(Press-News.org) This news release is available in French.
Chemotherapies are cancer treatments that work by inducing lesions in the DNA of tumour cells in order to inhibit their proliferation. However, the body naturally tries to repair these lesions, and thus reduces the efficacy of chemotherapy. Blocking the mechanisms for DNA repair would help to potentiate chemotherapy by reducing the resistance of cells to treatment. A team of researchers directed by Frédéric Coin, Inserm Research Director at the Institute of Genetics and Molecular and Cellular Biology (IGBMC) in Strasbourg (a Joint Inserm/CNRS/University of Strasbourg Research Unit), has discovered a new drug that inhibits repair: spironolactone, which seems likely to be used in the very short term as an adjuvant to chemotherapy.
Their results are published in Chemistry & Biology.
UV rays, physical or chemical agents—the human body is constantly subject to environmental insults that cause more or less damage to our DNA. The body has therefore developed a whole system for proofreading and repair. Among these mechanisms, NER (Nucleotide Excision Repair) has been studied for several years by the researchers in a team led by Frédéric Coin and Jean-Marc Egly at IGBMC. This mechanism can thus detect a lesion, and then replace the damaged DNA fragment with an intact fragment.
Cytotoxic chemotherapy is aimed at blocking the division of malignant cells in order to prevent tumour growth. Included among the drugs used to treat many cancers such as colorectal, face and neck, testicular, bladder, ovarian and lung cancers are medications based on platinum. These drugs bind to cellular DNA, induce damage in the latter, and thus prevent its replication. Blocking DNA repair mechanisms, specifically NER activity, would help to potentiate chemotherapy by reducing the resistance of cells to the treatment.
The researchers at IGBMC therefore sought a drug that would inhibit NER activity. They thus tested over 1,200 therapeutic drugs and demonstrated the action of spironolactone, a drug already used for the treatment of hypertension, on NER activity. Specifically, the researchers showed that its action, when combined with that of platinum derivatives, caused a substantial increase in cytotoxicity for malignant colonic and ovarian cells.
Since spironolactone is already in use for other purposes, it does not require a new application for marketing authorisation, and its side-effects are already known. This result thus bodes very well for the rapid development of new chemotherapy protocols that include spironolactone.
Immunofluorescence labelling, 1 h after treatment, of XPC proteins (in red) and XPB proteins (in green) involved in NER activity. On the right, treatment with spironolactone induces rapid degradation of XPB, which explains its inhibition of NER.
INFORMATION:
Sources
A small molecule screen identifies an inhibitor of DNA repair inducing the degradation of TFIIH and the chemosensitization of tumor cells to platinum
Sergey Alekseev, Mériam Ayadi, Laurent Brino, Jean-Marc Egly, Annette K. Larsen and Frédéric Coin.
Chemistry & Biology, http://dx.doi.org/10.1016/j.chembiol.2013.12.014 February 2014
Investigator contact
Frédéric Coin
Inserm Research Director
Institute of Genetics and Molecular and Cellular Biology (IGBMC), Strasbourg (Joint Inserm/CNRS/University of Strasbourg Research Unit)
+33 3 88 65 32 00
mfrederic.coin@igbmc.fr
Press contact :
Priscille Rivière
presse@inserm.fr
Enhancement of chemotherapy by prevention of tumor cell repair
2014-02-20
ELSE PRESS RELEASES FROM THIS DATE:
Zebrafish discovery may shed light on human kidney function
2014-02-20
ROCHESTER, Minn. — Feb. 20, 2014 — Researchers say the discovery of how sodium ions pass through the gill of a zebrafish may be a clue to understanding a key function in the human kidney. The findings from a collaboration between Mayo Clinic and the Tokyo Institute of Technology appear in the online issue of the American Journal of Physiology-Regulatory, Integrative and Comparative Physiology.
The researchers discovered a protein responsible for gas exchanges in the fish gill structure. Specifically they studied and characterized the Na+/H+ (sodium/hydrogen) exchanger ...
Multilevel approach to coping with stigmas identified
2014-02-20
Socially stigmatized groups have poorer health than non-stigmatized groups, but a team of researchers believes that more emphasis on two-way and multidisciplinary interventions will have a greater and more successful impact on relieving many health issues.
"We took an interdisciplinary approach to understanding how to reduce health disparities due to the effects of social stigma, including stigmas based on race, sexual orientation and chronic illness," said Jonathan Cook, assistant professor of psychology, Penn State.
