Perturbations in neuroinflammatory pathways are associated with paclitaxel-induced peripheral neuropathy in breast cancer survivors

Miaskowski, Christine; Topp, Kimberly; Conley, Yvette P.; Paul, Steven M.; Melisko, Michelle; Schumacher, Mark; Chesney, Margaret A.; Abrams, Gary; Levine, Jon D.; Kober, Kord M.

doi:10.1016/j.jneuroim.2019.577019

Cited by 10 publications

(11 citation statements)

References 86 publications

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“…Other risk factors included higher pro-in ammatory IL-1β (for numbness and tingling), pro-in ammatory IL-8 (for numbness/tingling), and lower IL-6 (for hot/coldness), which has both pro-and anti-in ammatory properties [51]. Our results are consistent with several prior studies: (1) one suggesting that blocking IL-1β signaling reduced CIPN symptoms in rats who received paclitaxel [52]; (2) a correlational study in humans suggesting that a single IL-1β polymorphism is a risk factor for CIPN [53]; and (3) a case-control study in humans suggesting perturbed gene expression in neuroin ammatory pathways in breast cancer survivors with CIPN vs. those without CIPN [54]. Our observations lend support and add speci city to theories that in ammation is involved in the etiology of CIPN in humans [26-28, 55], and can help advance and inform anti-in ammatory treatments for CIPN [56,57].…”

Section: Discussionsupporting

confidence: 91%

Longitudinal Study of Inflammatory, Behavioral, Clinical and Psychosocial Risk Factors for Chemotherapy-Induced Peripheral Neuropath

Kleckner

Jusko

Culakova

et al. 2021

Preprint

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Purpose. Chemotherapy-induced peripheral neuropathy (CIPN) is a common dose-limiting side effect of taxane and platinum chemotherapy for breast cancer. Clinicians cannot accurately predict CIPN severity partly because its pathophysiology is poorly understood. Although inflammation may play a role in CIPN, there are limited human studies. Here, we identified the strongest predictors of CIPN using variables measured before taxane- or platinum-based chemotherapy, including serum inflammatory markers.Methods. 116 sedentary women with breast cancer (mean age 55 years) rated (1) numbness and tingling and (2) hot/coldness in hands/feet on 0-10 scales before and after six weeks of taxane- or platinum-based chemotherapy. A sub-study was added to collect cytokine data in the final 55 patients. We examined all linear models to predict CIPN severity at 6 weeks using pre-chemotherapy assessments of inflammatory, behavioral, clinical, and psychosocial factors. The final model was selected via goodness of fit.Results. The strongest pre-chemotherapy predictors of numbness and tingling were worse fatigue/anxiety/depression (explaining 27% of variance), older age (9%), and baseline neuropathy (5%). The strongest predictors of hot/coldness in hands/feet were worse baseline neuropathy (11%) and fatigue/anxiety/depression (6%). Inflammation was a risk for CIPN, per more pro-inflammatory IL-1β (6%) predicting numbness/tingling and less anti-inflammatory IL-10 predicting numbness and tingling (6%) and hot/coldness in hands/feet (9%).Conclusions. The strongest pre-chemotherapy predictors of CIPN included worse fatigue/anxiety/depression and baseline neuropathy. A pro-inflammatory state also predicted CIPN. Because this is an exploratory study, these results suggest specific outcomes (e.g., IL-1β) and effect size estimates for designing replication and extension studies.Trial Registration. NCT00924651

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Section: Discussionsupporting

confidence: 91%

Longitudinal Study of Inflammatory, Behavioral, Clinical and Psychosocial Risk Factors for Chemotherapy-Induced Peripheral Neuropath

Kleckner

Jusko

Culakova

et al. 2021

Preprint

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“…An elegant study investigated the differential gene expression in breast cancer survivors, with and without neuropathy symptoms. Several neuroinflammatory pathways were found to be significantly perturbed in patients with neuropathic pain, including cytokines and their receptors, besides NF‐κB‐related signalling pathways (Miaskowski et al, 2019). Conversely, in a proteomic study carried out to identify potential biomarkers from serum exosomes, individuals with a low inflammatory response preceding the chemotherapy with taxanes presented a higher susceptibility to develop peripheral neuropathy.…”

