Abstract
SUMMARY
Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating and painful condition seen in patients undergoing treatment with common agents such as vincristine, paclitaxel, oxaliplatin and bortezomib. The mechanisms of this condition are diverse, and include an array of molecular and cellular contributions. Current research implicates genetic predispositions to this condition, which then may influence cellular responses to chemotherapy. Processes found to be influenced during CIPN include increased expression of inflammatory mediators, primarily cytokines, which can create cascading effects in neurons and glia. Changes in ion channels and neurotransmission, as well as changes in intracellular signaling and structures have been implicated in CIPN. This review explores these issues and suggests considerations for future research.
Papers of special note have been highlighted as: • of interest
References
- 1 Follow-up psychophysical studies in bortezomib-related chemoneuropathy patients. J. Pain 12(9), 1017–1024 (2011).
- 2 Chemotherapy dose reduction due to chemotherapy induced peripheral neuropathy in breast cancer patients receiving chemotherapy in the neoadjuvant or adjuvant settings. a single-center experience. Springerplus 3, 366 (2014).
- 3 Peripheral neurotoxicity of taxol in patients previously treated with cisplatin. Cancer 75, 1141–1150 (1995).
- 4 Characterization and diagnostic evaluation of chronic polyneuropathies induced by oxaliplatin and docetaxel comparing skin biopsy to quantitative sensory testing and nerve conduction studies. Eur. J. Neurol. 21(4), 623–629 (2014).
- 5 Quantitative sensory analysis of peripheral neuropathy produced by colorectal cancer and its exacerbation by cumulative dose of oxaliplatin chemotherapy. Cancer Res. 74(21), 5955–5962 (2014).
- 6 . Long term effects of vincristine on the peripheral nervous system. J. Neuroonocol. 15, 23–27 (1993).
- 7 . Dysfunction in multiple primary afferent fiber subtypes revealed by quantitative sensory testing in patients with chronic vincristine-induced pain. J. Pain Symptom Manage. 33(2), 166–179 (2007).
- 8 . Taxol-induced sensory disturbance is characterized by preferential impairment of myelinated fiber function in cancer patients. Pain 109, 132–142 (2004).
- 9 . Peripheral neuropathies from chemotherapeutics and targeted agents: diagnosis, treatment, and prevention. Neuro Oncol. 14(Suppl. 4), iv45–iv54 (2012).
- 10 Persistent chemoneuropathy in patients receiving the plant alkaloids paclitaxel and vincristine. Cancer Chemother. Pharmacol. 71, 619–626 (2013).
- 11 . Chemotherapy-induced peripheral neuropathy and its association with quality of life: a systematic review. Support. Care Cancer 22(8), 2261–2269 (2014).
- 12 . Chemotherapy-induced peripheral neurotoxicity in the era of pharmacogenomics. Lancet Oncol. 12(12), 1151–1161 (2011).
- 13 Association between glutathione S-transferase P1, T1, and M1 genetic polymorphism and survival of patients with metastatic colorectal cancer. J. Natl Cancer Inst. 94(12), 936–942 (2002).
- 14 Influence of GSTP1 I105V polymorphism on cumulative neuropathy and outcome of FOLFOX-4 treatment in Asian patients with colorectal carcinoma. Cancer Sci. 101(2), 530–535 (2010).
- 15 Associations between glutathione S-transferase pi Ile105Val and glyoxylate aminotransferase Pro11Leu and Ile340Met polymorphisms and early-onset oxaliplatin-induced neuropathy. Cancer Epidemiol. 34(2), 189–193 (2010).
- 16 Polymorphic markers associated with severe oxaliplatin-induced, chronic peripheral neuropathy in colon cancer patients. Cancer 118(11), 2828–2836 (2012).• Reported on single nucleotide polymorphisms that have significant predictive validity for chemotherapy-induced peripheral neuropathy (CIPN) development.
- 17 Sequencing of Charcot-Marie-Tooth disease genes in a toxic polyneuropathy. Ann. Neurol. 76(5), 727–737 (2014).
- 18 . A possible explanation for a neurotoxic effect of the anticancer agent oxaliplatin on neuronal voltage-gated sodium channels. J. Neurophysiol. 85(5), 2293–2297 (2001).
