Beyond Symptomatic Relief for Chemotherapy-Induced Peripheral Neuropathy: Targeting the Source

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) is a serious adverse side effect of many chemotherapeutic agents, affecting more than 60% of cancer patients. Moreover, CIPN persists long into survivorship in 20%‒30% of these patients. No drugs have been approved by the US Food and Drug Administration (FDA) to effectively manage chemotherapy-induced neuropathic pain. Most of the drugs tested for managing CIPN aim at symptom relief, including pain and paresthesia, yet are not very efficacious.

We propose that there is a need to acquire a more thorough understanding of the etiology of CIPN so that effective, mechanism-based, disease-modifying interventions can be developed. Importantly, such interventions should not interfere with the antitumor effects of chemotherapy.

Mitochondria are rod-shaped cellular organelles that represent the powerhouses of the cell, in that they convert oxygen and nutrients into the cellular energy “currency” adenosine triphosphate. In addition, mitochondria regulate cell death. Neuronal mitochondrial dysfunction and the associated nitro-oxidative stress represent crucial final common pathways of CIPN. Here we discuss the potential to prevent or reverse CIPN by protecting mitochondria and/or inhibiting nitro-oxidative stress with novel potential drugs, including the mitochondrial protectant pifithrin-μ, histone deacetylase 6 inhibitors, metformin, antioxidants, peroxynitrite decomposition catalysts, and anti-inflammatory mediators including interleukin-10. This review will hopefully contribute to bridging the gap between preclinical research and the development of realistic novel therapeutic strategies to prevent or reverse the devastating neurotoxic effects of chemotherapy on the (peripheral) nervous system.

Introduction

In 2017, an estimated 1.7 million new cases of cancer will be diagnosed in the United States alone. Despite this grim statistic, the numbers of successful cancer treatments and cancer survivors have increased dramatically over the last decade.^{1, 2} Managing cancer-related pain remains challenging, however. Cancer-related pain can be categorized either as pain related to active tumor growth, or as pain resulting from cancer treatment. The latter, when produced by chemotherapeutic agents, often manifests as chemotherapy-induced peripheral neuropathy (CIPN).³

CIPN is one of the most common adverse effects of cancer chemotherapy, affecting more than 60% of patients.³ A high incidence of CIPN is associated with widely used chemotherapeutics, including platinum derivatives (cisplatin, oxaliplatin), taxanes (paclitaxel, docetaxel), vinca alkaloids (vincristine, vinblastine), bortezomib, ixabepilone, and thalidomide.^{4, 5} CIPN symptoms include persistent shooting, stabbing, or burning pain even in the absence of potentially painful stimuli, and loss of sensation or ‘numbness’. These symptoms typically present in a “stocking and glove” distribution, starting in toes and fingers and spreading to legs and arms as the disorder progresses.⁴ CIPN symptoms often cause significant loss of functional abilities; moreover, CIPN represents a therapeutic challenge, given limited treatment options and the poor effectiveness of currently available therapies.^{5, 6} CIPN not only severely affects quality of life, but also frequently leads to chemotherapy dose reductions and even early cessation, thereby hampering treatment effectiveness. Several studies with large subsets of cancer patients have shown that CIPN does not resolve upon treatment completion, but persists long into survivorship.^{3, 7, 8} Therefore, prevention or management of CIPN is key to effective control of cancer and to improvement in quality of life for cancer patients and survivors.

Current clinical strategies for CIPN aim primarily at symptom relief, with a focus on pain. Unfortunately, anticonvulsant and antidepressant drugs, which are first-line treatments for symptomatic relief of neuropathic pain, have limited success⁹; only the serotonin‒norepinephrine reuptake inhibitors duloxetine and venlafaxine have been shown to ameliorate chemotherapy (oxaliplatin or paclitaxel)‐induced neuropathic pain in phase III placebo-controlled randomized clinical trials.^{10, 11} Other agents, including the Ca²⁺ channel blockers gabapentin and pregabalin and the Na⁺ channel blockers carbamazepine and oxcarbazepine, either failed in randomized trials or only showed effectiveness in small, non‒placebo-controlled trials.^12–17 Development of novel treatments to prevent or reverse CIPN is a pressing need that will require in-depth understanding of the underlying mechanisms.

