دورية أكاديمية
Combination therapies induce cancer cell death through the integrated stress response and disturbed pyrimidine metabolism
| العنوان: | Combination therapies induce cancer cell death through the integrated stress response and disturbed pyrimidine metabolism |
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| المؤلفون: | 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 |
| المصدر: | EMBO Molecular Medicine 13 (2021), Nr. 4 ; EMBO Molecular Medicine |
| بيانات النشر: | Wiley-VCH |
| سنة النشر: | 2021 |
| المجموعة: | Institutional Repository of Leibniz Universität Hannover |
| مصطلحات موضوعية: | cancer metabolism, integrated stress response, metabolic vulnerabilities, pyrimidine metabolism, tricyclic antidepressants, growth arrest and DNA damage inducible protein 153, pyrimidine, transcriptome, antineoplastic agent, niclosamide, pyrimidine derivative, animal experiment, animal model, cancer cell, catabolism, cell death, cell stress, controlled study, human, human cell, male, metabolome, mouse, nonhuman, organoid, pyrimidine synthesis, neoplasm, Antineoplastic Agents, Humans, Neoplasms |
| الوصف: | 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. © 2021 The Authors. Published under the terms of the CC BY 4.0 license |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| العلاقة: | ESSN:1757-4684; http://dx.doi.org/10.15488/12277Test; https://www.repo.uni-hannover.de/handle/123456789/12375Test |
| DOI: | 10.15488/12277 |
| الإتاحة: | https://doi.org/10.15488/12277Test https://doi.org/10.15252/emmm.202012461Test https://www.repo.uni-hannover.de/handle/123456789/12375Test |
| حقوق: | CC BY 4.0 Unported ; https://creativecommons.org/licenses/by/4.0Test/ ; frei zugänglich |
| رقم الانضمام: | edsbas.F0CCCEA |
| قاعدة البيانات: | BASE |
| DOI: | 10.15488/12277 |
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