Targeting BCL-2 proteins in pediatric cancer: Dual inhibition of BCL-X L and MCL-1 leads to rapid induction of intrinsic apoptosis
With the development of potent and selective inhibitors of MCL-1 (S63845) and BCL-X (A-1331852) novel cancer treatment options have emerged. BCL-2 family proteins are important regulators of apoptosis in pediatric solid tumors. In the current study, we discover that rhabdomyosarcoma, Ewing sarcoma,...
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| Veröffentlicht in: | Cancer letters 2020-07, Vol.482, p.19 |
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| creator | Kehr, Sarah Haydn, Tinka Bierbrauer, Annika Irmer, Barnabas Vogler, Meike Fulda, Simone |
| description | With the development of potent and selective inhibitors of MCL-1 (S63845) and BCL-X
(A-1331852) novel cancer treatment options have emerged. BCL-2 family proteins are important regulators of apoptosis in pediatric solid tumors. In the current study, we discover that rhabdomyosarcoma, Ewing sarcoma, osteosarcoma and neuroblastoma cell lines are co-dependent on BCL-X
and MCL-1 for survival. A-1331852/S63845 co-treatment, but not combinations of either inhibitor with ABT-199, synergistically induces rapid intrinsic apoptosis in vitro and demonstrates efficiency in an in vivo embryonic chicken model of rhabdomyosarcoma. Interestingly, A-1331852/S63845-induced apoptosis is BAX/BAK-dependent and mediated by displacement of BAK from BCL-X
and MCL-1, respectively. Moreover, BAK interacts with BAX to build a pore-forming complex in the outer mitochondrial membrane, leading to loss of mitochondrial outer membrane potential and caspase activation. Furthermore, in RD cells A-1331852/S63845 co-treatment disrupts BIM and NOXA in their interactions with BCL-X
and MCL-1, respectively, thereby contributing to apoptosis. Altogether, this study is the first to demonstrate the potency of A-1331852/S63845 in pediatric solid tumor cells and to describe the molecular mechanisms of A-1331852/S63845 co-treatment underlining the potential of BCL-X
and MCL-1 inhibition as treatment regime. |
| doi_str_mv | 10.1016/j.canlet.2020.02.041 |
| format | Article |
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(A-1331852) novel cancer treatment options have emerged. BCL-2 family proteins are important regulators of apoptosis in pediatric solid tumors. In the current study, we discover that rhabdomyosarcoma, Ewing sarcoma, osteosarcoma and neuroblastoma cell lines are co-dependent on BCL-X
and MCL-1 for survival. A-1331852/S63845 co-treatment, but not combinations of either inhibitor with ABT-199, synergistically induces rapid intrinsic apoptosis in vitro and demonstrates efficiency in an in vivo embryonic chicken model of rhabdomyosarcoma. Interestingly, A-1331852/S63845-induced apoptosis is BAX/BAK-dependent and mediated by displacement of BAK from BCL-X
and MCL-1, respectively. Moreover, BAK interacts with BAX to build a pore-forming complex in the outer mitochondrial membrane, leading to loss of mitochondrial outer membrane potential and caspase activation. Furthermore, in RD cells A-1331852/S63845 co-treatment disrupts BIM and NOXA in their interactions with BCL-X
and MCL-1, respectively, thereby contributing to apoptosis. Altogether, this study is the first to demonstrate the potency of A-1331852/S63845 in pediatric solid tumor cells and to describe the molecular mechanisms of A-1331852/S63845 co-treatment underlining the potential of BCL-X
and MCL-1 inhibition as treatment regime.</description><identifier>ISSN: 0304-3835</identifier><identifier>EISSN: 1872-7980</identifier><identifier>DOI: 10.1016/j.canlet.2020.02.041</identifier><identifier>PMID: 32145345</identifier><language>eng</language><publisher>Ireland: Elsevier Limited</publisher><subject>Animals ; Antibodies ; Apoptosis ; BAX protein ; Bcl-2 protein ; Bcl-x protein ; bcl-X Protein - metabolism ; Benzothiazoles - pharmacology ; Benzothiazoles - therapeutic use ; BIM protein ; Caspase ; Caspases - metabolism ; Cell activation ; Cell Line, Tumor ; Cell Survival - drug effects ; Chick Embryo ; Child ; Clinical trials ; Drug Synergism ; Embryos ; Ewing's sarcoma ; Ewings