The antimalarial drug amodiaquine stabilizes p53 through ribosome biogenesis stress, independently of its autophagy-inhibitory activity

• DOI: 10.1038/s41418-019-0387-5
• Publication Date: 2019-07-08T12:03:24Z
• Authors: Jaime A. Espinoza; Asimina Zisi; Dimitris C. Kanellis; Jordi Carreras-Pu...; Martin Henriksson; Daniela Hühn; Kenji Watanabe; Thomas Helleday; Mikael S. Lindström; Jiri Bartek
• Keywords: Amodiaquine; ribosome biogenesis

Abstract Pharmacological inhibition of ribosome biogenesis is a promising avenue for cancer therapy. Herein, we report novel activity the FDA-approved antimalarial drug amodiaquine which inhibits rRNA transcription, rate-limiting step biogenesis, in dose-dependent manner. Amodiaquine triggers degradation catalytic subunit RNA polymerase I (Pol I), with ensuing RPL5/RPL11-dependent stabilization p53. Pol shutdown occurs absence DNA damage and without subsequent ATM-dependent transcription. RNAseq analysis revealed mechanistic similarities BMH-21, first-in-class inhibitor, chloroquine, analog amodiaquine, well-established autophagy-inhibitory activity. Interestingly, autophagy caused by not involved suggesting two independent anticancer mechanisms. In vitro, more efficient than chloroquine restraining proliferation human cell lines derived from colorectal carcinomas, type predicted susceptibility to stress. Taken together, our data reveal an unsuspected approved used clinics over 30 years, provide rationale repurposing