Convergent effect of cisplatin and KW6002 on DNA double-strand breaks in lung tumor cells. Blue corresponds to cell nuclei and red to a protein that marks DNA damage. © Dewaeles et al.
Cisplatin is a chemotherapy indicated to fight once morest tumors in many cancers. However, it is accompanied by significant side effects, in particular toxicity to the kidneys which can lead to acute renal failure. In addition, patients treated with cisplatin also often report suffering from significant neuropathic pain. Scientists from Inserm, the University and University Hospital of Lille, the CNRS and the Institut Pasteur de Lille, within the CANTHER laboratories[1] and Lille Neuroscience & Cognition, in collaboration with researchers from Michigan State University (USA) have identified a drug that might be a game-changer for patients. Already authorized once morest Parkinson’s disease, this molecule called istradefylline might not only reduce the deleterious effects of chemotherapy but also improve its anti-tumor properties. These results will now have to be consolidated in the context of a clinical trial. The study is published in The Journal of Clinical Investigation.
Cisplatin is a chemotherapy used in the treatment of several cancers, including lung, ovarian and testicular cancer. If its anti-tumor efficacy is proven, this therapy is also accompanied by side effects, including intense pain (peripheral neuropathy) and kidney damage, which can go as far as acute renal failure in a third of cases. . At present, there is no specific solution to limit these problems which affect many patients exposed to cisplatin.
In order to improve their management, the development of new therapeutic strategies is therefore a major area of research for many scientists.
This is the case of the teams led by Christelle Cauffiez, David Blum and Geoffroy Laumet from the CANTHER laboratories (Inserm/ /CNRS/University of Lille/CHU of Lille), Lille Neuroscience & Cognition (Inserm/University of Lille/CHU of Lille) and the Department of Physiology at Michigan State University who have identified a molecule capable of reducing the side effects of cisplatin, while preserving or even increasing its anti-tumor properties.
A drug for Parkinson’s disease
Scientists were interested in a drug called “istradefylline” which has already been approved in the United States and Japan for the treatment of Parkinson’s disease. This drug works by blocking receptors on the surface of our cells, the adenosine receptors.
David Blum’s team, which works on neurodegenerative pathologies, had already noticed that these receptors are in increased quantity in the brain of patients in a pathological context and that this phenomenon is involved in the development of these diseases. However, a similar increase in adenosine receptors was also observed by Christelle Cauffiez’s team in the kidneys when the body is exposed to cisplatin.
Faced with this observation, the scientists therefore decided to work together to test the effects of istradefylline in order to determine whether blocking these receptors makes it possible to reduce the deleterious effects of cisplatin.
Results to be confirmed in a clinical trial
Their experiments, carried out using animal and cellular models, effectively suggested the beneficial role of istradefylline. Indeed, in mice exposed to this chemotherapy, the molecule acts by reducing not only the damage caused to kidney cells but also the pain induced by cisplatin.
Furthermore, the ability of cisplatin to reduce tumor growth was increased in animals that received istradefylline, which was later confirmed in cell models.
Before considering the generalization of this therapeutic approach to cancer patients, these results must first be consolidated by organizing a rigorous clinical trial. Nevertheless, the fact that istradefylline is already used in humans to treat another pathology is already an interesting prospect.
“In fact, we already have a lot of data from clinical trials that show this molecule is safe. If it is necessary to carry out a clinical study in order to test its effectiveness in reducing the side effects of chemotherapy, the possibility of therapeutic repositioning is a promising prospect for improving the management of patients in the short term”, say the researchers.
[1] Heterogeneity, plasticity and resistance to cancer therapy laboratory (CANTHER)