One of the most common issues caused by antineoplastic agents is chemotherapy-induced peripheral neuropathy (CIPN). In patients, CIPN is a sensory neuropathy accompanied by various motor and autonomic changes. With a high prevalence of cancer patients, CIPN is becoming a major problem for both cancer patients and for their health care providers. Nonetheless, there are lacking effective interventions preventing CIPN and treating the CIPN symptoms. A number of studies have demonstrated the cellular and molecular signaling pathways leading to CIPN using experimental models and the beneficial effects of some interventions on the CIPN symptoms related to those potential mechanisms. This review will summarize results obtained from recent human and animal studies, which include the abnormalities in mechanical and temperature sensory responses following chemotherapy such as representative bortezomib, oxaliplatin and paclitaxel. The underlying mechanisms of CIPN at cellular and molecular levels will be also discussed for additional in-depth studies needed to be better explored. Overall, this paper reviews the basic picture of CIPN and the signaling mechanisms of the most common antineoplastic agents in the peripheral and central nerve systems. A better understanding of the risk factors and fundamental mechanisms of CIPN is needed to develop effective preventive and therapeutic strategies.

Tumor Center The 1st Hospital of Jilin University Changchun Jilin China

Zobrazit více v PubMed

Finnerup NB, Kuner R, Jensen TS. Neuropathic Pain: From Mechanisms to Treatment. Physiol Rev. 2021;101:259–301. doi: 10.1152/physrev.00045.2019. PubMed DOI

Hanna M, Zylicz (B)Z. Cancer Pain. Springer; 2013. p. 286. DOI

Pasetto LM, D'Andrea MR, Rossi E, Monfardini S. Oxaliplatin-related neurotoxicity: How and why? Crit Rev Oncol Hematol. 2006;59:159–168. doi: 10.1016/j.critrevonc.2006.01.001. PubMed DOI

Hoskin PJ. Radiotherapy. In: SYKES N, BENNET M, YUAN C-S, editors. Clinical Pain Management: Cancer Pain. London: Hodder Arnold; 2008. pp. 251–255. DOI

Portenoy RK. Treatment of cancer pain. Lancet. 2011;377:2236–2247. doi: 10.1016/S0140-6736(11)60236-5. PubMed DOI

Loprinzi CL, Lacchetti C, Bleeker J, Cavaletti G, Chauhan C, Hertz DL, Kelley MR, et al. Prevention and Management of Chemotherapy-Induced Peripheral Neuropathy in Survivors of Adult Cancers: ASCO Guideline Update. J Clin Oncol. 2020;38:3325–3348. doi: 10.1200/JCO.20.01399. PubMed DOI

Zajączkowska R, Kocot-Kępska M, Leppert W, Wrzosek A, Mika J, Wordliczek J. Mechanisms of Chemotherapy-Induced Peripheral Neuropathy. Int J Mol Sci. 2019;20:1451. doi: 10.3390/ijms20061451. PubMed DOI PMC

Kim HK, Hwang SH, Abdi S. Tempol Ameliorates and Prevents Mechanical Hyperalgesia in a Rat Model of Chemotherapy-Induced Neuropathic Pain. Front Pharmacol. 2017;7:532. doi: 10.3389/fphar.2016.00532. PubMed DOI PMC

Kim HK, Hwang SH, Lee SO, Kim SH, Abdi S. Pentoxifylline Ameliorates Mechanical Hyperalgesia in a Rat Model of Chemotherapy-Induced Neuropathic Pain. Pain Physician. 2016;19:E589–E600. doi: 10.36076/ppj/2019.19.E589. PubMed DOI

Duan Z, Su Z, Wang H, Pang X. Involvement of pro-inflammation signal pathway in inhibitory effects of rapamycin on oxaliplatin-induced neuropathic pain. Mol Pain. 2018;14:1744806918769426. doi: 10.1177/1744806918769426. PubMed DOI PMC

Wang Q, Wang J, Gao D, Li J. Inhibition of PAR2 and TRPA1 signals alleviates neuropathic pain evoked by chemotherapeutic bortezomib. J Biol Regul Homeost Agents. 2017;31:977–983. PubMed

Yang Y, Luo L, Cai X, Fang Y, Wang J, Chen G, Yang J, et al. Nrf2 inhibits oxaliplatin-induced peripheral neuropathy via protection of mitochondrial function. Free Radic Biol Med. 2018;120:13–24. doi: 10.1016/j.freeradbiomed.2018.03.007. PubMed DOI

