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

Abstract

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

Emerging Approaches for the Management of Chemotherapy-Induced Peripheral Neuropathy (CIPN): Therapeutic Potential of the C5a/C5aR Axis

“…These findings prompted new studies to investigate IL-8 upstream events potentially involved in paclitaxel-induced CIPN, with the final goal to find new therapeutic approaches for CIPN treatment. Based on this rationale, and as better reported below, both the link found between the activation of the C5a/C5aR1 axis and neuropathic pain [ 72 ], and the recent demonstration of the binding of paclitaxel to C5aR1 as a crucial event for CIPN occurrence, constitute the first strong demonstration that C5aR1 may be regarded as a new potential target for the prevention and the treatment of CIPN [ 73 ], with this receptor having been identified as an upstream mediator of IL-8, capable of binding paclitaxel with high affinity.…”

“…Consequently, the emerging evidence suggests that inhibition of C5a activity by C5aR antagonists could represent a potential therapeutic approach for the control and/or treatment of acute and chronic neuropathic and neuroinflammatory pain [ 5 ], supported also by the reduction of paclitaxel-induced mechanical allodynia observed in a C3 knockout (KO) rat model that demonstrated a pivotal role of complement in CIPN, and stimulated research programs to explore this intriguing hypothesis [ 74 ]. Interestingly, a potentially striking confirmation of the role of the C5a/C5aR1 axis in neuropathic pain, and specifically in CIPN, recently emerged in preclinical studies addressing the molecular mechanisms underlying the undesirable effects of taxanes [ 73 ], as previously discussed, one of the most commonly used class of chemotherapeutics associated with CIPN development. Studies on activation pathways induced by taxanes in peripheral neural cells led researchers to identify and test both in vitro and in vivo that C5aR1 binding and activation by paclitaxel are crucial steps in the development and maintenance of taxane-induced CIPN, and that the blockage of C5aR1 is effective in preventing and counteracting CIPN [ 73 ].…”

“…Interestingly, a potentially striking confirmation of the role of the C5a/C5aR1 axis in neuropathic pain, and specifically in CIPN, recently emerged in preclinical studies addressing the molecular mechanisms underlying the undesirable effects of taxanes [ 73 ], as previously discussed, one of the most commonly used class of chemotherapeutics associated with CIPN development. Studies on activation pathways induced by taxanes in peripheral neural cells led researchers to identify and test both in vitro and in vivo that C5aR1 binding and activation by paclitaxel are crucial steps in the development and maintenance of taxane-induced CIPN, and that the blockage of C5aR1 is effective in preventing and counteracting CIPN [ 73 ]. In that study, C5aR1 was shown to be a molecular target of paclitaxel and involved in the previously reported taxane-induced IL-8 expression, and subsequent activation of CXCR1/2 signaling in neural cells, implicated in the taxane-induced neuropathic pain [ 73 ].…”

“…Studies on activation pathways induced by taxanes in peripheral neural cells led researchers to identify and test both in vitro and in vivo that C5aR1 binding and activation by paclitaxel are crucial steps in the development and maintenance of taxane-induced CIPN, and that the blockage of C5aR1 is effective in preventing and counteracting CIPN [ 73 ]. In that study, C5aR1 was shown to be a molecular target of paclitaxel and involved in the previously reported taxane-induced IL-8 expression, and subsequent activation of CXCR1/2 signaling in neural cells, implicated in the taxane-induced neuropathic pain [ 73 ]. As a result of the urgent need for effective treatments for CIPN, a targeted pharmacological approach based on C5aR inhibition could represent an innovative and valuable approach to improve health and quality of life in patients with cancer undergoing taxane therapy [ 161 ].…”

Therapeutics for Chemotherapy-Induced Peripheral Neuropathy: Approaches with Natural Compounds from Traditional Eastern Medicine

“…Chemotherapeutic agents also induce abnormal sensory signals and amplify pain through their action on ion channels in the cellular membrane [ 21 , 33 , 34 ]. These phenomena are mediated by activation of TRP (transient receptor potential) channels [ 33 , 35 ], voltage-dependent sodium channels [ 34 ], toll-like receptors [ 36 ], and/or other various receptors that indirectly affect ion channels [ 35 , 37 , 38 ]. The activation of ion channels in the primary afferent fibers also evokes nerve signals similar to the activation of nociceptors in the periphery endings.…”