</topic><topic>Multiple Myeloma - enzymology</topic><topic>Multiple Myeloma - pathology</topic><topic>Myeloid Cell Leukemia Sequence 1 Protein</topic><topic>Neoplasm Proteins - antagonists & inhibitors</topic><topic>Neoplasm Proteins - biosynthesis</topic><topic>Neoplasm Proteins - genetics</topic><topic>Proto-Oncogene Proteins - biosynthesis</topic><topic>Proto-Oncogene Proteins - genetics</topic><topic>Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors</topic><topic>Proto-Oncogene Proteins c-bcl-2 - biosynthesis</topic><topic>Proto-Oncogene Proteins c-bcl-2 - genetics</topic><topic>Tumor Suppressor Protein p53 - biosynthesis</topic><topic>Tumor Suppressor Protein p53 - genetics</topic><topic>Up-Regulation - drug effects</topic><topic>Up-Regulation - physiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Gómez-Benito, María</creatorcontrib><creatorcontrib>Marzo, Isabel</creatorcontrib><creatorcontrib>Anel, Alberto</creatorcontrib><creatorcontrib>Naval, Javier</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Immunology Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Molecular pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Gómez-Benito, María</au><au>Marzo, Isabel</au><au>Anel, Alberto</au><au>Naval, Javier</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Farnesyltransferase Inhibitor BMS-214662 Induces Apoptosis in Myeloma Cells through PUMA Up-Regulation, Bax and Bak Activation, and Mcl-1 Elimination</atitle><jtitle>Molecular pharmacology</jtitle><addtitle>Mol Pharmacol</addtitle><date>2005-06-01</date><risdate>2005</risdate><volume>67</volume><issue>6</issue><spage>1991</spage><epage>1998</epage><pages>1991-1998</pages><issn>0026-895X</issn><eissn>1521-0111</eissn><abstract>We have studied the mechanism of apoptosis elicited by the farnesyltransferase inhibitor ( R )-7-cyano-2,3,4,5-tetrahydro-1-(1 H -imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thienylsulfonyl)-1 H -1,4-benzodiazepine (BMS-214662) in human myeloma cell lines. Low concentrations of BMS-214662 efficiently inhibited protein
farnesylation but did not affect the activation of Akt. BMS-214662 treatment increased levels of the BH3-only protein PUMA;
induced proapoptotic conformational changes of Bax and Bak; reduced Mcl-1 levels; caused mitochondrial transmembrane potential
loss; induced cytochrome c release, caspase activation, apoptosis-inducing factor (AIF) nuclear translocation, and phosphatidylserine exposure; and
allowed the development of apoptotic morphology. Western blot analysis of cell extracts revealed the activation of caspases
2, 3, 8, and 9 upon treatment with BMS-214662. The general caspase inhibitor Z-VAD-fmk significantly prevented BMS-214662âinduced
death in U266 and RPMI 8226 cells but not in NCI-H929 cells. A mixture of selective caspase inhibitors for caspases 9 [ N -benzyloxycarbonyl-Leu-Glu-His-Asp-fluoromethyl ketone (Z-LEHD-fmk)], 3 (Z-DEVD-fmk), and 6 (Z-VEID-fmk) approached the protective
effect of Z-VAD upon cell death. However, Z-VAD-fmk did not prevent BMS-214662âinduced Bax and Bak activation and decrease
of Mcl-1 levels. According to its effect on cell death, Z-VAD-fmk inhibited nuclear translocation of AIF in RPMI 8226 and
U266 but not in NCI-H929 cells. These results suggest that apoptosis triggered by BMS-214662 is initiated by a PUMA/Bax/Bak/Mcl-1âdependent
mechanism. In some cell lines, Bax/Bak activation is not sufficient per se to induce mitochondrial failure and release of
apoptogenic proteins, and so caspases need to be activated to facilitate apoptosis. After ÎΨ m loss, execution of apoptosis was performed in all cases by a cytochrome c -enabled, caspase-9âtriggered, caspase cascade and the nuclear action of AIF.</abstract><cop>United States</cop><pub>American Society for Pharmacology and Experimental Therapeutics</pub><pmid>15738311</pmid><doi>10.1124/mol.104.007021</doi><tpages>8</tpages></addata></record> |
| fulltext | fulltext |
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| ispartof | Molecular pharmacology, 2005-06, Vol.67 (6), p.1991-1998 |
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| language | eng |
| recordid | cdi_proquest_miscellaneous_67834459 |
| source | MEDLINE; EZB-FREE-00999 freely available EZB journals; Free Full-Text Journals in Chemistry |
| subjects | Alkyl and Aryl Transferases - antagonists & inhibitors Alkyl and Aryl Transferases - metabolism Apoptosis - drug effects Apoptosis - physiology Apoptosis Regulatory Proteins bcl-2 Homologous Antagonist-Killer Protein bcl-2-Associated X Protein Benzodiazepines - pharmacology Cell Line, Tumor Dose-Response Relationship, Drug Enzyme Inhibitors - pharmacology Farnesyltranstransferase Humans Imidazoles - pharmacology Membrane Proteins - biosynthesis Membrane Proteins - genetics Multiple Myeloma - enzymology Multiple Myeloma - pathology Myeloid Cell Leukemia Sequence 1 Protein Neoplasm Proteins - antagonists & inhibitors Neoplasm Proteins - biosynthesis Neoplasm Proteins - genetics Proto-Oncogene Proteins - biosynthesis Proto-Oncogene Proteins - genetics Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors Proto-Oncogene Proteins c-bcl-2 - biosynthesis Proto-Oncogene Proteins c-bcl-2 - genetics Tumor Suppressor Protein p53 - biosynthesis Tumor Suppressor Protein p53 - genetics Up-Regulation - drug effects Up-Regulation - physiology |
| title | Farnesyltransferase Inhibitor BMS-214662 Induces Apoptosis in Myeloma Cells through PUMA Up-Regulation, Bax and Bak Activation, and Mcl-1 Elimination |
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