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Preclinical and Clinical Evidence of Therapeutic Agents for Paclitaxel-Induced Peripheral Neuropathy

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Preclinical and Clinical Evidence of Therapeutic Agents for Paclitaxel-Induced Peripheral Neuropathy International Journal of Molecular Sciences Review Preclinical and Clinical Evidence of Therapeutic Agents for Paclitaxel-Induced Peripheral Neuropathy Takehiro Kawashiri 1,* , Mizuki Inoue 1, Kohei Mori 1, Daisuke Kobayashi 1, Keisuke Mine 1, Soichiro Ushio 2, Hibiki Kudamatsu 1, Mayako Uchida 3 , Nobuaki Egashira 4 and Takao Shimazoe 1 1 Department of Clinical Pharmacy and Pharmaceutical Care, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan; [email protected] (M.I.); [email protected] (K.M.); [email protected] (D.K.); [email protected] (K.M.); [email protected] (H.K.); [email protected] (T.S.) 2 Department of Pharmacy, Okayama University Hospital, Okayama 700-8558, Japan; [email protected] 3 Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Doshisha Women’s College of Liberal Arts, Kyoto 610-0395, Japan; [email protected] 4 Department of Pharmacy, Kyushu University Hospital, Fukuoka 812-8582, Japan; [email protected] * Correspondence: [email protected]; Tel.: +81-92-642-6573 Abstract: Paclitaxel is an essential drug in the chemotherapy of ovarian, non-small cell lung, breast, gastric, endometrial, and pancreatic cancers. However, it frequently causes peripheral neuropathy as a dose-limiting factor. Animal models of paclitaxel-induced peripheral neuropathy (PIPN) have been established. The mechanisms of PIPN development have been elucidated, and many drugs and agents have been proven to have neuroprotective effects in basic studies. In addition, some of these Citation: Kawashiri, T.; Inoue, M.; drugs have been validated in clinical studies for their inhibitory PIPN effects. This review summarizes Mori, K.; Kobayashi, D.; Mine, K.; the basic and clinical evidence for therapeutic or prophylactic effects for PIPN. In pre-clinical research, Ushio, S.; Kudamatsu, H.; Uchida, M.; Egashira, N.; Shimazoe, T. Preclinical many reports exist of neuropathy inhibitors that target oxidative stress, inflammatory response, ion and Clinical Evidence of Therapeutic channels, transient receptor potential (TRP) channels, cannabinoid receptors, and the monoamine Agents for Paclitaxel-Induced nervous system. Alternatively, very few drugs have demonstrated PIPN efficacy in clinical trials. Peripheral Neuropathy. Int. J. Mol. Thus, enhancing translational research to translate pre-clinical research into clinical research is Sci. 2021, 22, 8733. https://doi.org/ important. 10.3390/ijms22168733 Keywords: paclitaxel; peripheral neuropathy; preclinical data; clinical evidence; adverse effects Academic Editor: Girolamo Ranieri Received: 5 July 2021 Accepted: 11 August 2021 1. Introduction Published: 13 August 2021 Paclitaxel and albumin-bound paclitaxel are important drugs in the treatment of ovarian [1,2], non-small cell lung [3,4], breast [5–7], gastric [8,9], endometrial [10], and Publisher’s Note: MDPI stays neutral pancreatic [11] cancers. However, they cause peripheral neuropathy as an adverse event. with regard to jurisdictional claims in published maps and institutional affil- In paclitaxel-induced peripheral neuropathy (PIPN), many patients develop sensory ab- iations. normalities (e.g., numbness, pain, and burning sensation in the hands and feet) [12]. PIPN is a dose-limiting factor that causes difficulty in continuing cancer chemotherapy [13]. However, no evidence-based prophylactic agents for PIPN were noted [14]. Since the late 1990s, many studies on the mechanism and therapeutic or prophylactic agents using PIPN animal models have been reported [15–17]. In addition, the mechanisms of PIPN Copyright: © 2021 by the authors. development have been gradually clarified [18]. This study reviewed the preclinical and Licensee MDPI, Basel, Switzerland. clinical evidence of therapeutic or prophylactic agents for PIPN. This article is an open access article distributed under the terms and 2. Methods conditions of the Creative Commons 2.1. Preclinical Evidence Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ All articles found in PubMed with the search term “paclitaxel neuropathy or paclitaxel 4.0/). neurotoxicity” were surveyed. The last search date was 30 April 2021. Clinical studies and Int. J. Mol. Sci. 2021, 22, 8733. https://doi.org/10.3390/ijms22168733 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, 8733 2 of 29 reports that did not include information on therapeutic agents were excluded from the analysis. Articles referring to the effects of local rather than systemic administration and articles published before 2015 were also excluded. Information on the name and dosage of the drugs that showed statistically significant improvement, mechanism of action, and the animal species in which they were used were extracted in the surveyed papers. 