Abstract
Aminoacridines, used for decades as antiseptic and antiparasitic agents, are prospective candidates for therapeutic repurposing and new drug development. Although the mechanisms behind their biological effects are not fully elucidated, they are most often attributed to the acridines’ ability to intercalate into DNA. Here, we characterized the effects of 9-aminoacridine (9AA) on pre-rRNA metabolism in cultured mammalian cells. Our results demonstrate that 9AA inhibits both transcription of the ribosomal RNA precursors (pre-rRNA) and processing of the already synthesized pre-rRNAs, thereby rapidly abolishing ribosome biogenesis. Using a fluorescent intercalator displacement assay, we further show that 9AA can bind to RNA in vitro, which likely contributes to its ability to inhibit post-transcriptional steps in pre-rRNA maturation. These findings extend the arsenal of small-molecule compounds that can be used to block ribosome biogenesis in mammalian cells and have implications for the pharmacological development of new ribosome biogenesis inhibitors.
Highlights
Ribosome biogenesis, a resource- and energy-demanding process of generating new ribosomes, is indispensable for cell growth and proliferation
We demonstrate the potent ability of 9AA to inhibit both transcription and post-transcriptional processing of pre-rRNA in cultured mouse and human cells
Aminoacridine-based compounds could serve as prospective candidates for therapeutic inhibition of ribosome biogenesis
Summary
A resource- and energy-demanding process of generating new ribosomes, is indispensable for cell growth and proliferation. There has been growing interest in targeting ribosome biogenesis as an anticancer therapeutic strategy [6,7,8]. One rationale for this is that in order to proliferate rapidly, tumor cells must upregulate the synthesis of ribosomes, making these cells susceptible to ribosome biogenesis inhibition [9,10]. Inhibitors of ribosome biogenesis activate the nucleolar stress response [11,12], which may potentiate cytotoxic effects by promoting cell death in certain cancer cells [8]. Cytostatic responses to nucleolar stress in nonmalignant cells could be beneficial by rendering these cells resistant to S phase-specific anticancer drugs [13]
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