- 19 . Oxaliplatin induces hyperexcitability at motor and autonomic neuromuscular junctions through effects on voltage-gated sodium channels. Br. J. Pharmacol. 146(7), 1027–1039 (2005).
- 20 . Acute abnormalities of sensory nerve function associated with oxaliplatin-induced neurotoxicity. J. Clin. Oncol. 27(8), 1243–1249 (2009).
- 21 . Oxaliplatin-induced neurotoxicity: changes in axonal excitability precede development of neuropathy. Brain 132(Pt 10), 2712–2723 (2009).
- 22 . Clinical management of oxaliplatin-associated neurotoxicity. Clin. Colorectal Cancer (5 Suppl. 1), S38–S46 (2005).
- 23 . Oxaliplatin-induced neurotoxicity: acute hyperexcitability and chronic neuropathy. Muscle Nerve 29(3), 387–392 (2004).
- 24 Cortical effect of oxaliplatin associated with sustained neuropathic pain: exacerbation of cortical activity and down-regulation of potassium channel expression in somatosensory cortex. Pain 153(8), 1636–1647 (2012).
- 25 Oxaliplatin-induced cold hypersensitivity is due to remodelling of ion channel expression in nociceptors. EMBO Mol. Med. 3(5), 266–278 (2011).
- 26 . Enhanced excitability of primary sensory neurons and altered gene expression of neuronal ion channels in dorsal root ganglion in paclitaxel-induced peripheral neuropathy. Anesthesiology 120(6), 1463–1475 (2014).
- 27 . HCN2 ion channels play a central role in inflammatory and neuropathic pain. Science 333(6048), 1462–1466 (2011).
- 28 . A possible link of oxaliplatin-induced neuropathy with potassium channel deficit. Muscle Nerve 45(3), 403–411 (2012).
- 29 . Neuroprotective effects of Kv7 channel agonist, retigabine, for cisplatin-induced peripheral neuropathy. Neurosci. Lett. 505(3), 223–227 (2011).
- 30 . Inhibition of paclitaxel-induced A-fiber hypersensitization by gabapentin. J. Pharmacol. Exp. Ther. 318(2), 735–740 (2006).
- 31 . Ethosuximide reverses paclitaxel- and vincristine-induced painful peripheral neuropathy. Pain 109(1–2), 150–161 (2004).
- 32 . Chemotherapy-evoked painful peripheral neuropathy: analgesic effects of gabapentin and effects on expression of the alpha-2-delta type-1 calcium channel subunit. Neuroscience 144(2), 714–720 (2007).
- 33 Serotonin 5-HT2A receptor involvement and Fos expression at the spinal level in vincristine-induced neuropathy in the rat. Pain 140(2), 305–322 (2008).
- 34 Serotonin transporter deficiency protects mice from mechanical allodynia and heat hyperalgesia in vincristine neuropathy. Neurosci. Lett. 495(2), 93–97 (2011).
- 35 . Chemotherapy-induced peripheral neuropathy: What do we know about mechanisms? Neurosci. Lett. (2014).
- 36 . Spinal administration of mGluR5 antagonist prevents the onset of bortezomib induced neuropathic pain in rat. Neuropharmacology 86, 294–300 (2014).
- 37 . Glutamate-mediated glial injury: mechanisms and clinical importance. GLIA 53(2), 212–224 (2006).
- 38 . Spinal astrocute gap junction and glutamate transporter expression contributes to a rat model of bortezomib-induced peripheral neuropathy. Neuroscience 285(1), 1–10 (2015).
- 39 . Altered discharges of spinal wide dynamic range neurons and down-regulation of glutamate transporter expression in rats with paclitaxel-induced hyperalgesia. Neuroscience 138(1), 329–338 (2006).
- 40 . Behavioral and electrophysiological studies in rats with cisplatin-induced chemoneuropathy. Brain Res. 1230, 91–98 (2008).
- 41 . Changes in sensory processing in the spinal dorsal horn accompany vincristine-induced hyperalgesia and allodynia. Pain 103, 131–138 (2003).
- 42 Spinal changes of a newly isolated neuropeptide endomorphin-2 concomitant with vincristine-induced allodynia. PLoS ONE 9(2), e89583 (2014).