sarcoma ; Flow cytometry ; Gene expression ; Gene Expression Regulation, Neoplastic - drug effects ; Hematology ; Humans ; Isoquinolines - pharmacology ; Isoquinolines - therapeutic use ; Leukemia ; Mcl-1 protein ; Medical prognosis ; Membrane potential ; Membrane Potential, Mitochondrial - drug effects ; Mice ; Mitochondria ; Molecular modelling ; Myeloid Cell Leukemia Sequence 1 Protein - metabolism ; Neuroblastoma - drug therapy ; Neuroblastoma - metabolism ; Osteosarcoma ; Osteosarcoma - drug therapy ; Osteosarcoma - metabolism ; Pediatrics ; Proteins ; Pyrimidines - pharmacology ; Pyrimidines - therapeutic use ; Rhabdomyosarcoma ; Rhabdomyosarcoma - drug therapy ; Rhabdomyosarcoma - metabolism ; Sarcoma ; Sarcoma, Ewing - drug therapy ; Sarcoma, Ewing - metabolism ; Solid tumors ; Thiophenes - pharmacology ; Thiophenes - therapeutic use ; Tumor cell lines ; Tumor cells ; Tumors</subject><ispartof>Cancer letters, 2020-07, Vol.482, p.19</ispartof><rights>Copyright © 2020 Elsevier B.V. All rights reserved.</rights><rights>2020. Elsevier B.V.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32145345$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kehr, Sarah</creatorcontrib><creatorcontrib>Haydn, Tinka</creatorcontrib><creatorcontrib>Bierbrauer, Annika</creatorcontrib><creatorcontrib>Irmer, Barnabas</creatorcontrib><creatorcontrib>Vogler, Meike</creatorcontrib><creatorcontrib>Fulda, Simone</creatorcontrib><title>Targeting BCL-2 proteins in pediatric cancer: Dual inhibition of BCL-X L and MCL-1 leads to rapid induction of intrinsic apoptosis</title><title>Cancer letters</title><addtitle>Cancer Lett</addtitle><description>With the development of potent and selective inhibitors of MCL-1 (S63845) and BCL-X
(A-1331852) novel cancer treatment options have emerged. BCL-2 family proteins are important regulators of apoptosis in pediatric solid tumors. In the current study, we discover that rhabdomyosarcoma, Ewing sarcoma, osteosarcoma and neuroblastoma cell lines are co-dependent on BCL-X
and MCL-1 for survival. A-1331852/S63845 co-treatment, but not combinations of either inhibitor with ABT-199, synergistically induces rapid intrinsic apoptosis in vitro and demonstrates efficiency in an in vivo embryonic chicken model of rhabdomyosarcoma. Interestingly, A-1331852/S63845-induced apoptosis is BAX/BAK-dependent and mediated by displacement of BAK from BCL-X
and MCL-1, respectively. Moreover, BAK interacts with BAX to build a pore-forming complex in the outer mitochondrial membrane, leading to loss of mitochondrial outer membrane potential and caspase activation. Furthermore, in RD cells A-1331852/S63845 co-treatment disrupts BIM and NOXA in their interactions with BCL-X
and MCL-1, respectively, thereby contributing to apoptosis. Altogether, this study is the first to demonstrate the potency of A-1331852/S63845 in pediatric solid tumor cells and to describe the molecular mechanisms of A-1331852/S63845 co-treatment underlining the potential of BCL-X
and MCL-1 inhibition as treatment regime.</description><subject>Animals</subject><subject>Antibodies</subject><subject>Apoptosis</subject><subject>BAX protein</subject><subject>Bcl-2 protein</subject><subject>Bcl-x protein</subject><subject>bcl-X Protein - metabolism</subject><subject>Benzothiazoles - pharmacology</subject><subject>Benzothiazoles - therapeutic use</subject><subject>BIM protein</subject><subject>Caspase</subject><subject>Caspases - metabolism</subject><subject>Cell activation</subject><subject>Cell Line, Tumor</subject><subject>Cell Survival - drug effects</subject><subject>Chick Embryo</subject><subject>Child</subject><subject>Clinical trials</subject><subject>Drug Synergism</subject><subject>Embryos</subject><subject>Ewing's sarcoma</subject><subject>Ewings sarcoma</subject><subject>Flow cytometry</subject><subject>Gene expression</subject><subject>Gene Expression Regulation, Neoplastic - drug effects</subject><subject>Hematology</subject><subject>Humans</subject><subject>Isoquinolines - pharmacology</subject><subject>Isoquinolines - therapeutic use</subject><subject>Leukemia</subject><subject>Mcl-1 protein</subject><subject>Medical prognosis</subject><subject>Membrane