Paclitaxel is widely used in the SUS against various types of cancer, including breast, lung and ovarian, and is a chemotherapy drug that has many side effects. The list includes pain, weakness, and even shortness of breath. There are cases when it becomes necessary to stop treatment. The mechanism behind adverse reactions is still unclear, but recently released research reveals a target that needs to be investigated.
The study was published in the journal Cell death and disease It demonstrates that the drug binds to and activates the C5aR1 cell receptor, which is implicated in inflammatory and neoplastic diseases. This association is considered essential for the origin of adverse reactions to chemotherapy, in particular so-called peripheral neuropathy. It occurs when there is a disruption in the connection of the peripheral nerves to the brain, causing pain, tingling, difficulty moving, and muscle loss, for example.
The result of the work points to a way for new studies to advance the search for a drug target, with the goal of preventing these interactions.
We have shown that the drug molecule is able to activate specific signaling pathways, in this case those of the C5aR1 receptor, and this is associated with adverse effects. If we understand what is behind this process and separate it from the anti-proliferative effect of chemotherapy, we can find a target to reduce and even prevent side reactions”, says one of the authors of the article, Professor Thiago Matar Cunha, of the Center for Research in Inflammatory Drugs Diseases (CRID) – Center for Research and Innovation and Publication (CEPID) of FAPESP based at the Ribeirão Preto School of Medicine, University of São Paulo (FMRP-USP).
Co-authoring the article was scientist Andreza Urba de Cuadros, of CRID, who also received support from FAPESP, and researchers from the Italian company Dompé Farmaceutici SpA, including corresponding author Marcello Allegetti.
According to Conha, the publication is the result of a combined effort of researchers and years of work. “Our group has been studying the C5aR1 receptor since 2000, and as early as 2008 we demonstrated its role in inflammatory pain. Since that time, we have deepened investigations. Along the way, there was a partnership with Dompé,” Professor Agência told FAPESP.
From previous studies showing a role for a cytokine, interleukin (IL)-8, in the adverse effects of paclitaxel in cancer treatments (neurotoxicity), scientists looked for proteins that activate the expression of IL-8.
To do this, they used the Exscalate supercomputing platform and performed molecular docking simulations – a method that predicts the preferential orientation of one molecule to a second, showing the compound formed when the two bond. Through these simulations, it was possible to reach the high affinity of C5aR1 with paclitaxel.
C5aR1 acts as a complement receptor, a group of proteins that are part of the innate immune system (first to act when a threat is present, and to initiate the defensive response). Activation of these receptors contributes to the regulation of the inflammatory response.
Although the importance of C5aR1 in pain appears to be enhanced, there are still many parts to explore in the puzzle involved in the mechanisms by which the receptor is involved in this process.
in validating predictions that are done through the computer (in silico), the group used the surface plasmon resonance system. The receptor was immobilized on a sensor, while paclitaxel flowed through it and the reaction occurred.
During the research phase in the laboratoryIn this study, scientists confirmed the specific nature of the C5aR1-paclitaxel binding in a lineage of neurons (mice). They found that it triggers a signaling pathway within the neuron, NFkB/P38 and c-Fos, involved in IL-8 activation.
In rat neurons and ganglia, C5aR1 inhibition protects against chemotherapy-induced neuropathological effects, whereas in rats treated with paclitaxel, the absence or inhibition of the receptor markedly attenuated symptoms of chemotherapy-induced adverse reactions.
Finally, research has shown that inhibition of C5aR1 can nullify the release of anaphylactic cytokines (which can lead to allergic reactions) induced by paclitaxel in macrophages. in the laboratoryAs well as the emergence of hypersensitivity reactions in mice.
Next steps include clinical trials using C5aR1-blocking drugs, which are already on the market, and possibly antibodies, which are more expensive. But first, we need to investigate to what extent this pathway can modulate paclitaxel activity in a tumor and whether its inactivation impairs the effect of the drug.
In 2020, the professor won the Patrick D. Wall Young Investigator Award for Basic Sciences, promoted by the International Association for the Study of Pain (IASP). Awarded every two years since 1985, the award is intended for scientists up to 40 years of age who have achieved a high level of excellence and leadership in pain research.
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