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Beyond symptomatic relief for chemotherapy-induced peripheral

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Review Article

Beyond Symptomatic Relief for Chemotherapy-Induced

Peripheral Neuropathy: Targeting the Source
Jiacheng Ma, PhD1; Annemieke Kavelaars, PhD1; Patrick M. Dougherty, PhD2; and Cobi J. Heijnen, PhD 1

Chemotherapy-induced peripheral neuropathy (CIPN) is a serious adverse side effect of many chemotherapeutic agents, affecting
>60% of patients with cancer. Moreover, CIPN persists long into survivorship in approximately 20% to 30% of these patients. To the
authors’ knowledge, no drugs have been approved to date by the US Food and Drug Administration to effectively manage
chemotherapy-induced neuropathic pain. The majority of the drugs tested for the management of CIPN aim at symptom relief, includ-
ing pain and paresthesia, yet are not very efficacious. The authors propose that there is a need to acquire a more thorough under-
standing of the etiology of CIPN so that effective, mechanism-based, disease-modifying interventions can be developed. It is
important to note that 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. Herein, the authors discuss the potential to pre-
vent or reverse CIPN by protecting mitochondria and/or inhibiting nitro-oxidative stress with novel potential drugs, including the
mitochondrial protectant pifithrin-l, histone deacetylase 6 inhibitors, metformin, antioxidants, peroxynitrite decomposition catalysts,
and anti-inflammatory mediators including interleukin 10. This review hopefully will contribute toward bridging the gap between pre-
clinical research and the development of realistic novel therapeutic strategies to prevent or reverse the devastating neurotoxic effects
of chemotherapy on the (peripheral) nervous system. Cancer 2018;000:000-000. V C 2018 American Cancer Society.

KEYWORDS: cancer, chemotherapy, chemotherapy-induced peripheral neuropathy (CIPN), intervention, mitochondria, nitro-oxidative,
pain, symptom.

INTRODUCTION
In 2017, it is estimated that 1.7 million new cases of cancer will have been 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 However, managing cancer-related pain remains challenging. 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 chemo-
therapeutic agents, often manifests as chemotherapy-induced peripheral neuropathy (CIPN).3
CIPN is one of the most common adverse effects of cancer chemotherapy, affecting >60% of patients.3 A high inci-
dence 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
the toes and fingers and spreading to the legs and arms as the disorder progresses.4 CIPN symptoms often cause significant
loss of functional abilities; moreover, CIPN represents a therapeutic challenge, given the 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 patients with cancer have shown that CIPN does not resolve at the time of treatment completion, but
persists long into survivorship.3,7,8 Therefore, prevention or management of CIPN is key to the effective control of cancer
and to improvements in quality of life for patients with cancer and cancer survivors.
Current clinical strategies for CIPN aim primarily at symptom relief, with a focus on pain. Unfortunately, anticon-
vulsant and antidepressant drugs, which are first-line treatments for the symptomatic relief of neuropathic pain, have

Corresponding author: Cobi J. Heijnen, PhD, Division of Internal Medicine, Department of Symptom Research, The University of Texas MD Anderson Cancer Cen-
ter, 1515 Holcombe Blvd, Unit 384, Houston, TX 77030; cjheijnen@mdanderson.org
1
Neuroimmunology Laboratory, Department of Symptom Research, The University of Texas MD Anderson Cancer Center, Houston, Texas; 2Department of Pain
Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas

We thank Jeanie F. Woodruff, BS, ELS, for scientific editing.

DOI: 10.1002/cncr.31248, Received: November 17, 2017; Revised: December 21, 2017; Accepted: December 29, 2017, Published online Month 00, 2018 in
Wiley Online Library (wileyonlinelibrary.com)