Here, we review current knowledge regarding the pathophysiological mechanisms underlying CIPN, with a focus on mitochondrial dysfunction, nitro-oxidative stress, and neuroinflammation. We also describe potential novel avenues for development of mechanism-based therapeutic strategies for the prevention and treatment of CIPN. A major concern in the development of novel therapeutic strategies is that such agents might interfere with tumor control by the chemotherapeutics. An optimal solution would be to identify agents that protect against CIPN while enhancing tumor control. Therefore, we focus on candidate agents that have the potential to meet both goals.

Targeting Neuronal Mitochondrial Dysfunction

Mitochondria are double-membrane‒bound organelles that function as a cell’s “power plant”, converting nutrients into the cellular energy “currency” adenosine triphosphate (ATP), primarily through oxidative phosphorylation. In neuronal cells, mitochondrial oxidative phosphorylation produces more than 90% of the ATP required for maintaining normal cellular activities. Failure of the mitochondria to synthesize adequate amounts of ATP for high-energy‒requiring neuronal activities such as action potential generation, synaptic transmission, and axonal transport is thought to be one of the prime mechanisms underlying CIPN.^{18, 19}

A wide array of chemotherapeutics that induce CIPN cause mitochondrial dysfunction in peripheral sensory neurons, despite marked differences in the mechanisms via which they exert their antitumor effects. For example, cisplatin and oxaliplatin intercalate mitochondrial DNA, leading to failure in mitochondrial protein synthesis and to mitochondrial dysfunction.²⁰ Paclitaxel induces opening of the mitochondrial permeability transition pore, which evokes mitochondrial membrane depolarization and Ca²⁺ release, resulting in vacuolated mitochondria with compromised functionality.²¹ Vincristine and bortezomib also dysregulate mitochondrial Ca²⁺ signaling, leading to defective energy production.^22–24

Persistent mitochondrial dysfunction generates nitro-oxidative stress (described below), which causes nitro-oxidative damage to mitochondrial DNA and proteins, further aggravating mitochondrial damage and leading to energy deficiency in sensory neurons.²⁵ Consistent with the mitotoxicity theory of CIPN, swollen and vacuolated mitochondria appear in peripheral nerves and dorsal root ganglion (DRG) neuronal cell bodies in rodent models of peripheral neuropathy induced by paclitaxel,^{26, 27} cisplatin,²⁸ oxaliplatin,²⁹ bortezomib,²⁴ or vincristine.²⁴ These abnormalities in mitochondrial morphology are accompanied by deficiencies in mitochondrial bioenergetics in DRG neurons and peripheral nerves in these models of CIPN.^{28, 30–32} More specifically, impairments in mitochondrial basal respiration, maximal respiration capacity, and ATP production are observed.^{28, 30–32}

Chemotherapy-induced mitochondrial dysfunction and the concomitant energy deficits in sensory neurons are thought to lead to failure of these cells to sustain normal cellular activities, and ultimately to the symptoms of CIPN. For example, the formation of intraepidermal nerve fibers (IENFs) requires nerve fibers originating from subepidermal nerve-fiber bundles to traverse the epidermal basal lamina and branch within the epidermis, which is a highly bioenergetically-demanding process.^{19, 30} In CIPN, the lack of sufficient energy supply has been proposed to result in the inability of IENFs to sprout within the epidermis^{19, 30} and thus to loss of IENFs—a clinical diagnostic marker of CIPN.³³ Mitochondrial deficits likely also lead to dysfunction of the Na⁺/K⁺ exchanger, a major energy consumer in neuronal cells.³⁴ Dysfunction of the Na⁺/K⁺ exchanger disrupts the electrochemical gradient across the cellular membrane, thereby facilitating spontaneous discharges in sensory neurons³⁵—another characteristic of CIPN that may well be responsible for the spontaneous shooting and burning pain that many patients report.

