Paclitaxel binds and activates C5aR1: A new potential therapeutic target for the prevention of chemotherapy-induced peripheral neuropathy and hypersensitivity reactions

• DOI: 10.1038/s41419-022-04964-w
• Publication Date: 2022-05-25T10:04:07Z
• Authors: Laura Brandolini; Michele d’Angelo; Rubina Novelli; Vanessa Castelli; Cristina Giorgio; Anna Sirico; Pasquale Cocchiaro; Francesco D’Egidio; Elisabetta Benedetti; Claudia Cristiano; Antonella Bugatti; Anna Ruocco; Pier Giorgio Amen...; Carmine Talarico; Candida Manelfi; Daniela Iaconis; Andrea Beccari; Andreza U. Quadros; Thiago M. Cunha; Arnaldo Caruso; Roberto Russo; Annamaria Cimini; Andrea Aramini; Marcello Allegretti
• Keywords: 0303 health sciences; Anaphylatoxin C5a; QH573-671; Paclitaxel; Peripheral Nervous System Diseases; Antineoplastic Agents; Article; Rats; 3. Good health; Molecular Docking Simulation; Mice; 03 medical and health sciences; Hyperalgesia; Animals; Cytology; Animals; Hyperalgesia; Mice; Molecular Docking Simulation; Paclitaxel; Rats; Receptor, Anaphylatoxin C5a; Antineoplastic Agents; Peripheral Nervous System Diseases; Receptor, Anaphylatoxin C5a; Receptor

Chemotherapy-induced peripheral neuropathy (CIPN) and hypersensitivity reactions (HSRs) are among the most frequent impairing side effects of antineoplastic agent paclitaxel. Here, we demonstrated that paclitaxel can bind activate complement component 5a receptor 1 (C5aR1) this binding is crucial in etiology paclitaxel-induced CIPN anaphylaxis. Starting from our previous data demonstrating role interleukin (IL)-8 neuronal toxicity, searched for proteins IL-8 expression and, by using Exscalate platform molecular docking simulations, predicted high affinity C5aR1 with By vitro studies, confirmed specific competitive nature C5aR1-paclitaxel found it triggers intracellularly NFkB/P38 pathway c-Fos. In F11 cells rat dorsal root ganglia, inhibition protected neuropathological effects, while paclitaxel-treated mice, absence (knock-out mice) or significantly ameliorated symptoms-in terms cold mechanical allodynia-and reduced chronic pathological state paw. Finally, counteract anaphylactic cytokine release macrophages vitro, as well onset HSRs mice. Altogether these identified a key mediator new potential pharmacological target prevention treatment induced