Combination therapies induce cancer cell death through the integrated stress response and disturbed pyrimidine metabolism
Abstract By accentuating drug efficacy and impeding resistance mechanisms, combinatorial, multi‐agent therapies have emerged as key approaches in the treatment of complex diseases, most notably cancer. Using high‐throughput drug screens, we uncovered distinct metabolic vulnerabilities and thereby id...
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| Autor*in: |
Hartleben, Goetz [verfasserIn] Schorpp, Kenji [verfasserIn] Kwon, Yun [verfasserIn] Betz, Barbara [verfasserIn] Tsokanos, Foivos‐Filippos [verfasserIn] Dantes, Zahra [verfasserIn] Schäfer, Arlett [verfasserIn] Rothenaigner, Ina [verfasserIn] Monroy Kuhn, José Manuel [verfasserIn] Morigny, Pauline [verfasserIn] Mehr, Lisa [verfasserIn] Lin, Sean [verfasserIn] Seitz, Susanne [verfasserIn] Tokarz, Janina [verfasserIn] Artati, Anna [verfasserIn] Adamsky, Jerzy [verfasserIn] Plettenburg, Oliver [verfasserIn] Lutter, Dominik [verfasserIn] Irmler, Martin [verfasserIn] Beckers, Johannes [verfasserIn] Reichert, Maximilian [verfasserIn] Hadian, Kamyar [verfasserIn] Zeigerer, Anja [verfasserIn] Herzig, Stephan [verfasserIn] Berriel Diaz, Mauricio [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2021 |
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| Schlagwörter: |
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| Anmerkung: |
© The Author(s) 2021 |
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| Übergeordnetes Werk: |
Enthalten in: EMBO Molecular Medicine - Nature Publishing Group UK, 2023, 13(2021), 4 vom: 05. März |
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| Übergeordnetes Werk: |
volume:13 ; year:2021 ; number:4 ; day:05 ; month:03 |
| Links: |
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| DOI / URN: |
10.15252/emmm.202012461 |
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| Katalog-ID: |
SPR058031405 |
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| 100 | 1 | |a Hartleben, Goetz |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Combination therapies induce cancer cell death through the integrated stress response and disturbed pyrimidine metabolism |
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| 520 | |a Abstract By accentuating drug efficacy and impeding resistance mechanisms, combinatorial, multi‐agent therapies have emerged as key approaches in the treatment of complex diseases, most notably cancer. Using high‐throughput drug screens, we uncovered distinct metabolic vulnerabilities and thereby identified drug combinations synergistically causing a starvation‐like lethal catabolic response in tumor cells from different cancer entities. Domperidone, a dopamine receptor antagonist, as well as several tricyclic antidepressants (TCAs), including imipramine, induced cancer cell death in combination with the mitochondrial uncoupler niclosamide ethanolamine (NEN) through activation of the integrated stress response pathway and the catabolic CLEAR network. Using transcriptome and metabolome analyses, we characterized a combinatorial response, mainly driven by the transcription factors CHOP and TFE3, which resulted in cell death through enhanced pyrimidine catabolism as well as reduced pyrimidine synthesis. Remarkably, the drug combinations sensitized human organoid cultures to the standard‐of‐care chemotherapy paclitaxel. Thus, our combinatorial approach could be clinically implemented into established treatment regimen, which would be further facilitated by the advantages of drug repurposing. | ||
| 520 | |a Synopsis This study identifies novel combinatorial drug treatments to induce death of different tumor cells, and defines the mechanisms of synergism between a mitochondrial uncoupler and antidepressants or dopamine receptor antagonists.Mitochondrial uncoupler NEN synergized with tricyclic antidepressants (TCAs) and dopamine receptor antagonists to induce tumor cell death.Synergistic cell death relied on the induction of the integrated stress response pathway and the catabolic CLEAR network.Combinatorial drug treatment sensitized human pancreatic cancer organoids to Paclitaxel chemotherapy. | ||
| 520 | |a Graphical Abstract This study identifies novel combinatorial drug treatments to induce death of different tumor cells, and defines the mechanisms of synergism between a mitochondrial uncoupler and antidepressants or dopamine receptor antagonists. | ||
| 650 | 4 | |a cancer metabolism |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a integrated stress response |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a metabolic vulnerabilities |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a pyrimidine metabolism |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a tricyclic antidepressants |7 (dpeaa)DE-He213 | |
| 700 | 1 | |a Schorpp, Kenji |e verfasserin |4 aut | |
| 700 | 1 | |a Kwon, Yun |e verfasserin |4 aut | |
| 700 | 1 | |a Betz, Barbara |e verfasserin |0 (orcid)0000-0002-2767-5062 |4 aut | |