Preventing Mitochondrial Damage by Targeting Mitochondrial p53

Given the fundamental role of mitochondrial dysfunction in the peripheral nervous system in the pathogenesis of CIPN, agents that protect mitochondria may represent good candidates for disease prevention.

Mitochondrial translocation of the tumor-suppressor molecule p53 has been identified as an early event leading to mitochondrial abnormalities in models of neurological disorders.^{36, 37} Recent studies indicate that chemotherapeutic agents trigger a similar damage pathway. For example, we showed that cisplatin treatment rapidly increases mitochondrial levels of p53 in DRG neurons, followed by a reduction in mitochondrial membrane potential and ultimately by disruption of mitochondrial integrity and function.²⁸ Interestingly, we found that the mitochondrial protectant pifithrin-μ, which prevents mitochondrial accumulation of p53, also prevented paclitaxel-induced and cisplatin-induced neuropathic pain and sensory loss and averted the loss of IENFs in mouse models of CIPN.^{27, 28} Pifithrin-μ not only prevented CIPN symptoms but also protected against loss of mitochondrial membrane potential, abnormalities in mitochondrial morphology, and functional mitochondrial deficiencies in DRG neurons.^{27, 28} Importantly, because pifithrin-μ targets the p53-mitochondrial pathway without affecting the transcriptional functions of p53,³⁸ it does not negatively affect the tumor-killing effects of chemotherapy.^{27, 37} Rather, in vivo studies have shown that pifithrin-μ can itself exert antitumor effects.³⁹ In vitro, co-administration of pifithrin-μ with paclitaxel or cisplatin enhanced tumor-cell killing.^{27, 40} Taken together, these data suggest that co-administration of pifithrin-μ with chemotherapeutics may represent a promising novel approach to improve cancer treatment while protecting against development of CIPN.^{27, 28}

Preventing or Reversing Neuronal Mitochondrial Abnormalities and CIPN by Inhibiting Histone Deacetylase 6

Pharmacological targeting of histone deacetylase 6 (HDAC6) is another potential therapeutic strategy for CIPN that targets the mitochondrial pathway and has potential antitumor effects.^{30, 41, 42} HDAC6 is a class IIB histone-deacetylase that has limited effect on histones and acts mainly in the cytosol, where it deacetylates tubulin, heat-shock protein 90, and many other substrates. Neuroprotective effects of HDAC6 inhibitors have been demonstrated in models of neurological disorders, including Alzheimer’s disease and Charcot-Marie Tooth disease.^43–45 The neuroprotective effects of HDAC6 inhibitors in these models are associated with improved mitochondrial axonal transport and reduced oxidative damage.^43–45 We recently showed that HDAC6 inhibitors prevent cisplatin-induced deficits in axonal mitochondrial transport in primary cultures of DRG neurons.³⁰ In vivo, co-administration of an HDAC6 inhibitor with cisplatin prevented cisplatin-induced neuropathic pain.

Notably, HDAC6 inhibition also has disease-modifying properties. Administration of the HDAC6 inhibitor ACY-1083 after completion of chemotherapy, when CIPN had fully developed, reversed the mitochondrial bioenergetic deficits in distal peripheral nerves and DRG neurons.³⁰ Consequently, HDAC6 inhibition reversed all symptoms of CIPN, including mechanical allodynia, spontaneous pain, and sensory loss. HDAC6 inhibitors also stimulated the regrowth of IENFs, presumably through promoting the distribution of bioenergetically functional mitochondria to nerve terminals where the energy-consuming processes take place.³⁰ Importantly, both the preventive and restorative effects of HDAC6 inhibition were maintained for months in mice after termination of treatment with the HDAC6 inhibitor, highlighting its disease-modifying effects.³⁰

Because HDAC6 inhibitors are already in clinical trials testing their potential capacity to increase the efficacy of chemotherapy, they are also of interest as treatment for neurotoxic side effects of cancer therapy.^{41, 42} Additional clinical trials that include evaluation of CIPN parameters in patient treated with a combination of HDAC6 inhibitors and paclitaxel or cisplatin as a secondary outcome are also underway (clinicaltrials.gov NCT02632071, NCT02661815, NCT02856568).