Cancer Month 00, 2018 1

Review Article
reportedly had only limited success9; only the serotonin-
norepinephrine reuptake inhibitors duloxetine and venlafax-
ine have been shown to ameliorate chemotherapy-induced
(oxaliplatin or paclitaxel) neuropathic pain in phase 3
placebo-controlled randomized clinical trials.10,11 Other
agents, including the Ca21 channel blockers gabapentin and
pregabalin and the Na1 channel blockers carbamazepine
and oxcarbazepine, either failed in randomized trials or
demonstrated effectiveness only in small, non–placebo-
controlled trials.12-17 The development of novel treatments
to prevent or reverse CIPN is a pressing need that will
require an in-depth understanding of the underlying
mechanisms.
Herein, 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 the development of mechanism-based
therapeutic strategies for the prevention and treatment of
CIPN. A major concern in the development of novel ther-
apeutic 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
have focused 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 tri-
phosphate (ATP), primarily through oxidative phosphor-
ylation. In neuronal cells, mitochondrial oxidative
phosphorylation produces >90% of the ATP required for
maintaining normal cellular activities. Failure of the mito-
chondria to synthesize adequate amounts of ATP for neu-
ronal activities that require high energy, 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 chemotherapeutic agents that induce
CIPN cause mitochondrial dysfunction in peripheral sen-
sory neurons, despite marked differences in the mecha-
nisms via which they exert their antitumor effects. For
example, cisplatin and oxaliplatin intercalate mitochon-
drial DNA, leading to failure in mitochondrial protein
synthesis and to mitochondrial dysfunction.20 Paclitaxel
induces opening of the mitochondrial permeability transi-
tion pore, which evokes mitochondrial membrane depo-
larization and Ca21 release, resulting in vacuolated
2 Cancer
mitochondria with compromised functionality.21 Vincris-
tine and bortezomib also dysregulate mitochondrial Ca21
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 pro-
teins, further aggravating mitochondrial damage and lead-
ing to energy deficiency in sensory neurons.25 Consistent
with the mitotoxicity theory of CIPN, swollen and vacuo-
lated mitochondria appear in peripheral nerves and dorsal
root ganglion (DRG) neuronal cell bodies in rodent mod-
els 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 bioenerget-
ics in DRG neurons and peripheral nerves in these models
of CIPN.28,30-32 More specifically, impairments in mito-
chondrial 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 believed to lead to the 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 epi-
dermal basal lamina and branch within the epidermis,
which is a highly bioenergetically demanding process.19,30
In CIPN, the lack of a sufficient energy supply has been
proposed to result in the inability of IENFs to sprout
within the epidermis19,30 and thus to loss of IENFs, a clin-
ical diagnostic marker of CIPN.33 Mitochondrial deficits
also are likely to lead to dysfunction of the Na1 /K1
exchanger, a major energy consumer in neuronal cells.34
Dysfunction of the Na1 /K1 exchanger disrupts the elec-
trochemical gradient across the cellular membrane,
thereby facilitating spontaneous discharges in sensory
neurons,35 which is 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 suppres-
sor molecule p53 has been identified as an early event
leading to mitochondrial abnormalities in models of
Month 00, 2018

