From Snapshots to Flipbook-Resolving the Dynamics of Ribosome Biogenesis with Chemical Probes.

The synthesis of ribosomes is one of the central and most resource demanding processes in each living cell. As ribosome biogenesis is tightly linked with the regulation of the cell cycle, perturbation of ribosome formation can trigger severe diseases, including cancer. Eukaryotic ribosome biogenesis starts in the nucleolus with pre-rRNA transcription and the initial assembly steps, continues in the nucleoplasm and is finished in the cytoplasm. From start to end, this process is highly dynamic and finished within few minutes. Despite the tremendous progress made during the last decade, the coordination of the individual maturation steps is hard to unravel by a conventional methodology. In recent years small molecular compounds were identified that specifically block either rDNA transcription or distinct steps within the maturation pathway. As these inhibitors diffuse into the cell rapidly and block their target proteins within seconds, they represent excellent tools to investigate ribosome biogenesis. Here we review how the inhibitors affect ribosome biogenesis and discuss how these effects can be interpreted by taking the complex self-regulatory mechanisms of the pathway into account. With this we want to highlight the potential of low molecular weight inhibitors to approach the dynamic nature of the ribosome biogenesis pathway.

Treating hematological malignancies with drugs inhibiting ribosome biogenesis: when and why.

It is well known that chemotherapy can cure only some cancers in advanced stage, mostly those with an intact p53 pathway. Hematological cancers such as lymphoma and certain forms of leukemia are paradigmatic examples of such scenario. Recent evidence indicates that the efficacy of many of the alkylating and intercalating agents, antimetabolites, topoisomerase, and kinase inhibitors used in cancer therapy is largely due to p53 stabilization and activation consequent to the inhibition of ribosome biogenesis. In this context, innovative drugs specifically hindering ribosome biogenesis showed preclinical activity and are currently in early clinical development in hematological malignancies. The mechanism of p53 stabilization after ribosome biogenesis inhibition is a multistep process, depending on specific factors that can be altered in tumor cells, which can affect the antitumor efficacy of ribosome biogenesis inhibitors (RiBi). In the present review, the basic mechanisms underlying the anticancer activity of RiBi are discussed based on the evidence deriving from available preclinical and clinical studies, with the purpose of defining when and why the treatment with drugs inhibiting ribosomal biogenesis could be highly effective in hematological malignancies.

Targeted cancer therapy with ribosome biogenesis inhibitors: a real possibility?

The effects of many chemotherapeutic drugs on ribosome biogenesis have been underestimated for a long time. Indeed, many drugs currently used for cancer treatment--and which are known to either damage DNA or hinder DNA synthesis--have been shown to exert their toxic action mainly by inhibiting rRNA synthesis or maturation. Moreover, there are new drugs that have been proposed recently for cancer chemotherapy, which only hinder ribosome biogenesis without any genotoxic activity. Even though ribosome biogenesis occurs in both normal and cancer cells, whether resting or proliferating, there is evidence that the selective inhibition of ribosome biogenesis may, in some instances, result in a selective damage to neoplastic cells. The higher sensitivity of cancer cells to inhibitors of rRNA synthesis appears to be the consequence of either the loss of the mechanisms controlling the cell cycle progression or the acquisition of activating oncogene and inactivating tumor suppressor gene mutations that up-regulate the ribosome biogenesis rate. This article reviews those cancer cell characteristics on which the selective cancer cell cytotoxicity induced by the inhibitors of ribosome biogenesis is based.