Preventing CIPN by Targeting Mitochondrial Pathways with Metformin

Recent preclinical studies suggest that metformin, an FDA-approved drug for glycemic control in patients with type 2 diabetes, alleviates neuropathic and inflammatory pain in various models.⁴⁶ We demonstrated that metformin also prevents cisplatin-induced neuropathic pain, numbness, and loss of IENFs.⁴⁷ Although the exact mechanisms underlying these protective effects need to be delineated, it is likely that metformin acts via modulation of mitochondria-dependent cellular metabolism. Metformin’s beneficial effects on energy metabolism include enhanced activity of carnitine palmitoyltransferase 1, an essential component of mitochondrial fatty acid oxidation.⁴⁸ Metformin also promoted restoration of mitochondrial membrane potential and reversal of mutation-associated alterations in energy metabolism in a model of Parkinson’s disease⁴⁹ and contributed to restoration of cellular energy by activating adenosine monophosphate-activated protein kinase.⁵⁰ Our preliminary data indicate that co-administration of metformin with cisplatin prevents the neuronal mitochondrial dysfunction that results from cisplatin treatment in a mouse model of CIPN. Intriguingly, epidemiological studies also reveal an association between metformin usage and decreased occurrence of cancer,⁵¹ suggesting that metformin may have anticancer effects. In addition, metformin has been shown to promote tumor cell death in vitro.^52–54 Further exploration of metformin as a potential two-pronged approach that targets both tumor growth and CIPN is therefore warranted.

Contribution of NITRO-OXidative Stress to CIPN

Downstream of mitochondrial dysfunction, oxidative stress is another important common pathway that could be targeted to prevent or reverse CIPN. Mitochondria are the most important endogenous source of reactive oxygen species (ROS). Whereas the amount of ROS produced is tightly regulated in intact mitochondria, chemotherapy-induced mitochondrial damage leads to dysregulation of ROS production and the generation of oxidative stress.⁵⁵ The peripheral nervous system is especially susceptible to chemotherapy-induced oxidative damage, due to its high content of phospholipids, mitochondria-rich axoplasm, and weak cellular antioxidant defenses.⁵⁶ Evidence for oxidative modification of lipids and proteins in sciatic nerve and spinal cord have been reported in a rat model of oxaliplatin-induced painful neuropathy.⁵⁷ Increased ROS levels in these tissues were also observed during early development of paclitaxel-induced neuropathic pain.⁵⁸

Nitrosative stress has emerged as an additional strong contributor to chemotherapy-induced neuropathic pain. Nitric oxide rapidly reacts with superoxide to form reactive nitrogen species—mainly peroxynitrite, a highly reactive oxidant under physiological conditions.⁵⁹ Peroxynitrite inactivates mitochondrial manganese superoxide dismutase (MnSOD), the primary antioxidant enzyme that keeps cellular superoxide levels under control, thereby generating a feed-forward loop of nitro-oxidative stress and mitochondrial dysfunction.⁶⁰ CIPN induced by paclitaxel, oxaliplatin, and bortezomib is associated with the nitration and inactivation of MnSOD, accompanied by mitochondrial bioenergetic deficits in peripheral sensory axons.³²