- 43 . Alterations in endocannabinoid tone following chemotherapy-induced peripheral neuropathy: effects of endocannabinoid deactivation inhibitors targeting fatty-acid amide hydrolase and monoacylglycerol lipase in comparison to reference analgesics following cisplatin treatment. Pharmacol. Res. 67(1), 94–109 (2013).
- 44 . Inhibition of anandamide hydrolysis attenuates nociceptor sensitization in a murine model of chemotherapy-induced peripheral neuropathy. J. Neurophysiol. 113(5), 1501–1510 (2015).
- 45 A3 adenosine receptor agonist prevents the development of paclitaxel-induced neuropathic pain by modulating spinal glial-restricted redox-dependent signaling pathways. Pain 155, 2560–2567 (2015).
- 46 . Pharmacology of the capsaicin receptor, transient receptor potential vanilloid type-1 ion channel. Prog. Drug Res. 68, 39–76 (2014).
- 47 . Dose-dependent pain and mechanical hyperalgesia in humans after intradermal injection of capsaicin. Pain 38, 99–107 (1989).
- 48 . Pain from excitation of identified muscle nociceptors in humans. Brain Res. 740(1–2), 109–116 (1996).
- 49 . Intramuscular and intradermal injection of capsaicin: a comparison of local and referred pain. Pain 84(2–3), 407–412 (2000).
- 50 Effect of paclitaxel on transient receptor potential vallinoid 1 in rat dorsal root ganglion. Pain 154, 882–889 (2013).
- 51 Bortezomib treatment produces nocifensive behavior and changes in the expression of TRPV1, CGRP, and substance P in the rat DRG, spinal cord, and sciatic nerve. Biomed. Res. Int. 2014, 180428 (2014).
- 52 . Transient Receptor Potential Vanilloid 1 is essential for cisplatin-induced heat hyperalgesia in mice. Mol. Pain 6, 15– (2010).
- 53 . TRPA1 channels: chemical and temperature sensitivity. Curr. Top. Membr. 74, 89–112 (2014).
- 54 Spinal transient receptor potential ankyrin 1 channel contributes to central pain hypersensitivity in various pathophysiological conditions in the rat. Pain 152(3), 582–591 (2011).
- 55 Oxaliplatin elicits mechanical and cold allodynia in rodents via TRPA1 receptor stimulation. Pain 152(7), 1621–1631 (2011).
- 56 . Acute cold hypersensitivity characteristically induced by oxaliplatin is caused by the enhanced responsiveness of TRPA1 in mice. Mol. Pain 8, 55 (2012).
- 57 TRPA1 and TRPV4 mediate paclitaxel-induced peripheral neuropathy in mice via a glutathione-sensitive mechanism. Pflugers Arch. 463, 561–569 (2012).
- 58 Species differences and molecular determinant of TRPA1 cold sensitivity. Nat. Commun. 4, 2501 (2013).• Species differences and molecular determinant of TRPA1 cold sensitivity.
- 59 . Proteinase-activated receptor 2 sensitizes transient receptor potential vanilloid 1, transient receptor potential vanilloid 4, and transient receptor potential ankyrin 1 in paclitaxel-induced neuropathic pain. Neuroscience 193, 440–451 (2011).
- 60 A heat-sensitive TRP channel expressed in keratinocytes. Science 296, 2046–2049 (2002).
- 61 Analgesia mediated by the TRPM8 cold receptor in chronic neuropathic pain. Curr. Biol. 16(16), 1591–1605 (2006).
- 62 . Reversal of dose-limiting carboplatin-induced peripheral neuropathy with TRM8 activator menthol, enables further effective chemotherapy delivery. J. Pain Symptom. Manag. 39(6), e2–e4 (2010).
- 63 . Taxol induces caspase-10-dependent apoptosis. J. Biol. Chem. 279(49), 51057–51067 (2004).
- 64 . Comparison of oxaliplatin- and cisplatin-induced painful peripheral neuropathy in the rat. J. Pain 10(5), 534–541 (2009).
- 65 . Caspase signalling in neuropathic and inflammatory pain in the rat. Eur. J. Neurosci. 20(11), 2896–2902 (2004).
- 66 . Neurotoxicity of oxaliplatin and cisplatin for dorsal root ganglion neurons correlates with platinum-DNA binding. Neurotoxicology 27(6), 992–1002 (2006).