| 700 | 1 | |a Tsokanos, Foivos‐Filippos |e verfasserin |4 aut | |
| 700 | 1 | |a Dantes, Zahra |e verfasserin |4 aut | |
| 700 | 1 | |a Schäfer, Arlett |e verfasserin |4 aut | |
| 700 | 1 | |a Rothenaigner, Ina |e verfasserin |4 aut | |
| 700 | 1 | |a Monroy Kuhn, José Manuel |e verfasserin |4 aut | |
| 700 | 1 | |a Morigny, Pauline |e verfasserin |4 aut | |
| 700 | 1 | |a Mehr, Lisa |e verfasserin |4 aut | |
| 700 | 1 | |a Lin, Sean |e verfasserin |0 (orcid)0000-0001-9691-5149 |4 aut | |
| 700 | 1 | |a Seitz, Susanne |e verfasserin |4 aut | |
| 700 | 1 | |a Tokarz, Janina |e verfasserin |4 aut | |
| 700 | 1 | |a Artati, Anna |e verfasserin |4 aut | |
| 700 | 1 | |a Adamsky, Jerzy |e verfasserin |4 aut | |
| 700 | 1 | |a Plettenburg, Oliver |e verfasserin |4 aut | |
| 700 | 1 | |a Lutter, Dominik |e verfasserin |4 aut | |
| 700 | 1 | |a Irmler, Martin |e verfasserin |4 aut | |
| 700 | 1 | |a Beckers, Johannes |e verfasserin |4 aut | |
| 700 | 1 | |a Reichert, Maximilian |e verfasserin |4 aut | |
| 700 | 1 | |a Hadian, Kamyar |e verfasserin |4 aut | |
| 700 | 1 | |a Zeigerer, Anja |e verfasserin |4 aut | |
| 700 | 1 | |a Herzig, Stephan |e verfasserin |0 (orcid)0000-0003-3950-3652 |4 aut | |
| 700 | 1 | |a Berriel Diaz, Mauricio |e verfasserin |0 (orcid)0000-0003-4670-919X |4 aut | |
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10.15252/emmm.202012461 doi (DE-627)SPR058031405 (SPR)emmm.202012461-e DE-627 ger DE-627 rakwb eng Hartleben, Goetz verfasserin aut Combination therapies induce cancer cell death through the integrated stress response and disturbed pyrimidine metabolism 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2021 Abstract By accentuating drug efficacy and impeding resistance mechanisms, combinatorial, multi‐agent therapies have emerged as key approaches in the treatment of complex diseases, most notably cancer. Using high‐throughput drug screens, we uncovered distinct metabolic vulnerabilities and thereby identified drug combinations synergistically causing a starvation‐like lethal catabolic response in tumor cells from different cancer entities. Domperidone, a dopamine receptor antagonist, as well as several tricyclic antidepressants (TCAs), including imipramine, induced cancer cell death in combination with the mitochondrial uncoupler niclosamide ethanolamine (NEN) through activation of the integrated stress response pathway and the catabolic CLEAR network. Using transcriptome and metabolome analyses, we characterized a combinatorial response, mainly driven by the transcription factors CHOP and TFE3, which resulted in cell death through enhanced pyrimidine catabolism as well as reduced pyrimidine synthesis. Remarkably, the drug combinations sensitized human organoid cultures to the standard‐of‐care chemotherapy paclitaxel. Thus, our combinatorial approach could be clinically implemented into established treatment regimen, which would be further facilitated by the advantages of drug repurposing. Synopsis This study identifies novel combinatorial drug treatments to induce death of different tumor cells, and defines the mechanisms of synergism between a mitochondrial uncoupler and antidepressants or dopamine receptor antagonists.Mitochondrial uncoupler NEN synergized with tricyclic antidepressants (TCAs) and dopamine receptor antagonists to induce tumor cell death.Synergistic cell death relied on the induction of the integrated stress response pathway and the catabolic CLEAR network.Combinatorial drug treatment sensitized human pancreatic cancer organoids to Paclitaxel chemotherapy. Graphical Abstract This study identifies novel combinatorial drug treatments to induce death of different tumor cells, and defines the mechanisms of synergism between a mitochondrial uncoupler and antidepressants or dopamine receptor antagonists. cancer metabolism (dpeaa)DE-He213 integrated stress response (dpeaa)DE-He213 metabolic vulnerabilities (dpeaa)DE-He213 pyrimidine metabolism (dpeaa)DE-He213 tricyclic antidepressants (dpeaa)DE-He213 Schorpp, Kenji verfasserin aut Kwon, Yun verfasserin aut Betz, Barbara verfasserin (orcid)0000-0002-2767-5062 aut Tsokanos, Foivos‐Filippos verfasserin aut Dantes, Zahra verfasserin aut Schäfer, Arlett verfasserin aut Rothenaigner, Ina verfasserin aut Monroy Kuhn, José Manuel verfasserin aut Morigny, Pauline verfasserin aut Mehr, Lisa verfasserin aut Lin, Sean verfasserin (orcid)0000-0001-9691-5149 aut Seitz, Susanne verfasserin aut Tokarz, Janina verfasserin aut Artati, Anna verfasserin aut Adamsky, Jerzy verfasserin aut Plettenburg, Oliver verfasserin aut Lutter, Dominik verfasserin aut Irmler, Martin verfasserin aut Beckers, Johannes verfasserin aut Reichert, Maximilian verfasserin aut Hadian, Kamyar verfasserin aut Zeigerer, Anja verfasserin aut Herzig, Stephan verfasserin (orcid)0000-0003-3950-3652 aut Berriel Diaz, Mauricio verfasserin (orcid)0000-0003-4670-919X aut Enthalten in EMBO Molecular Medicine Nature Publishing Group UK, 2023 13(2021), 4 vom: 05. März (DE-627)594772761 (DE-600)2485479-7 1757-4684 nnns volume:13 year:2021 number:4 day:05 month:03 https://dx.doi.org/10.15252/emmm.202012461 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4315 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 13 2021 4 05 03 |
