A luminescent representation reveals cells containing typical nucleoli (vivid orange) within nuclei (violet) encapsulated by actin threads (deep blue). Credit: Image attributed to Tamara Potapova, Gerton Lab, Stowers Institute for Medical Research.
This research holds the potential to augment the efficacy of cancer medication development.
Nearly 90% of pharmaceuticals never make it to the market, underlining the pressing necessity for enhanced proficiency in drug development. The scenario is not much different for medicines aimed at cancer treatment, many of which falter for a multitude of reasons. Scientists have now identified one particular cause behind the unanticipated side effects of certain anti-cancer agents. This understanding could assist in discerning why some medications are more efficacious than others and offer a novel tool for the selection of drug candidates.
A critical and energy-intensive cellular activity is the biosynthesis of ribosomes, the cell’s protein-manufacturing machines. For cancerous cells, this procedure is crucial. A new study published in the eLife journal by the Stowers Institute for Medical Research examined over 1,000 extant anti-cancer medications to gauge their effects on the structure and activity of the nucleolus, the cell’s omnipresent organelle where ribosomes are synthesized.
“All cells need to produce proteins for functionality, which means they also need to generate ribosomes, themselves protein complexes,” stated Tamara Potapova, Ph.D., the primary researcher in the lab overseen by Investigator Jennifer Gerton, Ph.D. “Cancer cells, in particular, must ramp up ribosome production to account for their elevated rates of proliferation, which demands even greater protein synthesis.”
A graphical depiction portrays a standard nucleolus and its altered state during stress instigated by chemotherapy agents inhibiting transcriptional cyclin-dependent kinase. Credit: Image attributed to Mark Miller and Tamara Potapova, Stowers Institute for Medical Research.
The nucleolus serves as a specialized region within the cellular nucleus where ribosomal DNA resides, and where the bulk of ribosomal RNA production and ribosome assembly occur. Nucleoli manifest significant variations in their appearance, acting as visual markers for the health of this process. The researchers exploited this attribute to investigate how chemotherapy medications influence the nucleolus, thereby inducing nucleolar stress.
“In our investigation, we did more than just evaluate how these anti-cancer agents modify nucleolar appearance. We also categorized drugs that result in distinct nucleolar forms,” Gerton noted. “This has allowed us to develop a classification system for nucleoli based on visual characteristics, a resource that could be beneficial for other research endeavors.”
Due to cancer’s inherent trait of uncontrolled growth, the majority of existing chemotherapy drugs are formulated to inhibit this. “We aimed to ascertain whether these medicines, either deliberately or inadvertently, have any bearing on ribosome biosynthesis and to what extent,” said Potapova. “Targeting ribosome biosynthesis might yield mixed results—it could compromise the survival of cancer cells while concurrently affecting protein synthesis in healthy cells.”
Different medications influence distinct pathways that are implicated in cancer proliferation. Those affecting ribosome biosynthesis can induce unique forms of nucleolar stress, manifesting in noticeable morphological changes. Measuring nucleolar stress, however, presents a challenge.
“One of the hurdles that had previously hindered progress in this domain was the complexity of describing a ‘normal’ nucleolus,” Potapova elucidated. “Cells may possess varying numbers of nucleoli with different dimensions and configurations. Our development of what we have termed the ‘nucleolar normality score’ has enabled precise measurement of nucleolar stress, a tool that other laboratories can employ in their experimental setups.”
Upon conducting an exhaustive review of anti-cancer compounds’ impact on nucleolar stress, the research team pinpointed a specific class of enzymes—cyclin-dependent kinases—whose inhibition leads to almost total nucleolar disintegration. Many such inhibitors have failed in clinical testing, and their adverse effects on the nucleolus were not comprehensively understood earlier.
Pharmaceuticals frequently falter in clinical assessments due to excessive and unintended toxicity, often engendered by off-target impacts. A molecule engineered to act on one specific pathway might also affect another pathway or suppress an enzyme vital for cellular activities. In this study, the team discovered an effect that compromises an entire cellular organelle.
Potapova concluded, “At the very least, I hope this study raises awareness that certain anti-cancer drugs may inadvertently disrupt nucleolar functions, an aspect that ought to be contemplated during the formulation of new medications.”
