Why some cancer drugs have unexpected side effects
Researchers have revealed one reason why certain anti-cancer compounds can cause unexpected side effects, which could help guide an understanding of why some drugs show more promise than others, and provide a new tool to be used to identify those drugs and other possible candidates.
One of the most essential and energy-consuming cellular processes is ribosome biogenesis, the formation of the cellular machines that manufacture all proteins.
For cancer cells, this process is paramount, reports News Medical.
A recent study published online in eLife – from the Stowers Institute for Medical Research – screened more than 1 000 existing anti-cancer drugs to assess how they affect the structure and function of the nucleolus, the ubiquitous cellular organelle where ribosomes are made.
“All cells must make proteins to function, so they have to make ribosomes, which are also protein complexes themselves. In cancer cells, ribosome production must be in overdrive to compensate for high proliferation rates requiring even more proteins,” said Tamara Potapova, Ph.D, lead author and research specialist in the lab of investigator Jennifer Gerton, Ph.D.
The nucleolus is a special part of the cell nucleus that houses ribosomal DNA, and where ribosomal RNA production and ribosome assembly largely takes place.
Nucleoli can vary greatly in appearance, serving as visual indicators of the overall health of this process. Thus, the team found a way to capitalise on this variation and asked how chemotherapy drugs impact the nucleolus, causing nucleolar stress.
“In this study, we not only evaluated how anti-cancer drugs alter the appearance of nucleoli, but also identified categories of drugs that cause distinct nucleolar shapes,” said Gerton. “This enabled us to create a classification system for nucleoli based on their appearance – which is a resource other researchers can use.”
Because cancer’s hallmark is unchecked proliferation, most existing chemotherapeutic agents are designed to slow this down. “The logic was to see whether these drugs, intentionally or unintentionally, are affecting ribosome biogenesis and to what degree,” said Potapova.
“Hitting ribosome biogenesis could be a double-edged sword – it would impair the viability of cancer cells while simultaneously altering protein production in normal cells.”
Different drugs have impacts on different pathways involved in cancer growth. Those that influence ribosome production can induce distinct states of nucleolar stress that manifest in easily seen morphological changes. However, nucleolar stress can be difficult to measure.
“This was one of the issues impeding this field,” said Potapova. “Cells can have different numbers of nucleoli with various sizes and shapes, so it’s been challenging to find a single parameter that can fully describe a ‘normal’ nucleolus.
“Developing this tool, that we termed ‘nucleolar normality score’, allowed us to measure nucleolar stress precisely, and can be used by other labs to measure nucleolar stress in their experimental models.”
Through the comprehensive screening of anti-cancer compounds on nucleolar stress, the team identified one class of enzymes in particular, cyclin-dependent kinases, whose inhibition destroys the nucleolus almost completely.
Many of these inhibitors failed in clinical trials, and their detrimental impact on the nucleolus was not fully appreciated previously.
Drugs often fail in clinical trials due to excessive and unintended toxicity that can be caused by their off-target effects. This means a molecule designed to target one pathway may also affect a different pathway or inhibit an enzyme required for cellular function. In this study, the team found an effect on an entire organelle.
Study details
Distinct states of nucleolar stress induced by anti-cancer drugs
Tamara Potapova, Jay Unruh, Juliana Conkright-Fincham, Charles Banks, Laurence Florens, David Schneider, Jennifer Gerton.
Published in eLife on 23 July 2023
Abstract
Ribosome biogenesis is one of the most essential and energy-consuming cellular functions. It takes place mainly in the nucleolus. For cancer cells, the nucleolar function is especially important due to the high demand for ribosomes to support continuous proliferation. The goal of this study was to assess the effects of existing chemotherapy drugs on the nucleolar state. For this, we conducted an imaging-based screen for anticancer drugs that induce morphological re-organisation consistent with nucleolar stress. For a readout, we developed a novel parameter termed ‘nucleolar normality score’, which measures ratios of dense fibrillar center and granular component in the nucleolus and nucleoplasm. We show that multiple classes of drugs cause nucleolar stress, including DNA intercalators, inhibitors of mTOR/PI3K, heat shock proteins, proteasome, and cyclin-dependent kinases (CDKs). Different classes of drugs induced morphologically and molecularly distinct states of nucleolar stress. By applying phospho-proteomics and live imaging strategies, we characterized in detail the nucleolar stress induced by inhibition of transcriptional CDKs, particularly CDK9, the main CDK that targets RNA Pol II. Inhibition of CDK9 dramatically reduced rRNA production, caused dissociation of RNA Polymerase I catalytic subunit POLR1A from ribosomal DNA and dispersal of the nucleolar granular component, a stress we refer to as the “bare scaffold” state. We identified multiple nucleolar CDK phosphorylation substrates, including RNA Pol I – associated protein Treacle, and demonstrated that CDK9 can phosphorylate Treacle in vitro. This implies that transcriptional CDKs coordinate the action of RNA pol I and RNA pol II. Furthermore, molecular dynamics analysis of the endogenous nucleolar protein NPM1 demonstrated that CDK inhibition vastly increased its mobility, consistent with the loss of nucleolar integrity. We conclude that many classes of chemotherapy compounds directly or indirectly target nucleolar structure and function, and recommend considering this in anticancer drug development.
eLife article – Distinct states of nucleolar stress induced by anti-cancer drugs (Open access)
News Medical article – Stowers researchers reveal why certain anti-cancer drugs can cause unexpected side effects (Open access)
See more from MedicalBrief archives:
SA cancer rates set to double by 2030, actuaries predict
No association between price and efficacy of cancer drugs — four-nation study
Most new cancer drugs don’t work — 5-year European study
We'd appreciate as much information as possible, however only an email address is required.