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10.15252/emmm.202012461 doi (DE-627)SPR058031405 (SPR)emmm.202012461-e DE-627 ger DE-627 rakwb eng Hartleben, Goetz verfasserin aut Combination therapies induce cancer cell death through the integrated stress response and disturbed pyrimidine metabolism 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2021 Abstract By accentuating drug efficacy and impeding resistance mechanisms, combinatorial, multi‐agent therapies have emerged as key approaches in the treatment of complex diseases, most notably cancer. Using high‐throughput drug screens, we uncovered distinct metabolic vulnerabilities and thereby identified drug combinations synergistically causing a starvation‐like lethal catabolic response in tumor cells from different cancer entities. Domperidone, a dopamine receptor antagonist, as well as several tricyclic antidepressants (TCAs), including imipramine, induced cancer cell death in combination with the mitochondrial uncoupler niclosamide ethanolamine (NEN) through activation of the integrated stress response pathway and the catabolic CLEAR network. Using transcriptome and metabolome analyses, we characterized a combinatorial response, mainly driven by the transcription factors CHOP and TFE3, which resulted in cell death through enhanced pyrimidine catabolism as well as reduced pyrimidine synthesis. Remarkably, the drug combinations sensitized human organoid cultures to the standard‐of‐care chemotherapy paclitaxel. Thus, our combinatorial approach could be clinically implemented into established treatment regimen, which would be further facilitated by the advantages of drug repurposing. Synopsis This study identifies novel combinatorial drug treatments to induce death of different tumor cells, and defines the mechanisms of synergism between a mitochondrial uncoupler and antidepressants or dopamine receptor antagonists.Mitochondrial uncoupler NEN synergized with tricyclic antidepressants (TCAs) and dopamine receptor antagonists to induce tumor cell death.Synergistic cell death relied on the induction of the integrated stress response pathway and the catabolic CLEAR network.Combinatorial drug treatment sensitized human pancreatic cancer organoids to Paclitaxel chemotherapy. Graphical Abstract This study identifies novel combinatorial drug treatments to induce death of different tumor cells, and defines the mechanisms of synergism between a mitochondrial uncoupler and antidepressants or dopamine receptor antagonists. cancer metabolism (dpeaa)DE-He213 integrated stress response (dpeaa)DE-He213 metabolic vulnerabilities (dpeaa)DE-He213 pyrimidine metabolism (dpeaa)DE-He213 tricyclic antidepressants (dpeaa)DE-He213 Schorpp, Kenji verfasserin aut Kwon, Yun verfasserin aut Betz, Barbara verfasserin (orcid)0000-0002-2767-5062 aut Tsokanos, Foivos‐Filippos verfasserin aut Dantes, Zahra verfasserin aut Schäfer, Arlett verfasserin aut Rothenaigner, Ina verfasserin aut Monroy Kuhn, José Manuel verfasserin aut Morigny, Pauline verfasserin aut Mehr, Lisa verfasserin aut Lin, Sean verfasserin (orcid)0000-0001-9691-5149 aut Seitz, Susanne verfasserin aut Tokarz, Janina verfasserin aut Artati, Anna verfasserin aut Adamsky, Jerzy verfasserin aut Plettenburg, Oliver verfasserin aut Lutter, Dominik verfasserin aut Irmler, Martin verfasserin aut Beckers, Johannes verfasserin aut Reichert, Maximilian verfasserin aut Hadian, Kamyar verfasserin aut Zeigerer, Anja verfasserin aut Herzig, Stephan verfasserin (orcid)0000-0003-3950-3652 aut Berriel Diaz, Mauricio verfasserin (orcid)0000-0003-4670-919X aut Enthalten in EMBO Molecular Medicine Nature Publishing Group UK, 2023 13(2021), 4 vom: 05. März (DE-627)594772761 (DE-600)2485479-7 1757-4684 nnns volume:13 year:2021 number:4 day:05 month:03 https://dx.doi.org/10.15252/emmm.202012461 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4315 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 13 2021 4 05 03 |
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10.15252/emmm.202012461 doi (DE-627)SPR058031405 (SPR)emmm.202012461-e DE-627 ger DE-627 rakwb eng Hartleben, Goetz verfasserin aut Combination therapies induce cancer cell death through the integrated stress response and disturbed pyrimidine metabolism 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2021 Abstract By accentuating drug efficacy and impeding resistance mechanisms, combinatorial, multi‐agent therapies have emerged as key approaches in the treatment of complex diseases, most notably cancer. Using high‐throughput drug screens, we uncovered distinct metabolic vulnerabilities and thereby identified drug combinations synergistically causing a starvation‐like lethal catabolic response in tumor cells from different cancer entities. Domperidone, a dopamine receptor antagonist, as