neurological disorders.36,37 Recent studies have indicated
that chemotherapeutic agents trigger a similar damage
pathway. For example, we demonstrated that cisplatin
treatment rapidly increases mitochondrial levels of p53 in
DRG neurons, followed by a reduction in mitochondrial
membrane potential and ultimately by the disruption of
mitochondrial integrity and function.28 It is interesting to
note that we found that the mitochondrial protectant
pifithrin-l, 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-l
not only prevented CIPN symptoms but also protected
against loss of mitochondrial membrane potential, abnor-
malities in mitochondrial morphology, and functional
mitochondrial deficiencies in DRG neurons.27,28 It is
important to note that because pifithrin-l targets the
p53-mitochondrial pathway without affecting the tran-
scriptional 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-l can itself exert
antitumor effects.39 In vitro, the coadministration of
pifithrin-l with paclitaxel or cisplatin enhanced tumor
cell killing.27,40 Taken together, these data suggest that
the coadministration of pifithrin-l with chemotherapeu-
tics may represent a promising novel approach with which
to improve cancer treatment while protecting against the
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, in which it deacetylates tubulin,
heat shock protein 90, and many other substrates. The
neuroprotective effects of HDAC6 inhibitors have been
demonstrated in models of neurological disorders, includ-
ing Alzheimer disease and Charcot-Marie-Tooth dis-
ease.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 demonstrated that HDAC6
inhibitors prevent cisplatin-induced deficits in axonal
mitochondrial transport in primary cultures of DRG neu-
rons.30 In vivo, the coadministration of an HDAC6
Cancer Month 00, 2018
Novel Therapeutic Strategies for CIPN/Ma et al
inhibitor with cisplatin prevented cisplatin-induced neu-
ropathic pain.
It is interesting to note that HDAC6 inhibition also
has disease-modifying properties. Administration of the
HDAC6 inhibitor ACY-1083 after the 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 ter-
minals in which the energy-consuming processes take
place.30 It is important to note that both the preventive
and restorative effects of HDAC6 inhibition were main-
tained for months in mice after the termination of treat-
ment with the HDAC6 inhibitor, highlighting its disease-
modifying effects.30
Because HDAC6 inhibitors already are in clinical
trials testing their potential capacity to increase the effi-
cacy of chemotherapy, they also are of interest as treat-
ment of the neurotoxic side effects of cancer therapy.41,42
Additional clinical trials that include the evaluation of
CIPN parameters in patients treated with a combination
of HDAC6 inhibitors and paclitaxel or cisplatin as a sec-
ondary outcome also currently are underway (Clinical-
Trials.gov identifiers NCT02632071, NCT02661815,
and NCT02856568).
Preventing CIPN by targeting mitochondrial
pathways with metformin
Recent preclinical studies have suggested that metformin,
a drug approved by the US Food and Drug Administra-
tion (FDA) 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. Metfor-
min’s beneficial effects on energy metabolism include
enhanced activity of carnitine palmitoyltransferase 1, an
essential component of mitochondrial fatty acid oxida-
tion.48 Metformin also promoted restoration of mito-
chondrial membrane potential and reversal of mutation-
associated alterations in energy metabolism in a model of
Parkinson disease49 and contributed toward the restora-
tion of cellular energy by activating adenosine
3
Review Article
monophosphate-activated protein kinase.50 Our prelimi-
nary data have indicated that the coadministration of met-
formin with cisplatin prevents the neuronal
mitochondrial dysfunction that results from cisplatin
treatment in a mouse model of CIPN. It is interesting to
note that epidemiological studies also have demonstrated
an association between metformin use and a 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 There-
fore, further exploration of metformin as a potential 2-
pronged approach that targets both tumor growth and
CIPN is 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 of the
oxidative modification of lipids and proteins in the sciatic
nerve and spinal cord has been reported in a rat model of
oxaliplatin-induced painful neuropathy.57 Increased ROS
levels in these tissues also were observed during the 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 oxi-
dant under physiological conditions.59 Peroxynitrite inacti-
vates mitochondrial manganese superoxide dismutase
(MnSOD), the primary antioxidant enzyme that keeps cel-
lular superoxide levels under control, thereby generating a
feed-forward loop of nitro-oxidative stress and mitochon-
drial dysfunction.60 CIPN induced by paclitaxel, oxalipla-
tin, 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 peroxy-
nitrite prevent the development of CIPN in various
rodent models. For example, antioxidants such as acetyl-
L-carnitine and a-lipoic acid are reported to have
4 Cancer
prevented mitochondrial damage and the 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
rats treated with paclitaxel.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, gluta-
thione, vitamin B6, omega-3 fatty acids, and a-lipoic
acid, have reported controversial results.69,70 For exam-
ple, acetyl-L-carnitine, despite demonstrating great
promise in initial clinical studies,71 was not found to be
effective in later clinical trials and even exacerbated
CIPN in some patients.72,73 Likewise, in a recent study
of 243 patients treated with a-lipoic acid while receiving
platinum chemotherapy, the agent demonstrated no pro-
tective effects.74 The failure of these antioxidants to alle-
viate CIPN might be attributed to their rapidly
exhausted antioxidant activity. Moreover, the majority of
antioxidants that have been tested clinically were chosen
for their availability and safety profiles rather than their
strong antioxidant properties. An alternative route to
external antioxidant supplementation would be to boost
endogenous antioxidant responses. The transcription fac-
tor peroxisome proliferator-activated receptor c (PPAR-c)
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 at the time of PPAR-c activation.76,77 It is
important to note that the neuroprotective effects of
PPAR-c agonists have been reported in various neurologi-
cal disorders, including nerve injury-induced neuropathic
pain and trigeminal neuropathic pain.78,79 Given that
PPAR-c agonists including pioglitazone and rosiglitazone
are approved by the FDA for type 2 diabetes, these agents
may be worth investigating for their therapeutic potential
in CIPN.
Conversely, therapeutic agents targeting peroxyni-
trite may be an appealing therapeutic approach. Unlike
ROS, whose existence at normal physiological concentra-
tions is necessary for synaptic plasticity and cognitive
function,80 to the best of our knowledge peroxynitrite has
no known beneficial effects. Peroxynitrite decomposition
catalysts have been shown to block the development
of neuropathic pain induced by paclitaxel, oxaliplatin, and
Month 00, 2018

