Mechanisms of Paclitaxel-induced peripheral neuropathy

Abstract

Peripheral neuropathy is a common adverse effect associated with the use of a group of chemotherapeutic agents including paclitaxel (PTX) which negatively affect the quality of life of cancer survivors. In addition, it is considered as a dose-limiting side effect that hinder completion of appropriate chemotherapy regimen. In spite of 27 years of research in mechanisms of PTX neuropathy, there is no approved therapy for prevention of PTX-induced peripheral neuropathy (PIPN). Thus, there is a continuous need to characterize the possible mechanisms associates with PIPN in order to find appropriate targeted therapy for this clinical problem. In this review, most of the recent findings of the cellular targets implicated in PIPN are summarized.

Peripheral mu-opioid receptor activation by dermorphin [D-Arg2, Lys4] (1–4) amide alleviates behavioral and neurobiological aberrations in rat model of chemotherapy-induced neuropathic pain

“…Calcium-sensitive TRP channels plays an pivotal role in modulating the heightened sensitivity to mechanical and cold stimuli in patients suffering from CINP. Our findings are consistent with previous reports suggesting the involvement of different TRP channels in the pathophysiology of CINP, reinforcing their significance in chemotherapy pain [ 29 , 44 ].…”

Time- and Concentration-Dependent Adverse Effects of Paclitaxel on Non-Neuronal Cells in Rat Primary Dorsal Root Ganglia

“…These effects were attributed to paclitaxel’s fast and strong mechanism of action on primary DRG non-neuronal cells, as these cells are non-transformed and proliferating cells. Therefore, paclitaxel selectively induces the death of transformed cells, possibly by arresting the cell cycle at G1 as well as G2/M phases [ 54 , 55 , 56 , 57 , 58 ].…”

“…The authors postulated a paclitaxel stabilizing effect on microtubules by binding to beta-tubulin units, which disrupts microtubule dynamics [ 58 ]. As a result, mitosis was arrested between metaphase and anaphase (G2/M phase), suggesting a mitotic block and proliferation inhibition [ 57 , 58 , 59 ].…”

“…Considerably, low concentrations of paclitaxel showed no effect on the overall architecture of the microtubule cytoskeleton (Jordan et al, 1993), as noticed with 0.01 µM paclitaxel in the current study. In contrast, higher doses of paclitaxel were found to cause massive microtubule damage [59,71,72] and activate kinase pathways such as JNK/SAPK and p34 (cdc2) pathways [73][74][75][76], all of which are associated with paclitaxelinduced apoptosis [57]. It is important to note that apoptosis induced by these pathways is not dependent on mitotic arrest at higher concentrations, suggesting that it may occur in cells at any phase of the cell cycle [55].…”

SAFit2 ameliorates paclitaxel-induced neuropathic pain by reducing spinal gliosis and elevating pro-resolving lipid mediators

“…Paclitaxel is a chemotherapeutic agent, which is used for the treatment of malignancies as it stabilizes microtubule formation and thereby disrupts cell proliferation and cytoskeleton related cellular functions [ 1 , 2 ]. Based on this mechanism of action, paclitaxel became a very important cytostatic, which enables the treatment of many different tumor types.…”