well as several tricyclic antidepressants (TCAs), including imipramine, induced cancer cell death in combination with the mitochondrial uncoupler niclosamide ethanolamine (NEN) through activation of the integrated stress response pathway and the catabolic CLEAR network. Using transcriptome and metabolome analyses, we characterized a combinatorial response, mainly driven by the transcription factors CHOP and TFE3, which resulted in cell death through enhanced pyrimidine catabolism as well as reduced pyrimidine synthesis. Remarkably, the drug combinations sensitized human organoid cultures to the standard‐of‐care chemotherapy paclitaxel. Thus, our combinatorial approach could be clinically implemented into established treatment regimen, which would be further facilitated by the advantages of drug repurposing. Synopsis This study identifies novel combinatorial drug treatments to induce death of different tumor cells, and defines the mechanisms of synergism between a mitochondrial uncoupler and antidepressants or dopamine receptor antagonists.Mitochondrial uncoupler NEN synergized with tricyclic antidepressants (TCAs) and dopamine receptor antagonists to induce tumor cell death.Synergistic cell death relied on the induction of the integrated stress response pathway and the catabolic CLEAR network.Combinatorial drug treatment sensitized human pancreatic cancer organoids to Paclitaxel chemotherapy. Graphical Abstract This study identifies novel combinatorial drug treatments to induce death of different tumor cells, and defines the mechanisms of synergism between a mitochondrial uncoupler and antidepressants or dopamine receptor antagonists. cancer metabolism (dpeaa)DE-He213 integrated stress response (dpeaa)DE-He213 metabolic vulnerabilities (dpeaa)DE-He213 pyrimidine metabolism (dpeaa)DE-He213 tricyclic antidepressants (dpeaa)DE-He213 Schorpp, Kenji verfasserin aut Kwon, Yun verfasserin aut Betz, Barbara verfasserin (orcid)0000-0002-2767-5062 aut Tsokanos, Foivos‐Filippos verfasserin aut Dantes, Zahra verfasserin aut Schäfer, Arlett verfasserin aut Rothenaigner, Ina verfasserin aut Monroy Kuhn, José Manuel verfasserin aut Morigny, Pauline verfasserin aut Mehr, Lisa verfasserin aut Lin, Sean verfasserin (orcid)0000-0001-9691-5149 aut Seitz, Susanne verfasserin aut Tokarz, Janina verfasserin aut Artati, Anna verfasserin aut Adamsky, Jerzy verfasserin aut Plettenburg, Oliver verfasserin aut Lutter, Dominik verfasserin aut Irmler, Martin verfasserin aut Beckers, Johannes verfasserin aut Reichert, Maximilian verfasserin aut Hadian, Kamyar verfasserin aut Zeigerer, Anja verfasserin aut Herzig, Stephan verfasserin (orcid)0000-0003-3950-3652 aut Berriel Diaz, Mauricio verfasserin (orcid)0000-0003-4670-919X aut Enthalten in EMBO Molecular Medicine Nature Publishing Group UK, 2023 13(2021), 4 vom: 05. März (DE-627)594772761 (DE-600)2485479-7 1757-4684 nnns volume:13 year:2021 number:4 day:05 month:03 https://dx.doi.org/10.15252/emmm.202012461 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4315 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 13 2021 4 05 03 |
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10.15252/emmm.202012461 doi (DE-627)SPR058031405 (SPR)emmm.202012461-e DE-627 ger DE-627 rakwb eng Hartleben, Goetz verfasserin aut Combination therapies induce cancer cell death through the integrated stress response and disturbed pyrimidine metabolism 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2021 Abstract By accentuating drug efficacy and impeding resistance mechanisms, combinatorial, multi‐agent therapies have emerged as key approaches in the treatment of complex diseases, most notably cancer. Using high‐throughput drug screens, we uncovered distinct metabolic vulnerabilities and thereby identified drug combinations synergistically causing a starvation‐like lethal catabolic response in tumor cells from different cancer entities. Domperidone, a dopamine receptor antagonist, as well as several tricyclic antidepressants (TCAs), including imipramine, induced cancer cell death in combination with the mitochondrial uncoupler niclosamide ethanolamine (NEN) through activation of the integrated stress response pathway and the catabolic CLEAR network. Using transcriptome and metabolome analyses, we characterized a combinatorial response, mainly driven by the transcription factors CHOP and TFE3, which resulted in cell death through enhanced pyrimidine catabolism as well as reduced pyrimidine synthesis. Remarkably, the drug combinations sensitized human organoid cultures to the standard‐of‐care chemotherapy paclitaxel. Thus, our combinatorial approach could be clinically implemented into established treatment regimen, which would be further facilitated by the advantages of drug repurposing. Synopsis This study identifies novel combinatorial drug treatments to induce death of different tumor cells, and defines the mechanisms of synergism between a mitochondrial uncoupler and antidepressants or dopamine receptor antagonists.Mitochondrial uncoupler