Abstract
Pharmacological inhibition of ribosome biogenesis is a promising avenue for cancer therapy. Herein, we report a novel activity of the FDA-approved antimalarial drug amodiaquine which inhibits rRNA transcription, a rate-limiting step for ribosome biogenesis, in a dose-dependent manner. Amodiaquine triggers degradation of the catalytic subunit of RNA polymerase I (Pol I), with ensuing RPL5/RPL11-dependent stabilization of p53. Pol I shutdown occurs in the absence of DNA damage and without the subsequent ATM-dependent inhibition of rRNA transcription. RNAseq analysis revealed mechanistic similarities of amodiaquine with BMH-21, the first-in-class Pol I inhibitor, and with chloroquine, the antimalarial analog of amodiaquine, with well-established autophagy-inhibitory activity. Interestingly, autophagy inhibition caused by amodiaquine is not involved in the inhibition of rRNA transcription, suggesting two independent anticancer mechanisms. In vitro, amodiaquine is more efficient than chloroquine in restraining the proliferation of human cell lines derived from colorectal carcinomas, a cancer type with predicted susceptibility to ribosome biogenesis stress. Taken together, our data reveal an unsuspected activity of a drug approved and used in the clinics for over 30 years, and provide rationale for repurposing amodiaquine in cancer therapy.
Highlights
While searching for polymerase I (Pol I) inhibitors among FDA-approved drugs, we assessed the impact of AQ on levels of 47S ribosomal RNA (rRNA), using a set of primers targeting mature 18S, 5.8S and 28S rRNAs and six primers for regions present exclusively in the 47S precursor rRNA
Our findings show that the FDA-approved antimalarial drug AQ inhibits ribosome biogenesis, an activity not shared by other 4-aminoquinoline family members
AQ triggers proteasome-dependent degradation of RPA194 (POLR1A), a feature reported for the experimental drugs BMH-21 [12] and BMH-22 [25, 56]
Summary
Transcription of ribosomal RNA (rRNA) is carried out exclusively by the RNA polymerase I (Pol I) inside the nucleolus. Beside the deleterious effects of actinomycin D on rRNA synthesis [8], new ribosome biogenesis inhibitors have emerged. The antineoplastic drug oxaliplatin, included in the clinical FOLFOX regimen and first-line treatment of colorectal cancer (CRC), exerts its chemotherapeutic effect predominantly through ribosome biogenesis stress rather than through DNA crosslinking, as its analog cisplatin [13]. These findings strongly support the rationale for developing new ribosome biogenesis inhibitors against CRC. We report the characterization of the FDA-approved drug AQ as a ribosome biogenesis inhibitor and promising anticancer compound
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