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Szklener, K.; Rudzińska, A.; Juchaniuk, P.; Kabała, Z.; Mańdziuk, S. Pathophysiology and Molecular Characteristics of Chemotherapy-Induced Peripheral Neuropathy. Encyclopedia. Available online: (accessed on 24 June 2024).
Szklener K, Rudzińska A, Juchaniuk P, Kabała Z, Mańdziuk S. Pathophysiology and Molecular Characteristics of Chemotherapy-Induced Peripheral Neuropathy. Encyclopedia. Available at: Accessed June 24, 2024.
Szklener, Katarzyna, Anna Rudzińska, Pola Juchaniuk, Zuzanna Kabała, Sławomir Mańdziuk. "Pathophysiology and Molecular Characteristics of Chemotherapy-Induced Peripheral Neuropathy" Encyclopedia, (accessed June 24, 2024).
Szklener, K., Rudzińska, A., Juchaniuk, P., Kabała, Z., & Mańdziuk, S. (2023, March 23). Pathophysiology and Molecular Characteristics of Chemotherapy-Induced Peripheral Neuropathy. In Encyclopedia.
Szklener, Katarzyna, et al. "Pathophysiology and Molecular Characteristics of Chemotherapy-Induced Peripheral Neuropathy." Encyclopedia. Web. 23 March, 2023.
Pathophysiology and Molecular Characteristics of Chemotherapy-Induced Peripheral Neuropathy

Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most detrimental toxicity to a patient’s quality of life. Pathophysiological mechanisms involved in CIPN pathogenesis are complex, multifactorial, and only partially examined. They are suspected to be associated with oxidative stress (OS), mitochondrial dysfunction, ROS-induced apoptosis, myelin sheath and DNA damage, and immunological and inflammatory processes.

CIPN ozone pain treatment

1. Introduction

Chemotherapy (CT) remains one of the mainstays of cancer treatment. Due to the advances in medicine and technology, its efficacy is growing and overall cancer mortality has decreased [1].
Unfortunately, oncological patients and cancer survivors have to face multiple unpleasant adverse consequences of using antineoplastic agents. This is caused by the fact that chemotherapeutics work by targeting rapidly dividing cancerous cells, but they also affect proper functioning, healthy cells. One of the most common mechanisms that underlie the causes of chemotherapy-induced toxicity involves loss of homeostatic control of reactive oxygen species (ROS) [2].
For some drugs, the most detrimental toxicity to a patient’s quality of life is chemotherapy-induced peripheral neuropathy (CIPN), which can occur in 19% to more than 85% of patients. Incidence of this condition varies among the different classes of agents. The risk of such impairment of the peripheral nervous system is the highest during platinum-based drug therapy—between 70% and 100% [3].
Pathophysiological mechanisms involved in CIPN pathogenesis are complex, multifactorial, and only partially examined. They are suspected to be associated with oxidative stress (OS), mitochondrial dysfunction, ROS-induced apoptosis, myelin sheath and DNA damage, and immunological and inflammatory processes [3][4][5].
CIPN displays sensory symptoms more often than motor symptoms. Its manifestation often includes paresthesia, dysesthesia, hypoalgesia or pain (burning, shooting or electric-shock-like), and cramping of the extremities [6][7]. Symptoms are symmetric and typically spread from distal to proximal level. With lower prevalence, the perioral region can be affected which leads to laryngospasm [6].
Painful symptoms sometimes persist well beyond the discontinuation of treatment [6][7].

2. Pathophysiology and Molecular Characteristics of CIPN

Classical antitumoral drugs are widely known for their cytotoxicity and prominent side effects, especially in fast-dividing cells such as those of the bone marrow, GI tract, reproductive system, and hair follicles [8]. Even though nervous tissue is not rapidly proliferating, antitumoral drugs may cause neurotoxicity, both directly and indirectly, causing sensory symptoms that include hyperalgesia, allodynia, spontaneous shooting or burning pain, dysesthesia, paresthesia, and other deficits in not only sensory but also autonomic and motor function [9]. Neurotoxicity induced by chemotherapy mainly affects the peripheral nervous system (PNS) due to its lack of protection from a structure similar to the blood–brain barrier (BBB) that protects the central nervous system (CNS) [10]. The longer the axon, the more vulnerable it is to the toxicity of chemotherapeutic agents which may be caused by their higher metabolic requirements [11].
The effects of anticancer drugs on the nervous system depend on their physical and chemical properties and their dosage, so they vary across the different classes of chemotherapeutics [10]. Research on CIPN from the past 20 years points to four main mechanisms of antitumor drugs: (1) directly targeting the mitochondria and producing oxidative stress; (2) functionally impairing ion channels; (3) triggering immunological mechanisms through activation of satellite glial cells; and/or (4) disruption of microtubules [12]. There are six main substance groups that contribute to the development of CIPN: the platinum-based antineoplastics (oxaliplatin and cisplatin), the vinca alkaloids (vincristine and vinblastine), the epothilones (ixabepilone), the taxanes (paclitaxel, docetaxel), the proteasome inhibitors (bortezomib), and the immunomodulatory drugs (thalidomide) [7].