2.2. Clinical Evidence The articles found in PubMed with the search term “paclitaxel neuropathy or pacli- taxel neurotoxicity” limited to “Randomized Controlled Trial” and “Meta-Analysis” were analyzed. The last search date was 30 April 2021. Reports other than trials about peripheral neuropathy were excluded. Moreover, information such as the investigational drug and its dosage, chemotherapy received by the patient, study design, number of patients, and results were collected. 3. Results 3.1. Therapeutic Agents in Preclinical Evidence In PubMed, 2667 articles were found when using the search term “paclitaxel neuropa- thy or paclitaxel neurotoxicity”. Of these, 150 articles reported on drugs that inhibit PIPN in animal studies. The following is a summary of the drugs that had therapeutic PIPN effects in these basic studies (Table1). Int. J. Mol. Sci. 2021, 22, 8733 3 of 29 Table 1. The therapeutic agents for paclitaxel-induced peripheral neuropathy in preclinical experiments. Therapeutic Targets Therapeutic Agents Dose Animals Symptoms that Showed Improvement Mechanisms References Anakinra, IL-1β Reductions of MDA, MPO and IL-1β 50–100 mg/kg, i.p. Rats Pain threshold [19] antagonist and increase in GSH in paws Antimycin A 0.2–0.6 mg/kg, i.p. Rats Mechanical hypersensitivity Inhibition of mitochondrial complex III [20] Reduction of NF-κB, TNF-α, IL-6, iNOS Histological changes in spinal cord and and GFAP, p53, caspase-3, Apaf-1, Curcumin 100–200 mg/kg, p.o. Rats [21] sciatic nerve LC3A, LC3B and beclin-1, and increase in Nrf2, HO-1, NQO1, Bcl-2, and Bcl-xL. Divya-Peedantak- Thermal hyperalgesia, mechanical Suppression of oxidative stress and Kwath, a herbal 69–615 mg/kg, p.o. Mice allodynia and hyperalgesia, and axonal [22] inflammation decoction degeneration Inhibiting PARP and p53 activation and Mechanical hyperalgesia and thermal Duloxetine 10–30 mg/kg, i.p. Mice regulating Bcl-2 family to reverse [23] nociception Oxidative stress and oxidative stress and apoptosis mitochondrial Downregulation of inflammatory and disfunction Mechanical hypersensitivity and chemoattractant cytokines (IL-1β, IL-6, Evodiamine 5 mg/kg Rats [24] thermal hypersensitivity TNF-α, and MCP-1), oxidative stress, and mitochondrial dysfunction in DRG. Tactile allodynia, cold allodynia and Inhibitions of TNF-α, IL-1β and free Flavonol 25–200 mg/kg, s.c. Mice [25] thermal hyperalgesia radicals Mechanical sensitivity, thermal Decreases in plasma oxidative and Ghrelin 300 nmol/kg, i.p. Mice sensitivity, DRG damage (ATF-3 nitrosative stress and increases in UCP2, [26] positive cells), and density of IENF SOD2, and PGC-1α Decreases of proinflammatory GKT137831, a NOX4 Mechanical sensitivity and thermal 1 mg/kg, i.p. Rats cytokines (IL-1β, IL-6, and TNF-α) in [27] inhibitor sensitivity the DRG Upregulation of total antioxidant capacity and NGF, and downregulation Thermal hyperalgesia and cold Lacosamide 30 mg/kg, p.o. Rats of NF-kB p65, TNF-α, active caspase-3, [28] allodynia Notch1 receptor, p-p38, and IL-6/p-JAK2/p-STAT3 Melatonin 5–50 mg/kg, p.o. Rats Mechanical sensitivity Reduction of mitochondrial damage [29] Int. J. Mol. Sci. 2021, 22, 8733 4 of 29 Table 1. Cont. Therapeutic Targets Therapeutic Agents Dose Animals Symptoms that Showed Improvement Mechanisms References Nicotinamide riboside 200 mg/kg, p.o. Rats Tactile hypersensitivity N.A. [30] Phenyl-N-tert- 100 mg/kg, i.p. Mice Mechanical hypersensitivity N.A. [31] butylnitrone Upregulation of total antioxidant capacity and NGF, and downregulation Thermal hyperalgesia and cold Pregabalin 30 mg/kg, p.o. Rats of NF-kB p65, TNF-α, active caspase-3, [28] allodynia Notch1 receptor, p-p38, and IL-6/p-JAK2/p-STAT3 Thermal hyperalgesia, cold Downregulations of IL-1β, oxidative Rosuvastatin 10 mg/kg, i.p. Mice [32] hyperalgesia, and mechanical allodynia stress Rotenone 1–5 mg/kg, i.p. Rats Mechanical hypersensitivity Inhibition of mitochondrial complex I [20] Decreases of proinflammatory Tempol, a mimetic of Mechanical sensitivity and thermal 20 mg/kg, i.p. Rats cytokines such as IL-1β, IL-6 and [27] SOD sensitivity TNF-α in the DRG Tactile allodynia, cold allodynia, and Inhibitions of TNF-α, IL-1β and free Trimethoxy flavones 25–200 mg/kg, s.c. Mice [33] thermal hyperalgesia radicals Umbelliprenin, a Decrease in serum IL-6 levels and 12.5–25 mg/kg, i.p. Mice Thermal hyperalgesia [34] prenylated coumarin oxidative stress Decreases of proinflammatory Mechanical sensitivity and thermal Vitamin C 500 mg/kg, i.p. Rats cytokines (IL-1β, IL-6 and TNF-α) in [27] sensitivity the DRG Suppressions of TNF-α, IL-1β, IL-6, Tactile allodynia, cold allodynia, CGRP, and substance P in the spinal 3-Hydroxyflavone 25–75 mg/kg, i.p. Rats thermal hyperalgesia, and [35] cord, and inhibition of the receptor of heat-hyperalgesia substance P AMD3100, a CXCR4 8 mg/kg, i.p. Mice Mechanical allodynia N.A. [36] antagonist Anakinra, IL-1β Reductions of MDA, MPO and IL-1β 50–100 mg/kg, i.p. Rats Pain threshold [19] antagonist and increase in GSH in paws Inflammatory Int. J. Mol. Sci. 2021, 22, 8733 5 of 29 Table 1. Cont. Therapeutic Targets Therapeutic Agents Dose Animals Symptoms that Showed Improvement Mechanisms References Anti-HMGB1- neutralizing 1 mg/kg, i.p.
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