Section: Taxane‐induced Peripheral Neuropathymentioning

confidence: 99%

Taxane‐induced neurotoxicity: Pathophysiology and therapeutic perspectives

Costa

Passos

Quintão

et al. 2020

British J Pharmacology

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Taxane-derived drugs are antineoplastic agents used for the treatment of highly common malignancies. Paclitaxel and docetaxel are the most commonly used taxanes; however, other drugs and formulations have been used, such as cabazitaxel and nabpaclitaxel. Taxane treatment is associated with neurotoxicity, a well-known and relevant side effect, very prevalent amongst patients undergoing chemotherapy. Painful peripheral neuropathy is the most dose-limiting side effect of taxanes, affecting up to 97% of paclitaxel-treated patients. Central neurotoxicity is an emerging side effect of taxanes and it is characterized by cognitive impairment and encephalopathy. Besides impairing compliance to chemotherapy treatment, taxane-induced neurotoxicity (TIN) can adversely affect the patient's life quality on a long-term basis. Despite the clinical relevance, not many reviews have comprehensively addressed taxaneinduced neurotoxicity when they are used therapeutically. This article provides an up-to-date review on the pathophysiology of TIN and the novel potential therapies to prevent or treat this side effect. Abbreviations: Ca v , voltage-gated calcium; CB 1 , cannabinoid receptor 1; CB 2 , cannabinoid receptor 2; CCL2, chemokine (C-C motif) ligand 2; CCR2, CC motif chemokine receptor 2; CIPN, chemotherapy-induced peripheral neuropathy; CREB, cAMP response element-binding; CX3CL1, C-X3-C motif chemokine ligand 1; CXCL1, C-X3-C motif chemokine ligand 1; CXCL12, C-X-C motif chemokine ligand 12; CXCR1, C-X-C motif chemokine receptor 1; CXCR2, C-X-C motif chemokine receptor 2; DRG, dorsal root ganglion; GHS-R, growth hormone secretagogue receptor; IENFs, intra-epidermal nerve fibres; K ATP , ATP-sensitive potassium channel; K v , voltage-gated potassium channel; mPTP, mitochondrial permeability transition pore; Na v , voltage-gated sodium channel; Nrf2, nuclear factor-2 erythroid-related factor-2; PIPN, paclitaxel-induced peripheral neuropathy; TICN, taxane-induced central neurotoxicity; TIN, taxane-induced neurotoxicity; TIPN, taxane-induced peripheral neuropathy; TLR4, toll-like receptor-4; TRPA1, transient receptor potential cation channel subfamily A member 1; TRPV1, transient receptor potential cation channel subfamily V member 1; TRPV4, transient receptor potential cation channel subfamily V member 4.

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“…Normally, microtubules undergo a process of dynamic instability, which is characterized by depolymerization and repolymerization phenomena. Taxanes exert their toxic activity binding the heterodimer β-tubulin, stabilizing the microtubules thus leading to the arrest of the cell cycle ( 93 , 94 ).…”

Section: Introductionmentioning

confidence: 99%

Neuroinflammatory Process Involved in Different Preclinical Models of Chemotherapy-Induced Peripheral Neuropathy

et al. 2021

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Peripheral neuropathies are characterized by nerves damage and axonal loss, and they could be classified in hereditary or acquired forms. Acquired peripheral neuropathies are associated with several causes, including toxic agent exposure, among which the antineoplastic compounds are responsible for the so called Chemotherapy-Induced Peripheral Neuropathy (CIPN). Several clinical features are related to the use of anticancer drugs which exert their action by affecting different mechanisms and structures of the peripheral nervous system: the axons (axonopathy) or the dorsal root ganglia (DRG) neurons cell body (neuronopathy/ganglionopathy). In addition, antineoplastic treatments may affect the blood brain barrier integrity, leading to cognitive impairment that may be severe and long-lasting. CIPN may affect patient quality of life leading to modification or discontinuation of the anticancer therapy. Although the mechanisms of the damage are not completely understood, several hypotheses have been proposed, among which neuroinflammation is now emerging to be relevant in CIPN pathophysiology. In this review, we consider different aspects of neuro-immune interactions in several CIPN preclinical studies which suggest a critical connection between chemotherapeutic agents and neurotoxicity. The features of the neuroinflammatory processes may be different depending on the type of drug (platinum derivatives, taxanes, vinca alkaloids and proteasome inhibitors). In particular, recent studies have demonstrated an involvement of the immune response (both innate and adaptive) and the stimulation and secretion of mediators (cytokines and chemokines) that may be responsible for the painful symptoms, whereas glial cells such as satellite and Schwann cells might contribute to the maintenance of the neuroinflammatory process in DRG and axons respectively. Moreover, neuroinflammatory components have also been shown in the spinal cord with microglia and astrocytes playing an important role in CIPN development. Taking together, better understanding of these aspects would permit the development of possible strategies in order to improve the management of CIPN.

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Perturbations in neuroinflammatory pathways are associated with paclitaxel-induced peripheral neuropathy in breast cancer survivors

Cited by 10 publications

References 86 publications

Longitudinal Study of Inflammatory, Behavioral, Clinical and Psychosocial Risk Factors for Chemotherapy-Induced Peripheral Neuropath

Longitudinal Study of Inflammatory, Behavioral, Clinical and Psychosocial Risk Factors for Chemotherapy-Induced Peripheral Neuropath

Taxane‐induced neurotoxicity: Pathophysiology and therapeutic perspectives

Neuroinflammatory Process Involved in Different Preclinical Models of Chemotherapy-Induced Peripheral Neuropathy

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