Supporting the pathogenic role of nitro-oxidative stress, experimental strategies targeting ROS and peroxynitrite prevent development of CIPN in various rodent models. For example, antioxidants such as acetyl-L-carnitine and α-lipoic acid prevented mitochondrial damage and development of neuropathic pain in response to paclitaxel, oxaliplatin, and bortezomib.^{24, 61–64} The free-radical scavenger phenyl N-tert-butylnitrone and the superoxide dismutase mimetic Tempol, ameliorated mechanical allodynia in paclitaxel-treated rats.^{65, 66} Mitochondria-targeted antioxidants, such as mitoVitE and melatonin, also attenuated paclitaxel-induced neuropathic pain.^{67, 68} However, despite positive results from preclinical studies, results from clinical studies are less satisfying. Clinical trials using nutraceuticals with antioxidant properties, including vitamin E, acetyl-L-carnitine, glutamine, glutathione, vitamin B6, omega-3 fatty acids, and α-lipoic acid, show controversial results.^{69, 70} For example, acetyl-L-carnitine, despite showing great promise in initial clinical studies,⁷¹ was not effective in later clinical trials and even exacerbated CIPN in some patients.^{72, 73} Likewise, in a recent study of 243 patients treated with α-lipoic acid while receiving platinum chemotherapy, the agent demonstrated no protective effects.⁷⁴ The failure of these antioxidants to alleviate CIPN might be attributed to their rapidly exhausted antioxidant activity. Moreover, most antioxidants that have been tested clinically, had been chosen for their availability and safety profiles, rather than their strong antioxidant properties. An alternative route to external antioxidants supplementation would be to boost endogenous antioxidant responses. The transcription factor peroxisome proliferator-activated receptor γ (PPARγ) has emerged as a central hub in endogenous responses against oxidative stress.⁷⁵ Upregulation of key antioxidant enzymes, including MnSOD and glutathione peroxidase, and enhanced mitochondrial energy metabolism have been observed upon PPARγ activation.^{76, 77} Importantly, neuroprotective effects of PPARγ agonists have been reported in various neurological disorders, including nerve injury-induced neuropathic pain and trigeminal neuropathic pain.^{78, 79} Given that PPARγ agonists including pioglitazone and rosiglitazone are FDA-approved for type 2 diabetes, these agents may be worth investigating for their therapeutic potential in CIPN.

Conversely, therapeutic agents targeting peroxynitrite may be an appealing therapeutic approach. Unlike ROS, whose existence at normal physiological concentrations is necessary for synaptic plasticity and cognitive function,⁸⁰ peroxynitrite has no known beneficial effects. Peroxynitrite decomposition catalysts have been shown to block development of neuropathic pain induced by paclitaxel, oxaliplatin, and bortezomib in rats, through attenuating chemotherapeutic-induced decrease in mitochondrial ATP production.^{32, 81} The protective effects were exerted without compromising the antitumor activity of the chemotherapeutics.^{32, 81}

Contribution of Neuroinflammation to CIPN

Although the widely accepted concept is that chemotherapeutics are immunosuppressive, recent studies have shown that they can actually enhance the immune response to assist T-cell–mediated killing of tumor cells.^{82, 83} In addition, increased levels of circulating pro-inflammatory cytokines have been reported in patients receiving chemotherapy.⁸⁴ It is well known that local or systemic inflammation and the production of pro-inflammatory cytokines can induce pain. Collectively, these findings suggest that neuroinflammation (ie, inflammation in the peripheral or central nervous tissues) is one of the major contributors to CIPN. Neuroinflammation is characterized by infiltration of immune cells, activation of glial cells, and production of inflammatory mediators in the nervous system. Notably, effects from chemotherapeutic drugs on innate and adaptive immune responses, along with glial cell activation, have been reported in rodent studies of CIPN.⁸⁴

In response to chemotherapy-induced damage, intracellular molecules known as damage-associated molecular patterns, such as mitochondrial DNA and high-mobility group box-1, are released and activate the receptor for advanced glycation end product (RAGE) and toll-like receptors (TLRs) on neurons and immune cells infiltrating the DRG, leading to neuroinflammation.^{85, 86} It has been proposed that chemotherapeutics such as paclitaxel may directly activate TLRs. In support of a role for TLRs in CIPN, it has been shown that co-administration of a TLR4 antagonist with paclitaxel prevented development of mechanical allodynia in rats.⁸⁷ Similarly, genetic ablation of either TLR4 or TLR3 protects mice from developing hyperalgesia after cisplatin treatment.⁸⁸ Intriguingly, despite previous studies suggesting that spinal cord TLR4 mediates mechanical hypersensitivity in inflammatory and injury-induced neuropathic pain models only in male mice,⁸⁹ development of (TLR4-dependent) cisplatin-induced mechanical allodynia was observed to be present in both male and female mice.⁹⁰ It is still not clear if such sex dimorphism exists in humans with CIPN.