bortezomib in rats, through attenuating chemotherapeutic-
induced decreases in mitochondrial ATP production.32,81
The protective effects were exerted without compromising
the antitumor activity of the chemotherapeutic agents.32,81
Contribution of Neuroinflammation to CIPN
Although the widely accepted concept is that chemothera-
peutics are immunosuppressive, recent studies have shown
that they actually can enhance the immune response to
assist T-cell–mediated killing of tumor cells.82,83 In addi-
tion, increased levels of circulating proinflammatory cyto-
kines have been reported in patients receiving
chemotherapy.84 It is well known that local or systemic
inflammation and the production of proinflammatory
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 character-
ized by infiltration of immune cells, activation of glial
cells, and the production of inflammatory mediators in
the nervous system. It is interesting to note that the 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, intra-
cellular 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 coadministration of a TLR4
antagonist with paclitaxel prevented the development of
mechanical allodynia in rats.87 Similarly, genetic ablation
of either TLR4 or TLR3 is reported to protect mice from
developing hyperalgesia after treatment with cisplatin.88 It
is interesting to note that, despite previous studies sugges-
ting that spinal cord TLR4 mediates mechanical hypersen-
sitivity in inflammatory and injury-induced neuropathic
pain models only in male mice,89 the development of
(TLR4-dependent) cisplatin-induced mechanical allodynia
was observed to be present in both male and female
mice.90 To the best of our knowledge, it remains unclear 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
Cancer Month 00, 2018
Novel Therapeutic Strategies for CIPN/Ma et al
produce proinflammatory cytokines that can lower the acti-
vation threshold of spinal and DRG neurons and lead to
hyperexcitability and spontaneous discharges, thereby con-
tributing 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
proinflammatory cytokines and chemokines, further
enhancing neuronal excitability and pain hypersensitiv-
ity.84,96,97 Blockade of proinflammatory signaling through
interleukin 1 receptor antagonist (IL-1ra) and antitumor
necrosis factor a (TNF-a) have been shown to attenuate
CIPN symptoms in rodents.96,98 In addition, depleting
macrophages through the administration of clodronate, or
blocking macrophage infiltration by the intrathecal admin-
istration of CCL2 or CX3CL1 neutralizing antibody, has
been reported to prevent CIPN in multiple models.92,99
Minocycline, a broad-spectrum antibiotic that
inhibits macrophage/microglia activation and proinflam-
matory cytokine production, prevented oxaliplatin-
induced and bortezomib-induced mechanical hyperalgesia
in rodents.99,100 A recent pilot clinical study demonstrated
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 con-
trol 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 ago-
nists also mitigated spinal neuroinflammatory processes,
including astrocyte activation and increases in IL-1b and
TNF-a, and blocked neuropathic pain caused by pacli-
taxel, oxaliplatin, and bortezomib without antagonizing
their antitumor effects.97,102 Fingolimod, an FDA-
approved immunomodulatory drug for the treatment of
multiple sclerosis, also prevented neuroinflammation and
ameliorated neuropathic pain induced by paclitaxel and
oxaliplatin without having a negative impact on their anti-
cancer effects.103 This drug targets the sphingosine-1-
phosphate receptor, thereby antagonizing chemotherapy-
induced activation of nuclear factor jB (NF-jB) and
enhanced formation of proinflammatory cytokines.103
Contribution of Neuroimmune Pathways Toward
Resolution of CIPN
In contrast to the pain-promoting effects of proinflamma-
tory cytokines such as TNF-a and IL-1b, evidence has
5
Review Article

Figure 1. Schematic overview of mechanisms underlying chemotherapy-induced peripheral neuropathy and mechanism-based
disease interventions. CCL2 indicates C-C motif chemokine 2; CX3CL1, C-X3-C motif chemokine ligand 1; HDAC6, histone deacety-
lase 6; IL-10, interleukin 10; IENF, intraepidermal nerve fiber; RNS, reactive nitrogen species; ROS, reactive oxygen species; SNRIs,
serotonin-norepinephrine reuptake inhibitors.