Reference: “Unique Forms of Nucleolar Stress Induced by Anti-Cancer Medications” by Tamara A. Potapova, Jay R. Unruh, Juliana Conkright-Fincham, Charles A. S. Banks, Laurence Florens, David A. Schneider, and Jennifer L. Gerton, 13 July 2023, eLife.
DOI: 10.7554/eLife.88799.1
The research was supported through institutional funding from the Stowers Institute for Medical Research.
Table of Contents
Frequently Asked Questions (FAQs) about Anti-Cancer Drug Research
What is the main focus of the research discussed in the article?
The primary focus of the research is to understand the unanticipated side effects of anti-cancer drugs, particularly how they affect the nucleolus, an organelle within the cell where ribosomes are synthesized. The findings aim to improve the efficiency of cancer drug development by offering insights into why some medications are more effective than others.
What is the nucleolus and why is it important in this research?
The nucleolus is a specialized region within the cell nucleus where ribosomal DNA is located and where most ribosomal RNA production and ribosome assembly occur. In the context of this research, the nucleolus is critical because it is heavily involved in ribosome biosynthesis, a process that is especially important for cancer cells due to their high rates of proliferation.
What is ribosome biogenesis and why is it significant for cancer cells?
Ribosome biogenesis is the formation of ribosomes, the cellular machinery responsible for protein synthesis. For cancer cells, this process is crucial because they need to produce proteins at an elevated rate to sustain their rapid growth and proliferation.
Who conducted this research and where was it published?
The research was conducted by a team at the Stowers Institute for Medical Research, led by Tamara Potapova, Ph.D., and Jennifer Gerton, Ph.D. The findings were published in the journal eLife.
What did the researchers find regarding the side effects of anti-cancer drugs?
The researchers discovered that certain anti-cancer drugs can cause unexpected changes in the nucleolus, leading to what is termed as “nucleolar stress.” This could potentially affect the viability of both cancerous and healthy cells and thus has implications for the development of more effective and safer cancer drugs.
What is nucleolar stress and how is it measured?
Nucleolar stress refers to changes or disruptions in the nucleolus, often induced by external factors such as chemotherapy drugs. Measuring nucleolar stress has been challenging due to the complexity of defining a “normal” nucleolus. However, the research team developed a tool called the “nucleolar normality score” to measure nucleolar stress with precision.
What is the significance of cyclin-dependent kinases in the study?
The research identified cyclin-dependent kinases as a particular class of enzymes whose inhibition almost completely disintegrates the nucleolus. Many inhibitors targeting these kinases have previously failed in clinical trials, and the study suggests that their impact on the nucleolus was not fully appreciated.
How can this research benefit future drug development?
The research provides a new tool and understanding that can be used to identify promising drug candidates and weed out those that are likely to produce unintended side effects, thereby increasing the efficiency and success rate of future cancer drug development.
Who funded this research?
The work was funded through institutional support from the Stowers Institute for Medical Research.
What are the implications of this research for existing cancer treatments?
The study highlights the need for careful evaluation of anti-cancer drugs’ impact on cellular organelles like the nucleolus. It suggests that unintended nucleolar disruption could be a contributing factor to the failure of some drugs in clinical trials and should be considered in the development of new medications.
More about Anti-Cancer Drug Research
- eLife Journal: Distinct states of nucleolar stress induced by anti-cancer drugs
- Stowers Institute for Medical Research
- Understanding Cancer Treatment: Chemotherapy
- Cyclin-Dependent Kinases: An Overview
- Drug Development Process
- Nucleolus: Structure and Functions
7 comments
Kinda scary to think that drugs aimed at helping can have such unintended consequences. Hope this research leads to better and safer treatments.
Wow, this is pretty groundbreaking. Never thought anti-cancer drugs could have such a ripple effect in the cell. Gotta keep an eye on this!
Loved how they coined a “nucleolar normality score” to actually measure the stress. Science is amazing.
so ribosome biogenesis is like, super important for cancer cells. Makes sense, but what are the implications for healthy cells? gotta dig deeper into this.
Cyclin-dependent kinases…Hmm, sounds like we were missing something big in cancer research. Glad someone’s looking into this.
i never thought the nucleolus would be such a big deal in cancer treatment. Just goes to show, every bit of the cell counts.
It’s crazy how complicated drug development is. 90% of drugs don’t make it? Man, we’ve got a long way to go…