Maruta T, Nemoto T, Hidaka K, Koshida T, Shirasaka T, Yanagita T, Takeya R, Tsuneyoshi I. Upregulation of ERK phosphorylation in rat dorsal root ganglion neurons contributes to oxaliplatin-induced chronic neuropathic pain. PLoS One. 2019;14:e0225586. doi: 10.1371/journal.pone.0225586. PubMed DOI PMC

Tian L, Fan T, Zhou N, Guo H, Zhang W. Role of PAR2 in regulating oxaliplatin-induced neuropathic pain via TRPA1. Transl Neurosci. 2015;6:111–116. doi: 10.1515/tnsci-2015-0010. PubMed DOI PMC

Brandolini L, Castelli V, Aramini A, Giorgio C, Bianchini G, Russo R, De Caro C, et al. DF2726A, a new IL-8 signalling inhibitor, is able to counteract chemotherapy-induced neuropathic pain. Sci Rep. 2019;9:11729. doi: 10.1038/s41598-019-48231-z. PubMed DOI PMC

Alé A, Bruna J, Morell M, van de Velde H, Monbaliu J, Navarro X, Udina E. Treatment with anti-TNF alpha protects against the neuropathy induced by the proteasome inhibitor bortezomib in a mouse model. Exp Neurol. 2014;253:165–173. doi: 10.1016/j.expneurol.2013.12.020. PubMed DOI

Alé A, Bruna J, Calls A, Karamita M, Haralambous S, Probert L, Navarro X, Udina E. Inhibition of the neuronal NFκB pathway attenuates bortezomib-induced neuropathy in a mouse model. Neurotoxicology. 2016;55:58–64. doi: 10.1016/j.neuro.2016.05.004. PubMed DOI

Carozzi VA, Renn CL, Bardini M, Fazio G, Chiorazzi A, Meregalli C, Oggioni N, et al. Bortezomib-induced painful peripheral neuropathy: an electrophysiological, behavioral, morphological and mechanistic study in the mouse. PLoS One. 2013;8:e72995. doi: 10.1371/journal.pone.0072995. PubMed DOI PMC

Liu C, Luan S, OuYang H, Huang Z, Wu S, Ma C, Wei J, Xin W. Upregulation of CCL2 via ATF3/c-Jun interaction mediated the Bortezomib-induced peripheral neuropathy. Brain Behav Immun. 2016;53:96–104. doi: 10.1016/j.bbi.2015.11.004. PubMed DOI

Liu CC, Huang ZX, Li X, Shen KF, Liu M, Ouyang HD, Zhang SB, et al. Upregulation of NLRP3 via STAT3-dependent histone acetylation contributes to painful neuropathy induced by bortezomib. Exp Neurol. 2018;302:104–111. doi: 10.1016/j.expneurol.2018.01.011. PubMed DOI

Miao H, Xu J, Xu D, Ma X, Zhao X, Liu L. Nociceptive behavior induced by chemotherapeutic paclitaxel and beneficial role of antioxidative pathways. Physiol Res. 2019;68:491–500. doi: 10.33549/physiolres.933939. PubMed DOI

Yamamoto S, Egashira N. Pathological Mechanisms of Bortezomib-Induced Peripheral Neuropathy. Int J Mol Sci. 2021;22:888. doi: 10.3390/ijms22020888. PubMed DOI PMC

Moi P, Chan K, Asunis I, Cao A, Kan YW. Isolation of NF-E2-related factor 2 (Nrf2), a NF-E2-like basic leucine zipper transcriptional activator that binds to the tandem NF-E2/AP1 repeat of the beta-globin locus control region. Proc Natl Acad Sci U S A. 1994;91:9926–9930. doi: 10.1073/pnas.91.21.9926. PubMed DOI PMC

Gold R, Kappos L, Arnold DL, Bar-Or A, Giovannoni G, Selmaj K, Tornatore C, et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med. 2012;367:1098–1107. doi: 10.1056/NEJMoa1114287. PubMed DOI

Gupta P, Makkar TK, Goel L, Pahuja M. Role of inflammation and oxidative stress in chemotherapy-induced neurotoxicity. Immunol Res. 2022;70:725–741. doi: 10.1007/s12026-022-09307-7. PubMed DOI

Yardim A, Gur C, Comakli S, Ozdemir S, Kucukler S, Celik H, Kandemir FM. Investigation of the effects of berberine on bortezomib-induced sciatic nerve and spinal cord damage in rats through pathways involved in oxidative stress and neuro-inflammation. Neurotoxicology. 2022;89:127–139. doi: 10.1016/j.neuro.2022.01.011. PubMed DOI