NEN synergized with tricyclic antidepressants (TCAs) and dopamine receptor antagonists to induce tumor cell death.Synergistic cell death relied on the induction of the integrated stress response pathway and the catabolic CLEAR network.Combinatorial drug treatment sensitized human pancreatic cancer organoids to Paclitaxel chemotherapy. Graphical Abstract This study identifies novel combinatorial drug treatments to induce death of different tumor cells, and defines the mechanisms of synergism between a mitochondrial uncoupler and antidepressants or dopamine receptor antagonists. cancer metabolism (dpeaa)DE-He213 integrated stress response (dpeaa)DE-He213 metabolic vulnerabilities (dpeaa)DE-He213 pyrimidine metabolism (dpeaa)DE-He213 tricyclic antidepressants (dpeaa)DE-He213 Schorpp, Kenji verfasserin aut Kwon, Yun verfasserin aut Betz, Barbara verfasserin (orcid)0000-0002-2767-5062 aut Tsokanos, Foivos‐Filippos verfasserin aut Dantes, Zahra verfasserin aut Schäfer, Arlett verfasserin aut Rothenaigner, Ina verfasserin aut Monroy Kuhn, José Manuel verfasserin aut Morigny, Pauline verfasserin aut Mehr, Lisa verfasserin aut Lin, Sean verfasserin (orcid)0000-0001-9691-5149 aut Seitz, Susanne verfasserin aut Tokarz, Janina verfasserin aut Artati, Anna verfasserin aut Adamsky, Jerzy verfasserin aut Plettenburg, Oliver verfasserin aut Lutter, Dominik verfasserin aut Irmler, Martin verfasserin aut Beckers, Johannes verfasserin aut Reichert, Maximilian verfasserin aut Hadian, Kamyar verfasserin aut Zeigerer, Anja verfasserin aut Herzig, Stephan verfasserin (orcid)0000-0003-3950-3652 aut Berriel Diaz, Mauricio verfasserin (orcid)0000-0003-4670-919X aut Enthalten in EMBO Molecular Medicine Nature Publishing Group UK, 2023 13(2021), 4 vom: 05. März (DE-627)594772761 (DE-600)2485479-7 1757-4684 nnns volume:13 year:2021 number:4 day:05 month:03 https://dx.doi.org/10.15252/emmm.202012461 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4315 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 13 2021 4 05 03 |
| allfieldsSound |
10.15252/emmm.202012461 doi (DE-627)SPR058031405 (SPR)emmm.202012461-e DE-627 ger DE-627 rakwb eng Hartleben, Goetz verfasserin aut Combination therapies induce cancer cell death through the integrated stress response and disturbed pyrimidine metabolism 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2021 Abstract By accentuating drug efficacy and impeding resistance mechanisms, combinatorial, multi‐agent therapies have emerged as key approaches in the treatment of complex diseases, most notably cancer. Using high‐throughput drug screens, we uncovered distinct metabolic vulnerabilities and thereby identified drug combinations synergistically causing a starvation‐like lethal catabolic response in tumor cells from different cancer entities. Domperidone, a dopamine receptor antagonist, as well as several tricyclic antidepressants (TCAs), including imipramine, induced cancer cell death in combination with the mitochondrial uncoupler niclosamide ethanolamine (NEN) through activation of the integrated stress response pathway and the catabolic CLEAR network. Using transcriptome and metabolome analyses, we characterized a combinatorial response, mainly driven by the transcription factors CHOP and TFE3, which resulted in cell death through enhanced pyrimidine catabolism as well as reduced pyrimidine synthesis. Remarkably, the drug combinations sensitized human organoid cultures to the standard‐of‐care chemotherapy paclitaxel. Thus, our combinatorial approach could be clinically implemented into established treatment regimen, which would be further facilitated by the advantages of drug repurposing. Synopsis This study identifies novel combinatorial drug treatments to induce death of different tumor cells, and defines the mechanisms of synergism between a mitochondrial uncoupler and antidepressants or dopamine receptor antagonists.Mitochondrial uncoupler NEN synergized with tricyclic antidepressants (TCAs) and dopamine receptor antagonists to induce tumor cell death.Synergistic cell death relied on the induction of the integrated stress response pathway and the catabolic CLEAR network.Combinatorial drug treatment sensitized human pancreatic cancer organoids to Paclitaxel chemotherapy. Graphical Abstract This study identifies novel combinatorial drug treatments to induce death of different tumor cells, and defines the mechanisms of synergism between a mitochondrial uncoupler and antidepressants or dopamine receptor antagonists. cancer metabolism (dpeaa)DE-He213 integrated stress response (dpeaa)DE-He213 metabolic vulnerabilities (dpeaa)DE-He213 pyrimidine metabolism (dpeaa)DE-He213 tricyclic antidepressants (dpeaa)DE-He213 Schorpp, Kenji verfasserin aut Kwon, Yun verfasserin aut Betz, Barbara verfasserin (orcid)0000-0002-2767-5062 aut Tsokanos, Foivos‐Filippos verfasserin aut Dantes, Zahra verfasserin aut Schäfer, Arlett verfasserin aut Rothenaigner, Ina verfasserin aut Monroy Kuhn, José Manuel verfasserin aut Morigny, Pauline verfasserin aut