Improving chemotherapy by preventing the repair of tumor cells
Visualization by immunofluorescence, 1h after treatment, of proteins XPC (red) and XPB (green) involved in NER activity. On the right panel, treatment with spironolactone induces a rapid degradation of XPB which explains the inhibition of NER.
Feb. 6, 2014
Chemotherapy is a cancer treatment strategy, the principle of which is to induce lesions in the DNA of tumor cells in order to inhibit their proliferation. However, in a natural way, the body tries to repair DNA damages, reducing the effectiveness of chemotherapy. Blocking mechanisms of DNA repair would therefore potentiate chemotherapy by reducing the cell resistance to treatment. A research team led by Frédéric Coin has discovered a new DNA repair inhibitory molecule, spironolactone, suggesting very short-term use as an adjuvant to chemotherapy. Their findings are published in Chemistry & Biology.
UV rays, chemical or physical agents, our body is continually attacked by the environment, causing more or less important damages in our DNA. A system of control and repair has then been developed. Among its mechanisms, the NER (Nucleotide Excision Repair) has been studied for several years by the team of Frédéric Coin and Jean-Marc Egly at IGBMC. This mechanism is able to detect a lesion and then replace the damaged DNA fragment by a sound one.
Cytotoxic chemotherapy aims at blocking the division of cancer cells in order to inhibit tumor proliferation. Platinum-based drugs are used for the treatment of numerous cancers such as colorectal, head and neck, testis, bladder, ovary or lung cancer. These molecules bind to cellular DNA, causing damages in the latter and thus preventing replication. Blocking mechanisms of DNA repair, in this case the NER activity, would then potentiate chemotherapy by reducing the cell resistance to treatment.
Researchers have tried to find a molecule that would inhibit the NER activity. They have tested about 1200 therapeutic molecules and highlighted the action on the NER activity of spironolactone, a molecule already used for the treatment of hypertension. Researchers have notably shown that its action combined with the platinum derivatives, caused a significant increase of cytotoxicity in colon and ovarian cancerous cells.
As spironolactone is already used elsewhere, it does not require a new marketing authorization and its side effects are known. This result suggests the rapid development of new chemotherapy protocols including spironolactone.