Inserm research Director
Institut de génétique et de biologie moléculaire et cellulaire de Strasbourg
(Unité mixte Inserm/CNRS/Université de Strasbourg)
03 88 65 32 00
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.
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.
© Inserm/ Frédéric Coin
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.
The researchers from Unit 1138, “Integrative Cancer Immunology,” (Inserm, Pierre and Marie Curie and Paris Descartes Universities) have analysed the tumours from 838 patients with colorectal cancer, in order to identify markers for their metastatic potential. The genomic characteristics of the cancer ...
Teams from the Paris Public Hospitals (AP-HP), Pierre and Marie Curie University, Inserm and the CarThera company, coordinated by Prof. Alexandre Carpentier, have successfully used ultrasound to temporarily permeabilise blood vessels in the brains of patients affected by recurrent malignant brain tumours. ...
A small molecule screen identifies an inhibitor of DNA repair inducing the degradation of TFIIH and the chemosensibilization of tumor cells to platinium
Sergey Alekseev, Mériam Ayadi, Laurent Brino, Jean-Marc Egly, Annette K. Larsen et Frédéric Coin.
Chemistry & Biology, february 2014