The Cell’s Nucleolus: an Emerging Target for Chemotherapeutic Intervention

Abstract

The transient nucleolus plays a central role in the upregulated synthesis of ribosomal RNA (rRNA) to sustain ribosome biogenesis, a hallmark of aberrant cell growth. This function, in conjunction with its unique pathohistological features in malignant cells and its ability to mediate apoptosis, renders this subnuclear structure a potential target for chemotherapeutic agents. In this Minireview, structurally and functionally diverse small molecules are discussed that have been reported to either interact with the nucleolus directly or perturb its function indirectly by acting on its dynamic components. These molecules include all major classes of nucleic acid-targeted agents, antimetabolites, kinase inhibitors, anti-inflammatory drugs, natural product antibiotics, oligopeptides, as well asnano-sized particles. Together, these molecules are invaluable probes of structure and function of the nucleolus. They also provide a unique opportunity to develop novel strategies for more selective and therefore better tolerated chemotherapeutic intervention. In this regard, inhibition of RNA polymerase I-mediated rRNA synthesis appears to be a promising mechanism of cancer cell kill. The recent development of molecules targeted at G-quadruplex forming rRNA gene sequences, which are currently undergoing clinical trials, seems to attest to the success of this approach.

Cell cycle specific distribution of killin: evidence for negative regulation of both DNA and RNA synthesis

“…[19][20][21][22][23] Furthermore, we also notice that in non-S-phase cells, RFP-Killin congregates in the nucleolus where rRNA transcription is known to be most active. 24 We provide evidence that throughout the cell cycle, RFPKillin is tightly associated with the nucleic acids. Together, these results provide a molecular basis for Killin in S-phase arrest, as well as potential negative regulation of RNA synthesis during other cell cycle phases of the cell.…”

Redesigning the DNA‐Targeted Chromophore in Platinum–Acridine Anticancer Agents: A Structure–Activity Relationship Study

“…They include a 24-mer representing the human telomeric repeat ([T 2 AG 3 ] n ), [29] as well as three of the guanine-rich sequences found in the genes encoding 45S pre-ribosomal RNA (rDNA), [30] which are transcribed by RNA polymerase I (Pol I) in the cell’s nucleolus (Figure 8a). [31] The ability of A1 , B1 , and B2 to induce the G4 structure in each of the sequences was first tested in an unbiased fashion in a Na + - and K + -free buffer. In titrations with the three chromophores, the random-coil form of TEL24 is converted into a quadruplex structure.…”

Cellular Recognition and Repair of Monofunctional–Intercalative Platinum–DNA Adducts

“…We have previously demonstrated using orthogonal fluorescent postlabeling techniques 44 that platinum–acridines accumulate in the nucleolar regions in cells, the sites of transcription of rRNA genes (rDNA) by RNA polymerase I (Pol I). 45 Furthermore, in cells treated with platinum–acridines the nucleoli show distinct morphological changes and appear considerably smaller than those in cisplatin-treated cells (Supporting Information). In experiments measuring the incorporation of fluorescently detectable ribonucleotide during transcription, NCI-H460 cells treated with P1-A1 showed signs consistent with disrupted rRNA synthesis.…”