potential</subject><subject>Membrane Potential, Mitochondrial - drug effects</subject><subject>Mice</subject><subject>Mitochondria</subject><subject>Molecular modelling</subject><subject>Myeloid Cell Leukemia Sequence 1 Protein - metabolism</subject><subject>Neuroblastoma - drug therapy</subject><subject>Neuroblastoma - metabolism</subject><subject>Osteosarcoma</subject><subject>Osteosarcoma - drug therapy</subject><subject>Osteosarcoma - metabolism</subject><subject>Pediatrics</subject><subject>Proteins</subject><subject>Pyrimidines - pharmacology</subject><subject>Pyrimidines - therapeutic use</subject><subject>Rhabdomyosarcoma</subject><subject>Rhabdomyosarcoma - drug therapy</subject><subject>Rhabdomyosarcoma - metabolism</subject><subject>Sarcoma</subject><subject>Sarcoma, Ewing - drug therapy</subject><subject>Sarcoma, Ewing - metabolism</subject><subject>Solid tumors</subject><subject>Thiophenes - pharmacology</subject><subject>Thiophenes - therapeutic use</subject><subject>Tumor cell lines</subject><subject>Tumor cells</subject><subject>Tumors</subject><issn>0304-3835</issn><issn>1872-7980</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo1kE1LxDAQhoMo7rr6D0QCnlsnX23qTddPqHhZwVtJk3TNspvWJj149ZcbdD3NwDzzvMwgdE4gJ0CKq02uld_amFOgkAPNgZMDNCeypFlZSThEc2DAMyaZmKGTEDYAIHgpjtGMUcIF42KOvldqXNvo_BrfLuuM4mHso3U-YOfxYI1TcXQapyhtx2t8N6ltmny41kXXe9x3v2vvuMbKG_ySeoK3VpmAY49HNTiTcDPpf9r55PMhKdXQD7EPLpyio05tgz3b1wV6e7hfLZ-y-vXxeXlTZwNhRcysNR23gkpBdNlqyyWnZSGhg7YinGsgRlpCrK5AKcqN0rLkjBSmkl0rOsoW6PLPm078nGyIzaafRp8iG8qpKCQjZZWoiz01tTtrmmF0OzV-Nf8vYz-II27d</recordid><startdate>20200710</startdate><enddate>20200710</enddate><creator>Kehr, Sarah</creator><creator>Haydn, Tinka</creator><creator>Bierbrauer, Annika</creator><creator>Irmer, Barnabas</creator><creator>Vogler, Meike</creator><creator>Fulda, Simone</creator><general>Elsevier Limited</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7TO</scope><scope>7U9</scope><scope>H94</scope><scope>K9.</scope><scope>NAPCQ</scope></search><sort><creationdate>20200710</creationdate><title>Targeting BCL-2 proteins in pediatric cancer: Dual inhibition of BCL-X L and MCL-1 leads to rapid induction of intrinsic apoptosis</title><author>Kehr, Sarah ; Haydn, Tinka ; Bierbrauer, Annika ; Irmer, Barnabas ; Vogler, Meike ; Fulda, Simone</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p136t-eedf4e52851c7bce48427680f0b9144c01d8e11ec90aa24dac874316d98fb5f23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Animals</topic><topic>Antibodies</topic><topic>Apoptosis</topic><topic>BAX protein</topic><topic>Bcl-2 protein</topic><topic>Bcl-x protein</topic><topic>bcl-X Protein - metabolism</topic><topic>Benzothiazoles - pharmacology</topic><topic>Benzothiazoles - therapeutic use</topic><topic>BIM protein</topic><topic>Caspase</topic><topic>Caspases - metabolism</topic><topic>Cell activation</topic><topic>Cell Line, Tumor</topic><topic>Cell Survival - drug effects</topic><topic>Chick Embryo</topic><topic>Child</topic><topic>Clinical trials</topic><topic>Drug Synergism</topic><topic>Embryos</topic><topic>Ewing's sarcoma</topic><topic>Ewings sarcoma</topic><topic>Flow cytometry</topic><topic>Gene expression</topic><topic>Gene Expression Regulation, Neoplastic - drug effects</topic><topic>Hematology</topic><topic>Humans</topic><topic>Isoquinolines - pharmacology</topic><topic>Isoquinolines - therapeutic use</topic><topic>Leukemia</topic><topic>Mcl-1 protein</topic><topic>Medical prognosis</topic><topic>Membrane potential</topic><topic>Membrane Potential, Mitochondrial - drug effects</topic><topic>Mice</topic><topic>Mitochondria</topic><topic>Molecular modelling</topic><topic>Myeloid Cell Leukemia Sequence 1 Protein - metabolism</topic><topic>Neuroblastoma - drug therapy</topic><topic>Neuroblastoma - metabolism</topic><topic>Osteosarcoma</topic><topic>Osteosarcoma - drug therapy</topic><topic>Osteosarcoma - metabolism</topic><topic>Pediatrics</topic><topic>Proteins</topic><topic>Pyrimidines - pharmacology</topic><topic>Pyrimidines - therapeutic use</topic><topic>Rhabdomyosarcoma</topic><topic>Rhabdomyosarcoma - drug therapy</topic><topic>Rhabdomyosarcoma - metabolism</topic><topic>Sarcoma</topic><topic>Sarcoma, Ewing - drug therapy</topic><topic>Sarcoma, Ewing - metabolism</topic><topic>Solid tumors</topic><topic>Thiophenes - pharmacology</topic><topic>Thiophenes - therapeutic use</topic><topic>Tumor cell lines</topic><topic>Tumor cells</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kehr, Sarah</creatorcontrib><creatorcontrib>Haydn, Tinka</creatorcontrib><creatorcontrib>Bierbrauer, Annika</creatorcontrib><creatorcontrib>Irmer, Barnabas</creatorcontrib><creatorcontrib>Vogler, Meike</creatorcontrib><creatorcontrib>Fulda, Simone</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><jtitle>Cancer letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kehr, Sarah</au><au>Haydn, Tinka</au><au>Bierbrauer, Annika</au><au>Irmer, Barnabas</au><au>Vogler, Meike</au><au>Fulda, Simone</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Targeting BCL-2 proteins in pediatric cancer: Dual inhibition of BCL-X L and MCL-1 leads to rapid induction of intrinsic apoptosis</atitle><jtitle>Cancer letters</jtitle><addtitle>Cancer Lett</addtitle><date>2020-07-10</date><risdate>2020</risdate><volume>482</volume><spage>19</spage><pages>19-</pages><issn>0304-3835</issn><eissn>1872-7980</eissn><abstract>With the development of potent and selective inhibitors of MCL-1 (S63845) and BCL-X
(A-1331852) novel cancer treatment options have emerged. BCL-2 family proteins are important regulators of apoptosis in pediatric solid tumors. In the current study, we discover that rhabdomyosarcoma, Ewing sarcoma, osteosarcoma and neuroblastoma cell lines are co-dependent on BCL-X
and MCL-1 for survival. A-1331852/S63845 co-treatment, but not combinations of either inhibitor with ABT-199, synergistically induces rapid intrinsic apoptosis in vitro and demonstrates efficiency in an in vivo embryonic chicken model of rhabdomyosarcoma. Interestingly, A-1331852/S63845-induced apoptosis is BAX/BAK-dependent and mediated by displacement of BAK from BCL-X
and MCL-1, respectively. Moreover, BAK interacts with BAX to build a pore-forming complex in the outer mitochondrial membrane, leading to loss of mitochondrial outer membrane potential and caspase activation. Furthermore, in RD cells A-1331852/S63845 co-treatment disrupts BIM and NOXA in their interactions with BCL-X
and MCL-1, respectively, thereby contributing to apoptosis. Altogether, this study is the first to demonstrate the potency of A-1331852/S63845 in pediatric solid tumor cells and to describe the molecular mechanisms of A-1331852/S63845 co-treatment underlining the potential of BCL-X
and MCL-1 inhibition as treatment regime.</abstract><cop>Ireland</cop><pub>Elsevier Limited</pub><pmid>32145345</pmid><doi>10.1016/j.canlet.2020.02.041</doi></addata></record> |
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| subjects | Animals Antibodies Apoptosis BAX protein Bcl-2 protein Bcl-x protein bcl-X Protein - metabolism Benzothiazoles - pharmacology Benzothiazoles - therapeutic use BIM protein Caspase Caspases - metabolism Cell activation Cell Line, Tumor Cell Survival - drug effects Chick Embryo Child Clinical trials Drug Synergism Embryos Ewing's sarcoma Ewings sarcoma Flow cytometry Gene expression Gene Expression Regulation, Neoplastic - drug effects Hematology Humans Isoquinolines - pharmacology Isoquinolines - therapeutic use Leukemia Mcl-1 protein Medical prognosis Membrane potential Membrane Potential, Mitochondrial - drug effects Mice Mitochondria Molecular modelling Myeloid Cell Leukemia Sequence 1 Protein - metabolism Neuroblastoma - drug therapy Neuroblastoma - metabolism Osteosarcoma Osteosarcoma - drug therapy Osteosarcoma - metabolism Pediatrics Proteins Pyrimidines - pharmacology Pyrimidines - therapeutic use Rhabdomyosarcoma Rhabdomyosarcoma - drug therapy Rhabdomyosarcoma - metabolism Sarcoma Sarcoma, Ewing - drug therapy Sarcoma, Ewing - metabolism Solid tumors Thiophenes - pharmacology Thiophenes - therapeutic use Tumor cell lines Tumor cells Tumors |
| title | Targeting BCL-2 proteins in pediatric cancer: Dual inhibition of BCL-X L and MCL-1 leads to rapid induction of intrinsic apoptosis |
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