- 67 Role of MAPKs in platinum-induced neuronal apoptosis. Neurotoxicology 30(2), 312–319 (2009).
- 68 NGF protects dorsal root ganglion neurons from oxaliplatin by modulating JNK/Sapk and ERK1/2. Neurosci. Lett. 486(3), 141–145 (2010).
- 69 . Studies of peripheral sensory nerves in paclitaxel-induced painful peripheral neuropathy: evidence for mitochondrial dysfunction. Pain 122(3), 245–257 (2006).
- 70 . Mitochondrial abnormality in sensory, but not motor, axons in paclitaxel-evoked painful peripheral neuropathy in the rat. Neuroscience 199, 461–469 (2011).
- 71 . Functional deficits in peripheral nerve mitochondria in rats with paclitaxel- and oxaliplatin-evoked painful peripheral neuropathy. Exp. Neurol. 232(2), 154–161 (2011).
- 72 . Effects of mitochondrial poisons on the neuropathic pain produced by the chemotherapeutic agents paclitaxel and oxaliplatin. Pain 153, 704–709 (2012).
- 73 . Mitotoxicity and bortezomib-induced chronic painful peripheral neuropathy. Exp. Neurol. 238(2), 225–234 (2012).
- 74 . Acetyl-L-carnitine prevents and reduces paclitaxel-induced painful peripheral neuropathy. Neurosci. Lett. 397(3), 219–223 (2006).• Indicated ALCAR as a potential prevention of CIPN.
- 75 Paclitaxel and cisplatin-induced neurotoxicity: a protective role of acetyl-L-carnitine. Clin. Cancer Res. 9(15), 5756–5767 (2003).
- 76 Acetyl-L-Carnitine prevents and reverts experimental chronic neurotoxicity induced by oxaliplatin, without altering its antitumor properties. Anticancer Res. 25(4), 2681–2687 (2005).
- 77 . Prevention of paclitaxel-evoked painful peripheral neuropathy by acetyl-L-carnitine: effects on axonal mitochondria, sensory nerve fiber terminal arbors, and cutaneous Langerhans cells. Exp. Neurol. 210(1), 229–237 (2008).
- 78 Symptomatic and neurophysiological responses of paclitaxel- or cisplatin-induced neuropathy to oral acetyl-L-carnitine. Eur. J. Cancer 41(12), 1746–1750 (2005).
- 79 . A pilot study on the effect of acetyl-L-carnitine in paclitaxel- and cisplatin-induced peripheral neuropathy. Tumori 91(2), 135–138 (2005).
- 80 Acetyl-L-carnitine (ALCAR) for the prevention of chemotherapy-induced peripheral neuropathy in patients with relapsed or refractory multiple myeloma treated with bortezomib, doxorubicin and low-dose dexamethasone: a study from the Wisconsin Oncology Network. Cancer Chemother. Pharmacol. 74(4), 875–882 (2014).• Clinical trial that did not find significant prevention of CIPN with ALCAR.
- 81 Randomized double-blind placebo-controlled trial of acetyl-L-carnitine for the prevention of taxane-induced neuropathy in women undergoing adjuvant breast cancer therapy. J. Clin. Oncol. 31(20), 2627–2633 (2013).
- 82 . Bortezomib and SAHA synergistically induce ROS-driven caspase-dependent apoptosis of nasopharyngeal carcinoma and block replication of Epstein-Barr virus. Mol. Cancer Ther. 12(5), 747–758 (2013).
- 83 Paclitaxel therapy potentiates cold hyperalgesia in streptozotocin-induced diabetic rats through enhanced mitochondrial reactive oxygen species production and TRPA1 sensitization. Pain 153(3), 553–561 (2012).
- 84 . Phenyl N-tert-butylnitrone, a free radical scavenger, reduces mechanical allodynia in chemotherapy-induced neuropathic pain in rats. Anesthesiology 112(2), 432–439 (2010).
- 85 . Global inhibition of reactive oxygen species (ROS) inhibits paclitaxel-induced painful peripheral neuropathy. PLoS ONE 6(9), e25212 (2011).
- 86 Targeting the overproduction of peroxynitrite for the prevention and reversal of paclitaxel-induced neuropathic pain. J. Neurosci. 32(18), 6149–6160 (2012).