Liu B, Wang H. Oxaliplatin induces ferroptosis and oxidative stress in HT29 colorectal cancer cells by inhibiting the Nrf2 signaling pathway. Exp Ther Med. 2022;23:394. doi: 10.3892/etm.2022.11321. PubMed DOI PMC

Lu Y, Wu S, Xiang B, Li L, Lin Y. Curcumin Attenuates Oxaliplatin-Induced Liver Injury and Oxidative Stress by Activating the Nrf2 Pathway. Drug Des Devel Ther. 2020;14:73–85. doi: 10.2147/DDDT.S224318. PubMed DOI PMC

Miao F, Wang R, Cui G, Li X, Wang T, Li X. Engagement of MicroRNA-155 in Exaggerated Oxidative Stress Signal and TRPA1 in the Dorsal Horn of the Spinal Cord and Neuropathic Pain During Chemotherapeutic Oxaliplatin. Neurotox Res. 2019;36:712–723. doi: 10.1007/s12640-019-00039-5. PubMed DOI

Fidanboylu M, Griffiths LA, Flatters SJ. Global inhibition of reactive oxygen species (ROS) inhibits paclitaxel-induced painful peripheral neuropathy. PLoS One. 2011;6:e25212. doi: 10.1371/journal.pone.0025212. PubMed DOI PMC

Duggett NA, Griffiths LA, McKenna OE, de Santis V, Yongsanguanchai N, Mokori EB, Flatters SJ. Oxidative stress in the development, maintenance and resolution of paclitaxel-induced painful neuropathy. Neuroscience. 2016;333:13–26. doi: 10.1016/j.neuroscience.2016.06.050. PubMed DOI PMC

Janes K, Doyle T, Bryant L, Esposito E, Cuzzocrea S, Ryerse J, Bennett GJ, Salvemini D. Bioenergetic deficits in peripheral nerve sensory axons during chemotherapy-induced neuropathic pain resulting from peroxynitrite-mediated post-translational nitration of mitochondrial superoxide dismutase. Pain. 2013;154:2432–2440. doi: 10.1016/j.pain.2013.07.032. PubMed DOI PMC

Altenhofer S, Kleikers PW, Radermacher KA, Scheurer P, Rob Hermans JJ, Schiffers P, Ho H, Wingler K, Schmidt HH. The NOX toolbox: validating the role of NADPH oxidases in physiology and disease. Cell Mol Life Sci. 2012;69:2327–2343. doi: 10.1007/s00018-012-1010-9. PubMed DOI PMC

Salvemini D, Little JW, Doyle T, Neumann WL. Roles of reactive oxygen and nitrogen species in pain. Free Radic Biol Med. 2011;51:951–966. doi: 10.1016/j.freeradbiomed.2011.01.026. PubMed DOI PMC

Lam GY, Huang J, Brumell JH. The many roles of NOX2 NADPH oxidase-derived ROS in immunity. Semin Immunopathol. 2010;32:415–430. doi: 10.1007/s00281-010-0221-0. PubMed DOI

Gavazzi G, Banfi B, Deffert C, Fiette L, Schappi M, Herrmann F, Krause KH. Decreased blood pressure in NOX1-deficient mice. FEBS Lett. 2006;580:497–504. doi: 10.1016/j.febslet.2005.12.049. PubMed DOI

Suzuki Y, Hattori K, Hamanaka J, Murase T, Egashira Y, Mishiro K, Ishiguro M, et al. Pharmacological inhibition of TLR4-NOX4 signal protects against neuronal death in transient focal ischemia. Sci Rep. 2012;2:896. doi: 10.1038/srep00896. PubMed DOI PMC

Kallenborn-Gerhardt W, Schroder K, Del Turco D, Lu R, Kynast K, Kosowski J, Niederberger E, et al. NADPH oxidase-4 maintains neuropathic pain after peripheral nerve injury. J Neurosci. 2012;32:10136–10145. doi: 10.1523/JNEUROSCI.6227-11.2012. PubMed DOI PMC

Zhao X, Liu L, Wang Y, Wang G, Zhao Y, Zhang Y. Electroacupuncture enhances antioxidative signal pathway and attenuates neuropathic pain induced by chemotherapeutic paclitaxel. Physiol Res. 2019;68:501–510. doi: 10.33549/physiolres.934084. PubMed DOI