Stigma results when a negative stereotype becomes ...
NASA's TRMM satellite saw extreme rainfall from Tropical Cyclone Guito
2014-02-20
VIDEO:
This animation of rainfall gathered from Feb. 11-19, 2014, by NASA's TRMM satellite revealed that Tropical Cyclone Guito produced as much as 16.9 inches/430 mm of rainfall in the center...
Click here for more information.
Tropical Cyclone Guito has been a powerful rainmaker, and fortunately, data from NASA's TRMM satellite shows that the heaviest rainfall has occurred over the open waters of the Mozambique Channel and not over land.
The Tropical Rainfall Measuring Mission ...
Dismantling pancreas cancer's armor
2014-02-20
SEATTLE – Pancreas cancer is notoriously impervious to treatment and resists both chemotherapy and radiotherapy. It has also been thought to provide few targets for immune cells, allowing tumors to grow unchecked. But new research from Fred Hutchinson Cancer Research Center shows that pancreas cancer "veils" itself from the immune system by recruiting specialized immune suppressor cells. The research team also found that removing these cells quickly triggers a spontaneous anti-tumor immune response.
The findings, published Feb. 20 in Gut, give hope for future immunotherapy ...
Clinical opinion published on use of maternal oxygen during labor
2014-02-20
When a fetal heartbeat pattern becomes irregular during labor, many practitioners give oxygen to the mother. But questions remain whether this oxygen supplementation benefits the fetus or may actually be potentially harmful.
A clinical opinion written by third year resident Maureen Hamel, MD, along with maternal-fetal medicine specialists Brenna Anderson, MD and Dwight Rouse, MD, of the Department of Obstetrics and Gynecology at Women & Infants Hospital of Rhode Island and The Warren Alpert Medical School of Brown University, has been published in the January 10, 2014 ...
Human and dog brains both have dedicated 'voice areas'
2014-02-20
The first study to compare brain function between humans and any nonprimate animal shows that dogs have dedicated voice areas in their brains, just as people do. Dog brains, like those of people, are also sensitive to acoustic cues of emotion, according to a study in the Cell Press journal Current Biology on February 20.
The findings suggest that voice areas evolved at least 100 million years ago, the age of the last common ancestor of humans and dogs, the researchers say. It also offers new insight into humans' unique connection with our best friends in the animal kingdom ...
Neuron-generating brain region could hold promise for neurodegenerative therapies
2014-02-20
Adult humans continuously produce new neurons in the striatum, a brain region involved in motor control and cognitive functions, and these neurons could play an important role in recovery from stroke and possibly finding new treatments for neurodegenerative disorders, according to a study published by Cell Press February 20th in the journal Cell. To detect the birth of new neurons in the striatum, the authors used a method that measures carbon-14 found in human DNA as a result of above-ground nuclear testing more than half a century ago. The findings reveal a surprise finding ...
Researchers regenerate sound-sensing cells in the ears of mice with hearing damage
2014-02-20
One of the major causes of hearing loss in mammals is damage to the sound-sensing hair cells in the inner ear. For years, scientists have thought that these cells are not replaced once they're lost, but new research appearing online February 20 in the journal Stem Cell Reports reveals that supporting cells in the ear can turn into hair cells in newborn mice. If the findings can be applied to older animals, they may lead to ways to help stimulate cell replacement in adults and to the design of new treatment strategies for people suffering from deafness due to hair cell loss.
Whereas ...
Mauritius kestrels show long-term legacy of man-made habitat change
2014-02-20
The widespread loss of forest to sugarcane fields on the island of Mauritius has forced kestrels living there to survive by speeding up their life histories, according to a report published online on February 20 in the Cell Press journal Current Biology. By getting an earlier start, the birds are managing to have just as many offspring, even though they die sooner.
Those changes to the kestrels' life history are apparently driven entirely by their early life experiences, the researchers say.
"This adaptive, plastic response is a testament to how resilient this species ...
CHOP researcher co-leads study finding genes that affect blood pressure
2014-02-20
A large international study analyzing genes in tens of thousands of individuals has discovered 11 new genetic signals associated with blood pressure levels. Ten of those signals are in or very near genes encoding proteins that appear to be likely targets for drugs already in existence or in development.
"The fact that most of these new gene signals are 'druggable' targets offers the possibility of expedited pharmaceutical development of therapeutics for high blood pressure, a serious risk factor for cardiovascular diseases," said geneticist Brendan J. Keating, D. Phil., ...