Pathomechanisms of Paclitaxel-Induced Peripheral Neuropathy

Ines Klein, Helmar C Lehmann, Ines Klein, Helmar C Lehmann

Abstract

Peripheral neuropathy is one of the most common side effects of chemotherapy, affecting up to 60% of all cancer patients receiving chemotherapy. Moreover, paclitaxel induces neuropathy in up to 97% of all gynecological and urological cancer patients. In cancer cells, paclitaxel induces cell death via microtubule stabilization interrupting cell mitosis. However, paclitaxel also affects cells of the central and peripheral nervous system. The main symptoms are pain and numbness in hands and feet due to paclitaxel accumulation in the dorsal root ganglia. This review describes in detail the pathomechanisms of paclitaxel in the peripheral nervous system. Symptoms occur due to a length-dependent axonal sensory neuropathy, where axons are symmetrically damaged and die back. Due to microtubule stabilization, axonal transport is disrupted, leading to ATP undersupply and oxidative stress. Moreover, mitochondria morphology is altered during paclitaxel treatment. A key player in pain sensation and axonal damage is the paclitaxel-induced inflammation in the spinal cord as well as the dorsal root ganglia. An increased expression of chemokines and cytokines such as IL-1β, IL-8, and TNF-α, but also CXCR4, RAGE, CXCL1, CXCL12, CX3CL1, and C3 promote glial activation and accumulation, and pain sensation. These findings are further elucidated in this review.

Keywords: CIPN; neuropathy; neurotoxicity; paclitaxel; paclitaxel-induced peripheral neuropathy; taxol.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Paclitaxel enhances microtubule stability. Under physiological conditions, guanosine triphosphate (GTP)-bound tubulin dimers get incorporated at the growing end of the microtubules. This structure is supposed to form a stabilizing cap of GTP-bound tubulin. The conformation change in tubulin dimers is due to the GTP getting hydrolyzed into guanosine diphosphate (GDP), and this destabilizes the microtubule lattice. Through the loss of the GTP-tubulin cap, the microtubules are getting depolymerized. This process of microtubule depolymerization gets prevented by paclitaxel binding to β-tubulin (pathological condition). Created with BioRender.com (accessed on 20 September 2021).
Figure 2
Figure 2
Pathomechanisms of paclitaxel-induced peripheral neuropathy in the peripheral nervous system. ATP—adenosine triphosphate, C3—complement component 3, CD11b—cluster of differentiation 11B, CD163—cluster of differentiation 163, CX3CL1—C-X3-C motif ligand 1, CXCL1—C-X-C motif chemokine ligand 1, CXCL12—C-X-C motif chemokine ligand 12, CXCR4—as C-X-C chemokine receptor type 4, GSH—glutathione, IL—interleukin, JNK—c-Jun N-terminal kinase, MCP-1—monocyte chemoattractant protein 1, MMP—matrix-metalloproteinase, RAGE—receptor for advanced glycation end products, ROS—reactive oxygen species, SGC—satellite glial cell, TNF-α—tumor necrosis factor; Created with BioRender.com (accessed on 20 September 2021).
Figure 3
Figure 3
Pathomechanisms of paclitaxel-induced peripheral neuropathy in the spinal cord. CB2—cannabinoid receptor type, CCL2—C-C motif ligand 2, CX3CL1—C-X3-C motif ligand 1, GFAP—glial fibrillary acidic protein, Iba1—ionized calcium-binding adapter molecule 1, IL—interleukin, NF-κB—nuclear factor kappa B, TNF-α—tumor necrosis factor; Created with BioRender.com (accessed on 20 September 2021).

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