1. Combination therapies induce cancer cell death through the integrated stress response and disturbed pyrimidine metabolism
- Author
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Johannes Beckers, Oliver Plettenburg, Sean Lin, Foivos-Filippos Tsokanos, Anna Artati, Susanne Seitz, Arlett Schäfer, Goetz Hartleben, Martin Irmler, Yun Kwon, Lisa Mehr, Mauricio Berriel Diaz, Kenji Schorpp, Anja Zeigerer, Barbara Betz, Zahra Dantes, Jerzy Adamsky, Pauline Morigny, José Manuel Monroy Kuhn, Stephan Herzig, Janina Tokarz, Kamyar Hadian, Ina Rothenaigner, Dominik Lutter, and Maximilian Reichert
- Subjects
0301 basic medicine ,pyrimidine ,Medicine (General) ,pyrimidine derivative ,cancer metabolism ,CHOP ,QH426-470 ,chemistry.chemical_compound ,0302 clinical medicine ,cell stress ,metabolic vulnerabilities ,Neoplasms ,Medicine ,antineoplastic agent ,Cancer ,cancer cell ,Cell Death ,catabolism ,Articles ,integrated stress response ,Drug repositioning ,Paclitaxel ,Pyrimidine metabolism ,tricyclic antidepressants ,Molecular Medicine ,metabolome ,Signal Transduction ,organoid ,animal experiment ,Antineoplastic Agents ,Article ,03 medical and health sciences ,R5-920 ,male ,pyrimidine synthesis ,Chemical Biology ,Metabolome ,Genetics ,Integrated stress response ,Humans ,controlled study ,ddc:610 ,human ,Cancer Metabolism ,Integrated Stress Response ,Metabolic Vulnerabilities ,Pyrimidine Metabolism ,Tricyclic Antidepressants ,mouse ,nonhuman ,business.industry ,animal model ,human cell ,niclosamide ,growth arrest and DNA damage inducible protein 153 ,medicine.disease ,pyrimidine metabolism ,030104 developmental biology ,Pyrimidines ,chemistry ,Cancer cell ,Cancer research ,Dewey Decimal Classification::600 | Technik::610 | Medizin, Gesundheit ,business ,transcriptome ,030217 neurology & neurosurgery ,neoplasm - 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., 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.
- Published
- 2021