- 87 . Oxidative stress and nerve damage: role in chemotherapy induced peripheral neuropathy. Redox. Biol. 2, 289–295 (2014).
- 88 . Role of the DNA base excision repair protein, APE1 in cisplatin, oxaliplatin, or carboplatin induced sensory neuropathy. PLoS ONE 9(9), e106485 (2014).
- 89 . Effects of Cisplatin in neuroblastoma rat cells: damage to cellular organelles. Int. J. Cell Biol. 2012, 424072 (2012).
- 90 . Different patterns of apoptosis in response to cisplatin in B50 neuroblastoma rat cells. Histol. Histopathol. 26(7), 831–842 (2011).
- 91 Pathological adaptive responses of Schwann cells to endoplasmic reticulum stress in bortezomib-induced peripheral neuropathy. GLIA 58(16), 1961–1976 (2010).
- 92 Incidence and characteristics of peripheral neuropathy during oxaliplatin-based chemotherapy for metastatic colon cancer. Acta Oncol. 46(8), 1131–1137 (2007).
- 93 . Peripheral neuropathy with microtubule-targeting agents: occurrence and management approach. Clin. Breast Cancer 11(2), 73–81 (2011).
- 94 . Peripheral neuropathy induced by microtubule-stabilizing agents. J. Clin. Oncol. 24(10), 1633–1642 (2006).
- 95 . Effects of eribulin, vincristine, paclitaxel and ixabepilone on fast axonal transport and kinesin-1 driven microtubule gliding: implications for chemotherapy-induced peripheral neuropathy. Neurotoxicology 37, 231–239 (2013).
- 96 Bortezomib alters microtubule polymerization and axonal transport in rat dorsal root ganglion neurons. Neurotoxicology 39, 124–131 (2013).
- 97 . Impairment of retrograde neuronal transport in oxaliplatin-induced neuropathy demonstrated by molecular imaging. PLoS ONE 7(9), e45776 (2012).
- 98 . Intraepidermal nerve fiber loss corresponds to the development of Taxol-induced hyperalgesia and can be prevented by treatment with minocycline. Pain 152(2), 308–313 (2011).
- 99 . Protection against oxaliplatin-induced mechanical hyperalgesia and intraepidermal nerve fiber loss by minocycline. Exp. Neurol. 229(2), 353–357 (2011).
- 100 . Mitochondrial dysfunction in distal axons contributes to human immunodeficiency virus sensory neuropathy. Ann. Neurol. 69(1), 100–110 (2011).
- 101 . The density of remaining nerve endings in human skin with and without postherpetic neuralgia after shingles. Pain 92(1–2), 139–145 (2001).
- 102 Induction of monocyte chemoattractant protein-1 (MCP-1) and its receptor CCR2 in primary sensory neurons contributes to paclitaxel-induced peripheral neuropathy. J. Pain 14(10), 1031–1044 (2013).
- 103 . Clinical and experimental findings in humans and animals with chemotherapy-induced peripheral neuropathy. Minerva Anes. 72, 151–169 (2006).
- 104 Distribution of paclitaxel within the nervous system of the rat after repeated intravenous administration. Neurotoxicology 21(3), 389–394 (2000).
- 105 . Effect of leukemia inhibitory factor in experimental cisplatin neuropathy in mice. Cytokine 29(1), 31–41 (2005).
- 106 Physiological characterization of taxol-induced large fiber sensory neuropathy in the rat. Ann. Neurol. 43, 46–55 (1998).
- 107 Enhanced excitability of nociceptive trigeminal ganglion neurons by satellite glial cytokine following peripheral inflammation. Pain 129(1–2), 155–166 (2007).
- 108 . The contribution of satellite glial cells to chemotherapy-induced neuropathic pain. Eur. J. Pain 17, 571–580 (2013).
- 109 . Evidence that spinal astrocytes but not microglia contribute to the pathogenesis of paclitaxel-induced painful neuropathy. J. Pain 13(3), 293–303 (2012).
- 110 . Astrocytes, but not microglia, are activated in oxaliplatin and bortezomib-induced peripheral neuropathy. Neuroscience 274(1), 308–317 (2014).• Bortezomib results in mechanical hyperalgesia via decreased glutamate transporter expression and increased astrocytic gap junction coupling.