Mehr, Lisa verfasserin aut Lin, Sean verfasserin (orcid)0000-0001-9691-5149 aut Seitz, Susanne verfasserin aut Tokarz, Janina verfasserin aut Artati, Anna verfasserin aut Adamsky, Jerzy verfasserin aut Plettenburg, Oliver verfasserin aut Lutter, Dominik verfasserin aut Irmler, Martin verfasserin aut Beckers, Johannes verfasserin aut Reichert, Maximilian verfasserin aut Hadian, Kamyar verfasserin aut Zeigerer, Anja verfasserin aut Herzig, Stephan verfasserin (orcid)0000-0003-3950-3652 aut Berriel Diaz, Mauricio verfasserin (orcid)0000-0003-4670-919X aut Enthalten in EMBO Molecular Medicine Nature Publishing Group UK, 2023 13(2021), 4 vom: 05. März (DE-627)594772761 (DE-600)2485479-7 1757-4684 nnns volume:13 year:2021 number:4 day:05 month:03 https://dx.doi.org/10.15252/emmm.202012461 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4315 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 13 2021 4 05 03 |
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Enthalten in EMBO Molecular Medicine 13(2021), 4 vom: 05. März volume:13 year:2021 number:4 day:05 month:03 |
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Enthalten in EMBO Molecular Medicine 13(2021), 4 vom: 05. März volume:13 year:2021 number:4 day:05 month:03 |
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Hartleben, Goetz @@aut@@ Schorpp, Kenji @@aut@@ Kwon, Yun @@aut@@ Betz, Barbara @@aut@@ Tsokanos, Foivos‐Filippos @@aut@@ Dantes, Zahra @@aut@@ Schäfer, Arlett @@aut@@ Rothenaigner, Ina @@aut@@ Monroy Kuhn, José Manuel @@aut@@ Morigny, Pauline @@aut@@ Mehr, Lisa @@aut@@ Lin, Sean @@aut@@ Seitz, Susanne @@aut@@ Tokarz, Janina @@aut@@ Artati, Anna @@aut@@ Adamsky, Jerzy @@aut@@ Plettenburg, Oliver @@aut@@ Lutter, Dominik @@aut@@ Irmler, Martin @@aut@@ Beckers, Johannes @@aut@@ Reichert, Maximilian @@aut@@ Hadian, Kamyar @@aut@@ Zeigerer, Anja @@aut@@ Herzig, Stephan @@aut@@ Berriel Diaz, Mauricio @@aut@@ |
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<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000naa a22002652 4500</leader><controlfield tag="001">SPR058031405</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20241024065233.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">241024s2021 xx |||||o 00| ||eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.15252/emmm.202012461</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)SPR058031405</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(SPR)emmm.202012461-e</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="100" ind1="1" ind2=" "><subfield code="a">Hartleben, Goetz</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">Combination therapies induce cancer cell death through the integrated stress response and disturbed pyrimidine metabolism</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2021</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="500" ind1=" " ind2=" "><subfield code="a">© The Author(s) 2021</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Abstract By accentuating drug efficacy and impeding resistance mechanisms, combinatorial, multi‐agent therapies have emerged as key approaches in the treatment of complex diseases, most notably cancer. Using high‐throughput drug screens, we uncovered distinct metabolic vulnerabilities and thereby identified drug combinations synergistically causing a starvation‐like lethal catabolic response in tumor cells from different cancer entities. Domperidone, a dopamine receptor antagonist, as well as several tricyclic antidepressants (TCAs), including imipramine, induced cancer cell death in combination with the mitochondrial uncoupler niclosamide ethanolamine (NEN) through activation of the integrated stress response pathway and the catabolic CLEAR network. Using transcriptome and metabolome analyses, we characterized a combinatorial response, mainly driven by the transcription factors CHOP and TFE3, which resulted in cell death through enhanced pyrimidine catabolism as well as reduced pyrimidine synthesis. Remarkably, the drug combinations sensitized human organoid cultures to the standard‐of‐care chemotherapy paclitaxel. Thus, our combinatorial approach could be clinically implemented into established treatment regimen, which would be further facilitated by the advantages of drug repurposing.</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Synopsis This study identifies novel combinatorial drug treatments to induce death of different tumor cells, and defines the mechanisms of synergism between a mitochondrial uncoupler and antidepressants or dopamine receptor antagonists.Mitochondrial uncoupler NEN synergized with tricyclic antidepressants (TCAs) and dopamine receptor antagonists to induce tumor cell death.Synergistic cell death relied on the induction of the integrated stress response pathway and the catabolic CLEAR network.Combinatorial drug treatment sensitized human pancreatic cancer organoids to Paclitaxel chemotherapy.</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Graphical Abstract This study identifies novel combinatorial drug 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| author |
