Details
| Original language | English |
|---|---|
| Article number | e12461 |
| Journal | EMBO molecular medicine |
| Volume | 13 |
| Issue number | 4 |
| Early online date | 5 Mar 2021 |
| Publication status | Published - 9 Apr 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.
Keywords
- cancer metabolism, integrated stress response, metabolic vulnerabilities, pyrimidine metabolism, tricyclic antidepressants
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
- Molecular Medicine
Sustainable Development Goals
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In: EMBO molecular medicine, Vol. 13, No. 4, e12461, 09.04.2021.
Research output: Contribution to journal › Article › Research › peer review
}
TY - JOUR
T1 - Combination therapies induce cancer cell death through the integrated stress response and disturbed pyrimidine metabolism
AU - Hartleben, Goetz
AU - Schorpp, Kenji
AU - Kwon, Yun
AU - Betz, Barbara
AU - Tsokanos, Foivos Filippos
AU - Dantes, Zahra
AU - Schäfer, Arlett
AU - Rothenaigner, Ina
AU - Monroy Kuhn, José Manuel
AU - Morigny, Pauline
AU - Mehr, Lisa
AU - Lin, Sean
AU - Seitz, Susanne
AU - Tokarz, Janina
AU - Artati, Anna
AU - Adamsky, Jerzy
AU - Plettenburg, Oliver
AU - Lutter, Dominik
AU - Irmler, Martin
AU - Beckers, Johannes
AU - Reichert, Maximilian
AU - Hadian, Kamyar
AU - Zeigerer, Anja
AU - Herzig, Stephan
AU - Berriel Diaz, Mauricio
N1 - Funding Information: This work was supported by an intramural drug development grant to G. H. and M. B. D., M. R., S. H., and M. B. D. are supported by the German Research Foundation (Deutsche Forschungsgemeinschaft, SFB1321 Modeling and Targeting Pancreatic Cancer, Project‐ID 329628492). M. R. is supported by the German Cancer Aid Foundation (Max Eder Program, Deutsche Krebshilfe 111273, M. R.) and the German Research Foundation (RE 3723/4‐1). This work was partially supported by the Helmholtz Alliance “Aging and Metabolic Programming, AMPro” (J. B.; S. H.). We thank Stefan Ambos, Eva Lederer, and Marcos Rios Garcia for technical help and discussions, and Manfred Roesner for advice on drug development. We thank Luke Harrison for his support with figure design. Open Access funding enabled and organized by Projekt DEAL.
PY - 2021/4/9
Y1 - 2021/4/9
N2 - 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.
AB - 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.
KW - cancer metabolism
KW - integrated stress response
KW - metabolic vulnerabilities
KW - pyrimidine metabolism
KW - tricyclic antidepressants
UR - http://www.scopus.com/inward/record.url?scp=85101901759&partnerID=8YFLogxK
U2 - 10.15252/emmm.202012461
DO - 10.15252/emmm.202012461
M3 - Article
C2 - 33665961
AN - SCOPUS:85101901759
VL - 13
JO - EMBO molecular medicine
JF - EMBO molecular medicine
SN - 1757-4676
IS - 4
M1 - e12461
ER -