- 111 JNK-Induced MCP-1 Production in spinal cord astrocytes contributes to central sensitization and neuropathic pain. J. Neurosci. 29(13), 4096–4108 (2009).
- 112 . Gap junction protein connexin 43 is involved in the induction of oxaliplatin-related neuropathic pain. J. Pain 14(2), 205–214 (2013).
- 113 . Cytokines, nerve growth factor and inflammatory hyperalgesia: the contribution of tumor necrosis factor a. Br. J. Pharmacol. 121, 417–424 (1997).
- 114 Nociceptors Are Interleukin-1 beta Sensors. J. Neurosci. 28(52), 14062–14073 (2008).
- 115 . Cytokine-mediated inflammatory hyperalgesia limited by interleukin-1 receptor antagonist. Br. J. Pharmacol. 130(6), 1418–1424 (2000).
- 116 . Tumour necrosis factor-a induces ectopic activity in nociceptive primary afferent fibres. Neuroscience 81(1), 255–262 (1997).
- 117 . Dorsal root sensitivity to interleukin-1 beta, interleukin-6 and tumor necrosis factor in rats. Eur. Spine J. 11, 467–475 (2002).
- 118 . Exogenous tumor necrosis factor-alpha induces abnormal discharges in rat dorsal horn neurons. Spine (Phila Pa 1976.) 27(15), 1618–1624 (2002).
- 119 . A p38 mitogen-activated protein kinase-dependent mechanism of disinhibition in spinal synaptic transmission induced by tumor necrosis factor-alpha. J. Neurosci. 30(38), 12844–12855 (2010).
- 120 . Immune and glial cell factors as pain mediators and modulators. Exp. Neurol. 192(2), 444–462 (2005).
- 121 . Targeting the pancreatic b-cell to treat diabetes. Nat. Rev. Drug Discov. 13(4), 278–289 (2014).
- 122 . Induction of proinflammatory and chemokine genes by lipopolysaccharide and paclitaxel (Taxol) in murine and human breast cancer cell lines. Cytokine 15(3), 156–165 (2001).
- 123 . Increased release of interleukin-1 and tumour necrosis factor by interleukin-2-induced lymphokine-activated killer cells in the presence of cisplatin and FK-565. Immunol. Cell Biol. 70(Pt 1), 15–24 (1992).
- 124 Severe atypical neuropathy associated with administration of hematopoietic colony-stimulating factors and vincristine. J. Clin. Oncol. 14(3), 935–940 (1996).
- 125 Intrathecal interleukin-10 gene therapy attenuates paclitaxel-induced mechanical allodynia and proinflammatory cytokine expression in dorsal root ganglia in rats. Brain Behav. Immun. 21, 686–698 (2007).
- 126 . The role of MyD88 and TLR4 in the LPS-mimetic activity of taxol. Eur. J. Immunol. 31, 2448–2457 (2001).
- 127 . Toll-like receptor 4 signaling in primary sensory neurons and spinal astrocytes contribute to paclitaxel-induced peripheral neuropathy. J. Pain 15(7), 712–725 (2014).
- 128 . Toll-like receptor signaling regulates cisplatin-induced mechanical allodynia in mice. Cancer Chemother. Pharmacol. 73(1), 25–34 (2014).
- 129 . Chemokine CCL2 and its receptor CCR2 in the medullary dorsal horn are involved in trigeminal neuropathic pain. J. Neuroinflammation 9, 136– (2012).
- 130 Impaired neuropathic pain responses in mice lacking the chemokine receptor CCR2. Proc. Natl Acad. Sci. USA 100(13), 7947–7952 (2003).
- 131 . Prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers: American Society of Clinical Oncology clinical practice guideline summary. J. Oncol. Pract. 10(6), e421–e424 (2014).• Recent review article summarizing the agents that have failed to demonstrate effective prevention of CIPN.
- 132 Clinical trial of the p38 MAP kinase inhibitor dilmapimod in neuropathic pain following nerve injury. Eur. J. Pain 15(10), 1040–1048 (2011).
- 133 Analgesic efficacy and safety of the novel p38 MAP kinase inhibitor, losmapimod, in patients with neuropathic pain following peripheral nerve injury: a double-blind, placebo-controlled study. Eur. J. Pain 17(6), 844–857 (2013).