Hartleben, Goetz |
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Hartleben, Goetz misc cancer metabolism misc integrated stress response misc metabolic vulnerabilities misc pyrimidine metabolism misc tricyclic antidepressants Combination therapies induce cancer cell death through the integrated stress response and disturbed pyrimidine metabolism |
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Hartleben, Goetz |
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electronic Article |
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keep |
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aut aut aut aut aut aut aut aut aut aut aut aut aut aut aut aut aut aut aut aut aut aut aut aut aut |
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springer |
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true |
| illustrated |
Not Illustrated |
| issn |
1757-4684 |
| topic_title |
Combination therapies induce cancer cell death through the integrated stress response and disturbed pyrimidine metabolism cancer metabolism (dpeaa)DE-He213 integrated stress response (dpeaa)DE-He213 metabolic vulnerabilities (dpeaa)DE-He213 pyrimidine metabolism (dpeaa)DE-He213 tricyclic antidepressants (dpeaa)DE-He213 |
| topic |
misc cancer metabolism misc integrated stress response misc metabolic vulnerabilities misc pyrimidine metabolism misc tricyclic antidepressants |
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misc cancer metabolism misc integrated stress response misc metabolic vulnerabilities misc pyrimidine metabolism misc tricyclic antidepressants |
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misc cancer metabolism misc integrated stress response misc metabolic vulnerabilities misc pyrimidine metabolism misc tricyclic antidepressants |
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Elektronische Aufsätze Aufsätze Elektronische Ressource |
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Combination therapies induce cancer cell death through the integrated stress response and disturbed pyrimidine metabolism |
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Combination therapies induce cancer cell death through the integrated stress response and disturbed pyrimidine metabolism |
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Hartleben, Goetz Schorpp, Kenji Kwon, Yun Betz, Barbara Tsokanos, Foivos‐Filippos Dantes, Zahra Schäfer, Arlett Rothenaigner, Ina Monroy Kuhn, José Manuel Morigny, Pauline Mehr, Lisa Lin, Sean Seitz, Susanne Tokarz, Janina Artati, Anna Adamsky, Jerzy Plettenburg, Oliver Lutter, Dominik Irmler, Martin Beckers, Johannes Reichert, Maximilian Hadian, Kamyar Zeigerer, Anja Herzig, Stephan Berriel Diaz, Mauricio |
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combination therapies induce cancer cell death through the integrated stress response and disturbed pyrimidine metabolism |
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Combination therapies induce cancer cell death through the integrated stress response and disturbed pyrimidine metabolism |
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Abstract By accentuating drug efficacy and impeding resistance mechanisms, combinatorial, multi‐agent therapies have emerged as key approaches in the treatment of complex diseases, most notably cancer. Using high‐throughput drug screens, we uncovered distinct metabolic vulnerabilities and thereby identified drug combinations synergistically causing a starvation‐like lethal catabolic response in tumor cells from different cancer entities. Domperidone, a dopamine receptor antagonist, as well as several tricyclic antidepressants (TCAs), including imipramine, induced cancer cell death in combination with the mitochondrial uncoupler niclosamide ethanolamine (NEN) through activation of the integrated stress response pathway and the catabolic CLEAR network. Using transcriptome and metabolome analyses, we characterized a combinatorial response, mainly driven by the transcription factors CHOP and TFE3, which resulted in cell death through enhanced pyrimidine catabolism as well as reduced pyrimidine synthesis. Remarkably, the drug combinations sensitized human organoid cultures to the standard‐of‐care chemotherapy paclitaxel. Thus, our combinatorial approach could be clinically implemented into established treatment regimen, which would be further facilitated by the advantages of drug repurposing. Synopsis This study identifies novel combinatorial drug treatments to induce death of different tumor cells, and defines the mechanisms of synergism between a mitochondrial uncoupler and antidepressants or dopamine receptor antagonists.Mitochondrial uncoupler NEN synergized with tricyclic antidepressants (TCAs) and dopamine receptor antagonists to induce tumor cell death.Synergistic cell death relied on the induction of the integrated stress response pathway and the catabolic CLEAR network.Combinatorial drug treatment sensitized human pancreatic cancer organoids to Paclitaxel chemotherapy. Graphical Abstract This study identifies novel combinatorial drug treatments to induce death of different tumor cells, and defines the mechanisms of synergism between a mitochondrial uncoupler and antidepressants or dopamine receptor antagonists. © The Author(s) 2021 |
