Widely used in the Joint Health System (SUS) to treat a variety of cancers, including breast, lung, and ovarian cancer, paclitaxel is a chemotherapy drug that has several side effects. The list includes pain, weakness, and even shortness of breath. There are cases when it is necessary to stop treatment. The mechanism of adverse reactions remains unclear, but a recently published study has identified a target for investigation.
A study published in the journal Cell Death & Disease shows that the drug binds to and activates the C5aR1 cell receptor, which is involved in inflammatory diseases and tumors. This connection is crucial for the occurrence of adverse reactions of chemotherapy, mainly the so-called peripheral neuropathy. It occurs when the connection of peripheral nerves to the brain is disrupted, causing pain, tingling, difficulty moving, and loss of muscle mass, for example.
The result of the work points the way for new research in the search for a pharmacological target aimed at preventing these reactions.
“We have shown that the drug molecule is able to activate certain signaling pathways, in this case the C5aR1 receptor, and this is associated with side effects. If we understand what is behind this process and separate it from the antiproliferative effects of chemotherapy, we can find a target for reducing and even blocking adverse reactions,” says one of the authors of the article, Professor Thiago Mattar Cunha from the Center for Research in Diseases, Inflammatory Diseases. Medicines (CRID) – Center for Research, Innovation and Dissemination (CEPID) FAPESP based at the Ribeirão Preto Faculty of Medicine of the University of São Paulo (FMRP-USP).
The article brought together scientist Andres Urba de Quadros of CRID, who also received support from FAPESP, and researchers from the Italian company Dompé Farmaceutici SpA, including corresponding author Marcello Alleghetti.
According to Cunya, the publication is the result of a collaborative effort between researchers and years of work. “Our group has been studying the C5aR1 receptor since the 2000s, and already in 2008 we demonstrated its role in inflammatory pain. Since then, we have been deepening our investigations. Along the way, a partnership with Dompe emerged,” says Professor Agência FAPESP.
Stages
From previous studies that demonstrated a role for the cytokine interleukin (IL-8) in the side effects caused by paclitaxel in cancer treatment (neuronal toxicity), scientists were looking for proteins that upregulate IL-8 expression.
To do this, they used the Exscalate supercomputer platform and performed molecular docking simulations, a technique that predicts the preferred orientation of one molecule over another, showing the complex formed when they bind. With these simulations, a high affinity of C5aR1 for paclitaxel was achieved.
C5aR1 functions as complement receptors, a set of proteins that are part of the innate immune system (the first to act upon a threat, initiating a defensive response). Activation of these receptors contributes to the regulation of the inflammatory response. Although the relevance of C5aR1 in pain appears to be confirmed, several pieces of the puzzle regarding the mechanisms by which the receptor is involved in this process remain to be uncovered.
When testing the computer-assisted prediction (in silico), the group used a surface plasmon resonance system. The receptor was immobilized on the sensor, while paclitaxel flowed through it and interaction took place.
At the stage of in vitro studies, scientists confirmed the specific nature of the binding of C5aR1-paclitaxel in a line of neurons (mouse). And they found that it triggers a signaling pathway within the nerve cell, NFkB/P38 and c-Fos, involved in IL-8 activation.
In rat nerve cells and ganglia, inhibition of C5aR1 protected against chemotherapy-induced neuropathological effects, while in paclitaxel-treated mice, absence or inhibition of the receptor significantly improved symptoms of chemotherapy-induced adverse reactions.
Finally, studies have shown that inhibition of C5aR1 can counteract the release of anaphylactic cytokines (which can cause allergic reactions) induced by paclitaxel in macrophages in vitro, as well as the occurrence of hypersensitivity reactions in mice.
“Next steps include clinical trials using C5aR1 blocking drugs that are already on the market and possibly more expensive antibodies. But first we need to find out how much this pathway can modulate the activity of paclitaxel in the tumor and whether its deactivation affects the action of the drug, ”explains Cunha, a specialist in pain and inflammation.
In 2020, the professor received the Patrick D. Wall Award for Young Investigators in Basic Science, established by the International Association for the Study of Pain (IASP). The award has been presented every two years since 1985 and is intended for scientists under the age of 40 who have achieved a high level of excellence and leadership in pain research (for more information, visit: agencia.FAPESP.br/32327/).
Artigo Paclitaxel binds and activates C5aR1: a new potential therapeutic target for the prevention of chemotherapy-induced peripheral neuropathy and hypersensitivity reactions.
Luciana Constantino of Agência FAPESP