Country South Africa United States of America Aaland Islands Afghanistan Albania Algeria American Samoa Andorra Angola Anguilla Antarctica Antigua And Barbuda Argentina Armenia Aruba Australia Austria Azerbaijan Bahamas Bahrain Bangladesh Barbados Belarus Belgium Belize Benin Bermuda Bhutan Bolivia Bosnia and Herzegovina Botswana Bouvet Island Brazil British Indian Ocean Territory Brunei Darussalam Bulgaria Burkina Faso Burundi Cambodia Cameroon Canada Cape Verde Cayman Islands Central African Republic Chad Chile China Christmas Island Cocos (Keeling) Islands Colombia Comoros Congo Cook Islands Costa Rica Cote D'Ivoire Croatia Cuba Curacao Cyprus Czech Republic Democratic Republic of the Congo Denmark Djibouti Dominica Dominican Republic Ecuador Egypt El Salvador Equatorial Guinea Eritrea Estonia Ethiopia Falkland Islands Faroe Islands Fiji Finland France French Guiana French Polynesia French Southern Territories Gabon Gambia Georgia Germany Ghana Gibraltar Greece Greenland Grenada Guadeloupe Guam Guatemala Guernsey Guinea Guinea-Bissau Guyana Haiti Heard and Mc Donald Islands Honduras Hong Kong Hungary Iceland India Indonesia Iran Iraq Ireland Isle of Man Israel Italy Jamaica Japan Jersey (Channel Islands) Jordan Kazakhstan Kenya Kiribati Kuwait Kyrgyzstan Lao People's Democratic Republic Latvia Lebanon Lesotho Liberia Libya Liechtenstein Lithuania Luxembourg Macau Macedonia Madagascar Malawi Malaysia Maldives Mali Malta Marshall Islands Martinique Mauritania Mauritius Mayotte Mexico Micronesia, Federated States of Moldova, Republic of Monaco Mongolia Montenegro Montserrat Morocco Mozambique Myanmar Namibia Nauru Nepal Netherlands Netherlands Antilles New Caledonia New Zealand Nicaragua Niger Nigeria Niue Norfolk Island North Korea Northern Mariana Islands Norway Oman Pakistan Palau Palestine Panama Papua New Guinea Paraguay Peru Philippines Pitcairn Poland Portugal Puerto Rico Qatar Republic of Kosovo Reunion Romania Russia Rwanda Saint Kitts and Nevis Saint Lucia Saint Vincent and the Grenadines Samoa (Independent) San Marino Sao Tome and Principe Saudi Arabia Senegal Serbia Seychelles Sierra Leone Singapore Sint Maarten Slovakia Slovenia Solomon Islands Somalia South Korea South Sudan Spain Sri Lanka St. Helena St. Pierre and Miquelon Sudan Suriname Svalbard and Jan Mayen Islands Swaziland Sweden Switzerland Syria Taiwan Tajikistan Tanzania Thailand Timor-Leste Togo Tokelau Tonga Trinidad and Tobago Tunisia Turkey Turkmenistan Turks & Caicos Islands Turks and Caicos Islands Tuvalu Uganda Ukraine United Arab Emirates United Kingdom Uruguay USA Minor Outlying Islands Uzbekistan Vanuatu Vatican City State (Holy See) Venezuela Vietnam Virgin Islands (British) Virgin Islands (U.S.) Wallis and Futuna Islands Western Sahara Yemen Zambia Zimbabwe
Stay informed! Visit the SA Department of Health's website for COVID-19 updates: sacoronavirus.co.za
It is critical to keep the HPCSA updated on changes to contact details, especially email addresses, writes Dr Yash Naidoo,… [More]
Digestion problems like constipation or difficulty in swallowing can double the chance of Parkinson’s disease, according to a recent study,… [More]
A review of thousands of cases from the first years of the Covid-19 pandemic – using pulse oximeters – found levels… [More]
Experts say the dangers posed by the increasing and alarming global consumption of ultra-processed food – raised BP levels, heart… [More]
The private healthcare industry is right to be nervous that potential fraud will give NHI proponents proper ammunition, writes Helena… [More]
An international study of 198 000 people has suggested that a gene variant, found almost exclusively in the genomes of… [More]
There’s been an alarming rise in cardiovascular diseases (CVDs) and non-communicable diseases (NCDs) in Africa, with 50% to 88% of… [More]
The success of a novel, African-led trial, which has entered its last stages, could mark the start of a new… [More]
A recent study has had implications for genetic breast cancer investigations and criteria for who should be offered testing, with… [More]
The stark reality is that the South African private healthcare sector, in its current format, is unsustainable, writes Gary Feldman… [More]
The tax increases the state needs to finance National Health Insurance are unrealistic, says organised business, warning that to raise… [More]
Researchers have revealed one reason why certain anti-cancer compounds can cause unexpected side effects, which could help guide an understanding… [More]
An American medical specialist and law expert has raised questions over the recently published case in which doctors at NYU… [More]
The male sex chromosome has finally been decoded in a breakthrough that will help illuminate why some men are afflicted… [More]
Scientists have developed a device that translates paralysed people’s brain signals into words at faster speeds than before, with plans… [More]
News MedicaleLifeStowers Institute for Medical ResearchStudy detailsDistinct states of nucleolar stress induced by anti-cancer drugsAbstracteLife article – Distinct states of nucleolar stress induced by anti-cancer drugs (Open access)News Medical article – Stowers researchers reveal why certain anti-cancer drugs can cause unexpected side effects (Open access)See more from MedicalBrief archives:SA cancer rates set to double by 2030, actuaries predictNo association between price and efficacy of cancer drugs — four-nation studyMost new cancer drugs don’t work — 5-year European studyStay informed!