Taxane‐induced neurotoxicity: Pathophysiology and therapeutic perspectives

Abstract

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.

Development of Newly Synthesized Chromone Derivatives with High Tumor Specificity against Human Oral Squamous Cell Carcinoma

“…However, many reports, including ours, demonstrated that microtubule-targeted agents have potent neurotoxicity, adversely affecting the quality of life of patients on a long-term basis [ 61 , 62 , 63 , 64 ]. Iijima et al recently reported that carboplatin (CBDCA) was highly neurotoxic (TS N = 0.11 (3.2/27.9)), calculated using the data of Table 2 in Ref.…”

Transcriptome profiling of long noncoding RNAs and mRNAs in spinal cord of a rat model of paclitaxel-induced peripheral neuropathy identifies potential mechanisms mediating neuroinflammation and pain

“…The neuropathic pain symptoms of PIPN occur among 50–100% of patients receiving chemotherapy, depending on the doses [ 6 , 7 ]. The painful peripheral neuropathy is the most dose-limiting side effect of taxanes [ 8 ]. The sensory abnormalities and pain can even become chronic and persist after paclitaxel treatment is terminated, which severely affect the life quality of the patients [ 9 ].…”

Antitumor Effects and Tumor-specificity of Guaiazulene-3-Carboxylate Derivatives Against Oral Squamous Cell Carcinoma In Vitro

“…We have recently reported that several G 2 /M blockers such as taxanes paclitaxel [Taxol ® , the first microtubule stabilizing agent (24)] and docetaxel (25), and 3-styrylchromone derivatives [7-methoxy-3-[(1E)-2-phenylethenyl]-4H-1benzopyran-4-one, 3-[(1E)-2-(4-hydroxyphenyl)ethenyl]-7methoxy-4H-1-benzopyran-4-one] show very high TS values (>7267, >86122, 301 and 182, respectively) (26). However, many reports, including ours, demonstrated that microtubuletargeted agents have potent neurotoxicity, adversely affecting the quality of life of patients on a long-term basis (27)(28)(29)(30). We have also reported that doxorubicin induced very potent keratinocyte toxicity by inducing apoptosis, characterized by the loss of cell surface microvilli, chromatin condensation, nuclear fragmentation and caspase-3 activation (31).…”