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 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

SUBMITTER: Dr. Mauricio Berriel Diaz 

PROVIDER: S-SCDT-EMM-2020-12461 | biostudies-other |

REPOSITORIES: biostudies-other