Researchers at the Institute of Neurosciences UMH-CSIC, in collaboration with scientists at ESTEVE Pharmaceuticals, have uncovered a molecular mechanism that prevents the neuropathic pain associated with chemotherapy in the treatment of colorectal cancer, the second most diagnosed type of cancer. The study, carried out in mice, has been published in the journal Brain .
A high percentage of cancer patients treated with chemotherapy develop adverse sensory symptoms, including hypersensitivity to cold and touch in the extremities and oral cavity. This is known as chemotherapy-induced peripheral neuropathy. The development of this painful neuropathy limits the maximum dose of chemotherapeutic agent administered, thus compromising its efficacy and patient survival.
However, "the results of our work show that treatment during chemotherapy with a Sigma-1 receptor antagonist, a key protein in pain control, largely prevents the development of these neuropathic symptoms associated with the administration of one of the components of chemotherapy: oxaliplatin, by a mechanism involving the nociceptive channel TRPA1", explains the researcher Elvira de la Peña, who has led the research together with Félix Viana.
Colorectal cancer will be the tumor with the highest number of new diagnoses in Spain in 2022 and is the second leading cause of death from cancer. Its treatment with chemotherapy includes the use of oxaliplatin in combination with other antitumor drugs. In a large number of patients, oxaliplatin causes numbness or tingling in the fingers or pain in the hands and feet when touching metal objects, when going outside in cold weather or even when showering or washing hands. These discomforts can become very disabling and affect the normal performance of everyday activities such as walking outside or dressing.
"The first objective of our work was to replicate in an experimental model in mice the adverse sensory effects produced by oxaliplatin in cancer patients," explains Elvira de la Peña, to verify that the mice treated with oxaliplatin developed the usual painful symptoms in many patients treated with this drug: an exaggerated response to tactile or cold stimuli.
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 in the laboratory of Ardem Patapoutian, recent winner of the Nobel Prize in Physiology or Medicine.
Using biochemical techniques, the researchers demonstrated 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. Previous work had established that Sigma-1 receptor antagonists could attenuate the painful symptoms produced by oxaliplatin but the mechanism of action of this experimental drug class was unknown.
Additional work from the spanish researchers found that a Sigma 1 receptor antagonist alters the formation of the molecular complex between the TRPA1 ion channel and the Sigma-1 receptor. Incubation of sensory neurons sensing painful stimuli, called nociceptors, with the Sigma-1 receptor antagonist reduced the expression of the TRPA1 ion channel on their plasma membrane, damping their response to chemical irritants. Moreover, they found that mice treated with the Sigma-1 receptor antagonist during oxaliplatin administration normalized their response to painful stimuli.
"As with any basic research, performed on experimental animals, we must be cautious about translating these findings to the clinic. It needs to be validated with rigorous clinical trials in patients," warns Félix Viana. However, he considers that "these results are an important step in the understanding of 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. In fact, a phase II clinical trial published in 2018 already showed that patients treated with the antagonist suffered fewer premature withdrawals from treatment and showed less severe neuropathies.
Led by Elvira de la Peña and Félix Viana, this work (TRPA1 modulation by Sigma-1 receptor prevents oxaliplatin-induced painful peripheral neuropathy) has been published in the journal Brain and is the result of several years of research by the Sensory Transduction and Nociception Group of the Institute of Neurosciences CSIC-UMH, in Alicante, in collaboration with researchers from the company ESTEVE Pharmaceuticals.
Given that there are different chemotherapeutic agents and each one gives rise to a somewhat different spectrum of symptoms, the next step will be to determine whether what they have discovered for oxaliplatin can be generalized to other anticancer drugs used in the treatment of different tumors.
Pilar Quijada/ CSIC Comunicación
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TRPA1 modulation by Sigma-1 receptor prevents oxaliplatin-induced painful peripheral neuropathy
24-Jul-2022