Chemotherapy-induced infiltration of macrophages into the DRG is mediated via the chemoattractants C-C motif chemokine 2 (CCL2) and C-X3-C motif chemokine ligand 1 (CX3CL1).^{87, 91–93} Infiltrating macrophages produce pro-inflammatory cytokines that can lower the activation threshold of spinal and DRG neurons and lead to hyperexcitability and spontaneous discharges, thereby contributing to pain.^{94, 95} In response to these inflammatory stimuli, glial cells (including Schwann cells and satellite cells in the peripheral nervous system, and astrocytes in the spinal cord) undergo phenotypic changes and secrete more pro-inflammatory cytokines and chemokines, further enhancing neuronal excitability and pain hypersensitivity.^{84, 96, 97} Blockade of pro-inflammatory signaling through interleukin-1 receptor antagonist (IL-1ra) and anti-tumor necrosis factor (TNF)-α have been shown to attenuate CIPN symptoms in rodents.^{96, 98} In addition, depleting macrophages by administration of clodronate, or blocking macrophage infiltration by intrathecal administration of CCL2 or CX3CL1 neutralizing antibody, prevents CIPN in multiple models.^{92, 99}

Minocycline, a broad-spectrum antibiotic that inhibits macrophage/microglia activation and pro-inflammatory cytokine production, prevented oxaliplatin-induced and bortezomib-induced mechanical hyperalgesia in rodents.^{99, 100} A recent pilot clinical study showed significant reductions in the daily average pain score with the use of minocycline, although it did not fully prevent paclitaxel-induced neuropathy.¹⁰¹ Further studies are needed to examine the usefulness and safety of minocycline as a preventive intervention for CIPN.

Pharmacological modulation of pathways that control neuroinflammation can mitigate chemotherapy-induced neuropathic pain. For example, rodent studies have shown that orally available A₃ adenosine receptor (A₃AR) agonists protect against CIPN. These A₃AR agonists also mitigated spinal neuroinflammatory processes, including astrocyte activation and increase of IL-1β and TNF-α, and blocked neuropathic pain caused by paclitaxel, oxaliplatin, and bortezomib without antagonizing their antitumor effects.^{97, 102} Fingolimod, an FDA-approved immunomodulatory drug for treatment of multiple sclerosis, also prevented neuroinflammation and ameliorated neuropathic pain induced by paclitaxel and oxaliplatin without negative impact on their anticancer effects.¹⁰³ This drug targets the sphingosine-1-phosphate receptor, thereby antagonizing chemotherapy-induced activation of nuclear factor-κB (NF-κB) and enhanced formation of pro-inflammatory cytokines.¹⁰³

Contribution of Neuroimmune Pathways to Resolution of CIPN

In contrast to the pain-promoting effects of pro-inflammatory cytokines like TNF-α and IL-1β, evidence suggests that regulatory T cells (Treg) and cytokines like IL-10 are needed to recover from CIPN. For example, reduced numbers of Treg have been reported in models of paclitaxel-induced and oxaliplatin-induced pain.^{104, 105} In this regard, boosting the endogenous anti-inflammatory state might serve as another route to pain resolution in CIPN. Several studies demonstrated that boosting the Treg subpopulation through intrathecal adoptive transfer of Tregs or administration of the Treg-enhancing bee venom-derived phospholipase A₂ reduces chemotherapy-induced neuropathic pain in rodents.^{104, 106} With respect to regulatory cytokines, oxaliplatin-induced mechano-hypersensitivity is associated with reduced levels of the anti-inflammatory cytokines IL-10 and IL-4 in the spinal dorsal horn.¹⁰⁷ Conversely, intrathecal IL-10 gene therapy or intrathecal administration of recombinant IL-10 has been shown to progressively reverse the allodynic state associated with paclitaxel treatment.^{96, 108} In vitro, IL-10 suppressed paclitaxel-induced spontaneous discharges in DRG neurons.¹⁰⁸

