Researchers at the Institute of Neurosciences (IN) − a joint center of the Higher Council for Scientific Research and the Miguel Hernández University (UMH) − have discovered in mice how to prevent neuropathic pain associated with chemotherapy in colon cancer treatments, one of the most diagnosed tumors. The study, published in the journal ‘Brain’, was carried out in collaboration with scientists from the company ESTEVE Pharmaceuticals.
A high percentage of cancer patients treated with chemotherapy develop hypersensitivity to cold and touch in the extremities and mouth. It is what is known as painful neuropathy due to chemotherapeutic agents. Its development determines the maximum dose of medication administered and compromises its effectiveness. Sometimes it can even force treatment to be abandoned, compromising the survival of patients.
“The results of our work show that treatment before chemotherapy with an antagonist of the sigma-1 receptor, a key protein in pain control, largely prevents the development of these neuropathic symptoms, which are associated with the administration of one of the components of chemotherapy: oxaliplatin”, explains researcher Elvira de la Peña, professor at the UMH and lead author of the study.
A possible strategy against painful neuropathy
Colorectal is one of the most common tumors and, worldwide, is the second leading cause of death from cancer. His chemotherapy treatment includes the use of oxaliplatin in combination with other antitumor drugs. In a large number of patients, this compound causes numbness or tingling in the fingers or pain in the hands and feet when touching metal objects, going outside in cold weather or even when showering or washing hands. These discomforts can become very disabling and affect the normal performance of daily activities, such as walking or dressing.
The tactile and thermal hypersensitivity in this neuropathy is known to be associated with alterations in a molecular sensor known as the TRPA1 ion channel −discovered by Ardem Patapoutian, recent Nobel Prize winner in Physiology or Medicine−.
“Using biochemical techniques we show that the TRPA1 channel needs to interact with the sigma-1 receptor, forming a molecular complex, for its correct expression on the surface of neurons”, adds de la Peña. This molecular interaction is the cause of the development of painful symptoms.
The researchers observed that certain molecules, defined sigma-1 ‘antagonists’, inhibit TRPA1 function. They then used an experimental model of oxaliplatin neuropathy in mice to find out if treatment with a sigma-1 antagonist, called S1RA, could prevent pain transmission.
“We verified that the mice treated with S1RA during the administration of oxaliplatin normalized their response to painful stimuli”, says the researcher.
“As in any basic research, carried out in experimental animals, we must be cautious when transferring these findings to humans. A clinical trial in patients is needed. However, these results are an important step in understanding this pathology and offer hope that in the future they can be used as a new therapy for the treatment and prevention of these disabling side effects of anticancer treatments”, concludes researcher Félix Viana, principal investigator at the IN and co-author of the study.
In future studies, the IN researchers plan to determine whether what they have discovered for oxaliplatin can be generalized to other anticancer agents used in the treatment of different tumors.
Marcotti et al., ‘TRPA1 modulation by Sigma-1 receptor prevents oxaliplatin-induced painful peripheral neuropathy’. (2022) ‘Brain‘