Pathogenesis of paclitaxel-induced peripheral neuropathy: A current review of in vitro and in vivo findings using rodent and human model systems

Abstract

Paclitaxel (Brand name Taxol) is widely used in the treatment of common cancers like breast, ovarian and lung cancer. Although highly effective in blocking tumor progression, paclitaxel also causes peripheral neuropathy as a side effect in 60-70% of chemotherapy patients. Recent efforts by numerous labs have aimed at defining the underlying mechanisms of paclitaxel-induced peripheral neuropathy (PIPN). In vitro models using rodent dorsal root ganglion neurons, human induced pluripotent stem cells, and rodent in vivo models have revealed a number of molecular pathways affected by paclitaxel within axons of sensory neurons and within other cell types, such as the immune system and peripheral glia, as well skin. These studies revealed that paclitaxel induces altered calcium signaling, neuropeptide and growth factor release, mitochondrial damage and reactive oxygen species formation, and can activate ion channels that mediate responses to extracellular cues. Recent studies also suggest a role for the matrix-metalloproteinase 13 (MMP-13) in mediating neuropathy. These diverse changes may be secondary to paclitaxelinduced microtubule transport impairment. Human genetic studies, although still limited, also highlight the involvement of cytoskeletal changes in PIPN. Newly identified molecular targets resulting from these studies could provide the basis for the development of therapies with which to either prevent or reverse paclitaxel-induced peripheral neuropathy in chemotherapy patients.

Positive Allosteric Modulation of CB1 Cannabinoid Receptor Signaling Enhances Morphine Antinociception and Attenuates Morphine Tolerance Without Enhancing Morphine- Induced Dependence or Reward

“…Mechanisms underlying the development of paclitaxelinduced neuropathic allodynia remain incompletely understood. Loss of intraepidermal nerve fibers, abnormal mitochondrial function, infiltration of damage-associated molecular patterns and pro-inflammatory cytokine and chemokines within dorsal root ganglia and spinal cord as well as aberrant brain resting state connectivity have all been implicated in contributing to chemotherapy-induced neuropathy produced by paclitaxel (Ferris et al, 2019;Staff et al, 2020).…”

The New Application of Real-time Cell-monitoring Analysis System to Detect Cellular Responses in Human Umbilical Vein Endothelial to Paclitaxel

“…A large number of studies using rodent dorsal root ganglion neurons or in vivo rodent models have been performed to elucidate the mechanisms of angialgia, such as those underlying paclitaxel-induced neuropathic pain. (17,18) However, these mechanisms are likely complex, and a quantitative evaluation of angialgia that represents the degree of pain caused by chemotherapy is difficult using conventional methods. Human evaluation of pain is confounded by the fact that it is a subjective phenomenon.…”

Chemotherapy-induced peripheral neuropathy: part 1—current state of knowledge and perspectives for pharmacotherapy

“…The influence of vincristine on mitochondria is thought to involve altered mitochondrial calcium signaling, and the maintenance of intracellular calcium homeostasis is beneficial for preventing CIPN [51,52]. Paclitaxel does not directly affect mitochondrial DNA but induces swollen and vacuolated mitochondria in both myelinated and unmyelinated sensory axons, and these changes are accompanied by increased production of reactive oxygen species in the nervous system [20,[53][54][55].…”