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Abstract By accentuating drug efficacy and impeding resistance mechanisms, combinatorial, multi‐agent therapies have emerged as key approaches in the treatment of complex diseases, most notably cancer. Using high‐throughput drug screens, we uncovered distinct metabolic vulnerabilities and thereby identified drug combinations synergistically causing a starvation‐like lethal catabolic response in tumor cells from different cancer entities. Domperidone, a dopamine receptor antagonist, as well as several tricyclic antidepressants (TCAs), including imipramine, induced cancer cell death in combination with the mitochondrial uncoupler niclosamide ethanolamine (NEN) through activation of the integrated stress response pathway and the catabolic CLEAR network. Using transcriptome and metabolome analyses, we characterized a combinatorial response, mainly driven by the transcription factors CHOP and TFE3, which resulted in cell death through enhanced pyrimidine catabolism as well as reduced pyrimidine synthesis. Remarkably, the drug combinations sensitized human organoid cultures to the standard‐of‐care chemotherapy paclitaxel. Thus, our combinatorial approach could be clinically implemented into established treatment regimen, which would be further facilitated by the advantages of drug repurposing. Synopsis This study identifies novel combinatorial drug treatments to induce death of different tumor cells, and defines the mechanisms of synergism between a mitochondrial uncoupler and antidepressants or dopamine receptor antagonists.Mitochondrial uncoupler NEN synergized with tricyclic antidepressants (TCAs) and dopamine receptor antagonists to induce tumor cell death.Synergistic cell death relied on the induction of the integrated stress response pathway and the catabolic CLEAR network.Combinatorial drug treatment sensitized human pancreatic cancer organoids to Paclitaxel chemotherapy. Graphical Abstract This study identifies novel combinatorial drug treatments to induce death of different tumor cells, and defines the mechanisms of synergism between a mitochondrial uncoupler and antidepressants or dopamine receptor antagonists. © The Author(s) 2021 |
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Abstract By accentuating drug efficacy and impeding resistance mechanisms, combinatorial, multi‐agent therapies have emerged as key approaches in the treatment of complex diseases, most notably cancer. Using high‐throughput drug screens, we uncovered distinct metabolic vulnerabilities and thereby identified drug combinations synergistically causing a starvation‐like lethal catabolic response in tumor cells from different cancer entities. Domperidone, a dopamine receptor antagonist, as well as several tricyclic antidepressants (TCAs), including imipramine, induced cancer cell death in combination with the mitochondrial uncoupler niclosamide ethanolamine (NEN) through activation of the integrated stress response pathway and the catabolic CLEAR network. Using transcriptome and metabolome analyses, we characterized a combinatorial response, mainly driven by the transcription factors CHOP and TFE3, which resulted in cell death through enhanced pyrimidine catabolism as well as reduced pyrimidine synthesis. Remarkably, the drug combinations sensitized human organoid cultures to the standard‐of‐care chemotherapy paclitaxel. Thus, our combinatorial approach could be clinically implemented into established treatment regimen, which would be further facilitated by the advantages of drug repurposing. Synopsis This study identifies novel combinatorial drug treatments to induce death of different tumor cells, and defines the mechanisms of synergism between a mitochondrial uncoupler and antidepressants or dopamine receptor antagonists.Mitochondrial uncoupler NEN synergized with tricyclic antidepressants (TCAs) and dopamine receptor antagonists to induce tumor cell death.Synergistic cell death relied on the induction of the integrated stress response pathway and the catabolic CLEAR network.Combinatorial drug treatment sensitized human pancreatic cancer organoids to Paclitaxel chemotherapy. Graphical Abstract This study identifies novel combinatorial drug treatments to induce death of different tumor cells, and defines the mechanisms of synergism between a mitochondrial uncoupler and antidepressants or dopamine receptor antagonists. © The Author(s) 2021 |
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Combination therapies induce cancer cell death through the integrated stress response and disturbed pyrimidine metabolism |
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|
| score |
7.4000015 |