Intriguingly, we recently found that spontaneous resolution of CIPN is dependent on endogenous IL-10 signaling; blocking IL-10 signaling by intrathecal administration of a neutralizing antibody delayed recovery from CIPN.¹⁰⁸ Consistently, IL-10‒deficient mice did not recover from CIPN. These findings indicate that IL-10 signaling is part of the natural resolution pathway for CIPN and further underlines the therapeutic potential of IL-10 therapy to reverse CIPN. One concern is that enhancing IL-10 levels might suppress the immune response to the tumor; however, evidence suggests that IL-10 signaling may actually prevent tumor formation and contribute to antitumor effects of CD8⁺ T cells. Specifically, mice deficient in IL-10 signaling develop tumors spontaneously, and treatment with recombinant IL-10 stimulates cytotoxicity of tumor-resident CD8⁺ T cells and promotes long-lasting antitumor immunity.¹⁰⁹ Therefore, reinforcing IL-10 signaling through gene therapy or recombinant IL-10 may also be a promising approach that could simultaneously stimulate antitumor immunity and reverse CIPN.

Conclusions and Future Perspectives

Clinically, various analgesics have been tested in attempt to control neuropathic pain induced by chemotherapy, with only serotonin‒norepinephrine reuptake inhibitors and Ca²⁺ and Na⁺ channel blockers showing limited success.^{10, 11, 13, 15, 16}

Although the exact mechanisms remain elusive, a central role for mitochondrial dysfunction and nitro-oxidative stress in the pathogenesis of CIPN has been identified (Figure 1). Preclinical data show great promise for compounds targeting this pathway, such as pifithrin-μ, HDAC6 inhibitors, and metformin, as well as antioxidants and peroxynitrite decomposition catalysts as prophylactic treatment for CIPN.^{24, 27, 30, 47, 61–68, 110} Of note, HDAC6 inhibitors were effective in both preventing and reversing CIPN,³⁰ with reported synergistic effects on tumor-killing in combination with chemotherapy.^{41, 42} Given these unique features, HDAC6 inhibition may be a preferred treatment option for patients already under chemotherapy. Conversely, “repurposing” metformin has the advantage of utilizing an inexpensive drug with a well-known safety profile to actively prevent CIPN, so long as it is administered before the first chemotherapy treatment. Because metformin is already being tested in clinical trials for potential anticancer effects, rapid evaluation of preventive effects in CIPN should be achievable.¹¹¹ Fingolimod, A₃AR agonists, and minocycline are candidates for targeting the proinflammatory pathways that contribute to CIPN.^{97, 99, 100, 107} IL-10 gene therapy or recombinant IL-10 treatment may represent a more efficacious approach to promote recovery from CIPN in both cancer patients and survivors, because it engages natural pain-resolution pathways and therefore is likely to have true disease-modifying effects.^{96, 108}

Figure 1.

Schematic overview of mechanisms underlying chemotherapy-induced peripheral neuropathy and mechanism-based disease interventions. Abbreviations: ROS, reactive oxygen species; RNS, reactive nitrogen species; CCL2, C-C motif chemokine 2; CX3CL1, C-X3-C Motif Chemokine Ligand 1; SNRIs, serotonin-norepinephrine reuptake inhibitors; IENF, intra-epidermal nerve fiber.

In summary, preclinical studies have identified novel potential targets for mechanism-based preventive and curative interventions for CIPN. Clinical trials are underway to focus not only on symptom relief, but also on mechanism-based preventive and curative interventions.