Li Y, Yin C, Li X, Liu B, Wang J, Zheng X, Shao X, et al. Electroacupuncture Alleviates Paclitaxel-Induced Peripheral Neuropathic Pain in Rats via Suppressing TLR4 Signaling and TRPV1 Upregulation in Sensory Neurons. Int J Mol Sci. 2019;20:5917. doi: 10.3390/ijms20235917. PubMed DOI PMC

Ghelardini C, Menicacci C, Cerretani D, Bianchi E. Spinal administration of mGluR5 antagonist prevents the onset of bortezomib induced neuropathic pain in rat. Neuropharmacology. 2014;86:294–300. doi: 10.1016/j.neuropharm.2014.08.004. PubMed DOI

Di Cesare Mannelli L, Pacini A, Matera C, Zanardelli M, Mello T, De Amici M, Dallanoce C, Ghelardini C. Involvement of α7 nAChR subtype in rat oxaliplatin-induced neuropathy: effects of selective activation. Neuropharmacology. 2014;79:37–48. doi: 10.1016/j.neuropharm.2013.10.034. PubMed DOI

Branca JJV, Maresca M, Morucci G, Becatti M, Paternostro F, Gulisano M, Ghelardini C, et al. Oxaliplatin-induced blood brain barrier loosening: a new point of view on chemotherapy-induced neurotoxicity. Oncotarget. 2018;9:23426–23438. doi: 10.18632/oncotarget.25193. PubMed DOI PMC

Ferrier J, Bayet-Robert M, Dalmann R, El Guerrab A, Aissouni Y, Graveron-Demilly D, Chalus M, et al. Cholinergic Neurotransmission in the Posterior Insular Cortex Is Altered in Preclinical Models of Neuropathic Pain: Key Role of Muscarinic M2 Receptors in Donepezil-Induced Antinociception. J Neurosci. 2015;35:16418–16430. doi: 10.1523/JNEUROSCI.1537-15.2015. PubMed DOI PMC

Bouchenaki H, Bernard A, Bessaguet F, Frachet S, Richard L, Sturtz F, Magy L, et al. Neuroprotective Effect of Ramipril Is Mediated by AT2 in a Mouse MODEL of Paclitaxel-Induced Peripheral Neuropathy. Pharmaceutics. 2022;14:848. doi: 10.3390/pharmaceutics14040848. PubMed DOI PMC

Ferris CF, Nodine S, Pottala T, Cai X, Knox TM, Fofana FH, Kim S, Kulkarni P, Crystal JD, Hohmann AG. Alterations in brain neurocircuitry following treatment with the chemotherapeutic agent paclitaxel in rats. Neurobiol Pain. 2019;6:100034. doi: 10.1016/j.ynpai.2019.100034. PubMed DOI PMC

Saifee TA, Elliott KJ, Rabin N, Yong KL, D'Sa S, Brandner S, Lunn MP, Blake J, Reilly MM. Bortezomib-induced inflammatory neuropathy. J Peripher Nerv Syst. 2010;15:366–368. doi: 10.1111/j.1529-8027.2010.00287.x. PubMed DOI

Wadd N, Peedell C, Polwart C. Real-World Assessment of Cancer Drugs Using Local Data Uploaded to the Systemic Anti-Cancer Therapy Dataset in England. Clin Oncol (R Coll Radiol) 2022;34:497–507. doi: 10.1016/j.clon.2022.04.012. PubMed DOI

Ciarimboli G. Anticancer Platinum Drugs Update. Biomolecules. 2021;11:1637. doi: 10.3390/biom11111637. PubMed DOI PMC

Babajani A, Manzari-Tavakoli A, Jamshidi E, Tarasi R, Niknejad H. Anti-cancer effects of human placenta-derived amniotic epithelial stem cells loaded with paclitaxel on cancer cells. Sci Rep. 2022;12:18148. doi: 10.1038/s41598-022-22562-w. PubMed DOI PMC

Zhang Y, Yang SH, Guo XL. New insights into Vinca alkaloids resistance mechanism and circumvention in lung cancer. Biomed Pharmacother. 2017;96:659–666. doi: 10.1016/j.biopha.2017.10.041. PubMed DOI

Ibrahim NK. Ixabepilone: Overview of Effectiveness, Safety, and Tolerability in Metastatic Breast Cancer. Front Oncol. 2021;11:617874. doi: 10.3389/fonc.2021.617874. PubMed DOI PMC

Richardson P, Hideshima T, Anderson K. Thalidomide in multiple myeloma. Biomed Pharmacother. 2002;56:115–128. doi: 10.1016/S0753-3322(02)00168-3. PubMed DOI