suggested that regulatory T cells (Tregs) and cytokines
such as IL-10 are needed to recover from CIPN. For
example, reduced numbers of Tregs 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 patients with CIPN. Several studies have
demonstrated that boosting the Treg subpopulation
through the intrathecal adoptive transfer of Tregs or the
administration of the Treg-enhancing bee venom-derived
phospholipase A2 reduces chemotherapy-induced neuro-
pathic pain in rodents.104,106 With respect to regulatory
cytokines, oxaliplatin-induced mechanohypersensitivity 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 the intra-
thecal 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
It is interesting to note that we recently found that
spontaneous resolution of CIPN depends on endogenous
IL-10 signaling; blocking IL-10 signaling through the
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 resolu-
tion pathway for CIPN, and further underscores the ther-
apeutic 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 has
suggested that IL-10 signaling actually may prevent tumor
formation and contribute toward the antitumor effects of
CD81 T cells. Specifically, mice deficient in IL-10 signal-
ing develop tumors spontaneously, and treatment with

6 Cancer Month 00, 2018

 Novel Therapeutic Strategies for CIPN/Ma et al

Figure 2. Site of action of chemotherapeutics and mechanism-based treatments for chemotherapy-induced peripheral neuropa-
thy. CCL2 indicates C-C motif chemokine 2; CX3CL1, C-X3-C motif chemokine ligand 1; DRG, dorsal root ganglion; HDAC6, histone
deacetylase 6; IENF, intraepidermal nerve fiber; IL-1b, interleukin-1 beta; IL-10, interleukin 10; SNRI, serotonin-norepinephrine reup-
take inhibitors; TNF-a, tumor necrosis factor a.

recombinant IL-10 stimulates the cytotoxicity of tumor-
resident CD81 T cells and promotes long-lasting antitu-
mor immunity.109 Therefore, reinforcing IL-10 signaling
through gene therapy or recombinant IL-10 also may be a
promising approach that could simultaneously stimulate
antitumor immunity and reverse CIPN.
Conclusions and Future Perspectives
Clinically, various analgesics have been tested in an
attempt to control neuropathic pain induced by chemo-
therapy, with only serotonin-norepinephrine reuptake
inhibitors and Ca21 and Na1 channel blockers demon-
strating 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 (Fig. 1). Preclinical data have demonstrated
great promise for compounds targeting this pathway, such
as pifithrin-l, HDAC6 inhibitors, and metformin, as
well as antioxidants and peroxynitrite decomposition cata-
lysts as prophylactic treatment of CIPN.24,27,30,47,61-68,110
It is interesting to note that HDAC6 inhibitors were found
to be effective in both preventing and reversing CIPN,30
with reported synergistic effects on tumor killing in combi-
nation with chemotherapy.41,42 Given these unique fea-
tures, HDAC6 inhibition may be a preferred treatment
option for patients already receiving chemotherapy.
Conversely, “repurposing” metformin has the advantage of
using an inexpensive drug with a well-known safety profile
to actively prevent CIPN, provided it is administered
before the first chemotherapy session. Because metformin
already is being tested in clinical trials for potential antican-
cer effects, the rapid evaluation of its preventive effects in
CIPN should be achievable.111 Fingolimod, A3AR
agonists, and minocycline are candidates for targeting
the proinflammatory pathways that contribute to

Cancer Month 00, 2018 7

Review Article
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 patients with cancer
and cancer survivors because it engages natural pain resolu-
tion pathways and therefore is likely to have true disease-
modifying effects.96,108
Preclinical studies have identified novel potential
targets for mechanism-based preventive and curative
interventions for CIPN (Fig. 2). Clinical trials currently
are underway to focus not only on symptom relief, but
also on mechanism-based preventive and curative
interventions.
FUNDING SUPPORT
Supported by National Institutes of Health grants R21CA183736,
R01NS073939, and R01CA208371; Regenacy Pharmaceuticals;
and The University of Texas MD Anderson Cancer Center Knowl-
edge Gap funding.
CONFLICT OF INTEREST DISCLOSURES
Annemieke Kavelaars and Cobi J. Heijnen have received partial
funding from Regenacy Pharmaceuticals for work performed as
part of the current study and have a patent pending (US App. No.
15 of 170,335).
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