2.1. Oxidative Stress in CIPN Development

Many antineoplastic agents are known for their ability to cause oxidative stress, which is the imbalance between the production of ROS and the ability to detoxify their detrimental effects [13]. Both bortezomib and paclitaxel can increase the production of ROS, which is also produced in small amounts in healthy tissues as a by-product of oxygen metabolism but in excess may worsen mitochondrial function [14]. Overproduction of ROS can lead to damage of intracellular biomolecules such as phospholipids, which results in demyelination, oxidation of proteins, releasing carbonyl by-products that can sensitize TRPV channels, inactivate antioxidant enzymes, and damage microtubules [15]. ROS can also indicate the activation of apoptotic pathways and the overproduction of pro-inflammatory mediators [16].
The role of oxidative stress and mitochondria dysfunction in the pathobiology of CIPN is supported by many in vitro and in vivo studies [11]. Observations of sectioned peripheral nerves in rodents previously treated with anticancer drugs show swollen and vacuolated mitochondria [4][17]. Preclinical studies on strategies targeting ROS based on external antioxidant stimulation were promising but it did not translate into clinical studies. With the results of many studies on antioxidants such as α-lipoic acid being disputed, endogenous antioxidants and peroxisome-proliferator-activated receptors (PPARs) were proposed as potential targets for in vivo CIPN studies [11][14]. Substantial evidence shows that further study of 4-hydroxy-2-nonenal (4-HNE), a secondary intermediate of oxidative stress and one of the most formidable reactive aldehydes, and the mechanisms of its regulation may be applicable to many oxidative-stress-related injuries. Furthermore, it is to be expected that other molecular targets, such as aldehyde dehydrogenase (ALDH2) and Alda-1, a selective activator of ALDH2, will be increasingly studied [18].
The transient receptor potential ankyrin 1 (TRPA1) channel is a major oxidant sensor profusely expressed by a subpopulation of primary sensory neurons. It is proposed that, during the therapy with some antitumoral drugs such as thalidomide, platinum-based antitumor drugs, vinca alkaloids, and paclitaxel pain may be induced through the upregulation of its expression [5].

2.2. Platinum-Induced Neurotoxicity

Platinum-based drugs are an important part of chemotherapy which are used to treat different types of solid tumors; however, PT chemotherapy is not tumor-specific and always affects normal tissue leading to many serious side effects such as neurotoxicity. Platinum-induced neurotoxicity can be the result of the following mechanisms: nuclear DNA damage in dorsal root ganglion (DRG) neurons, mitochondrial DNA damage, channelopathy, oxidative stress and mitochondrial dysfunction, and intracellular signaling pathway dysregulation [19][20]. Currently, there are three members of this drug family in use: cisplatin, carboplatin, and oxaliplatin [21]. Carboplatin neurotoxicity seems to be insignificant compared with that of cisplatin and oxaliplatin. It requires a 10-fold higher drug concentration than cisplatin to induce the same cytotoxic effect and predominantly affects the hematopoietic system, while cisplatin and oxaliplatin are primarily associated with CIPN [7][19].

2.2.1. Damage in DRG Neurons

The bodies of sensory neurons located in DRG are believed to be the main target of Pt-based drugs because they need to sustain high metabolism for the maintenance of long axons [20]. Cisplatin and oxaliplatin are apparently substrates of transporters on the neuronal plasma membrane, such as the copper transporters (CTR-1), the organic cation transporters (OCT-1, OCT-2), and the cation and carnate transporters (OCTN-1, OCTN-2) which are likely involved in the influx of Pt-based drugs into DRG neurons [18]. Once inside the cell, platinum compounds reach the nucleus and form DNA adducts, which results in lesions that block DNA replication and transcription [22] that finally leads to accelerated accumulation of unrepaired platinum–DNA adducts and results in cell death [23].

2.2.2. Oxidative Stress and Mitochondrial Dysfunction

Preclinical studies demonstrated that cisplatin forms adducts with mitochondrial DNA at a similar rate as nuclear DNA, which results in inhibition of mtDNA replication, disruption of mtDNA transcription, and morphological changes within mitochondria [24]. However, the main mechanism of platinum-induced toxicity is associated with the overproduction of ROS [25].

2.2.3. Neuroinflammation

Oxaliplatin treatment may trigger an acute inflammatory response that leads to an increase in pro-inflammatory cytokines. Research on rats showed an increase in IL-1β and TNF-α and a decrease in IL-10 and IL-4 in the spinal cord after 25 days of Oxaliplatin treatment [26]. Platinum compounds may also indicate the increase in pro-nociceptive acting chemokines, such as CCL2/CCR2, which are proven to have a significant role in chronic pain in rodents [20]. In addition to changes in cytokine concentrations, the main mechanisms of platinum-related neurotoxicity are also suspected to be supported by the decrease in levels of vitamin E and prealbumin [25].

2.2.4. Enhanced Responsiveness of TRP Channels

Studies in rodents support the idea of TRPV1’s responsibility for the heat-sensitive hyperalgesia and mechanical allodynia in sensory neurons induced by cisplatin, oxaliplatin, bortezomib, and paclitaxel [20].

2.3. Neurotoxicity Caused by Vinca Alkaloids

Vincristine alters neuron structure primarily by disrupting the normal assembly and disassembly functions of microtubules, which leads to mitosis block and cell death [27].

2.4. Taxane-Induced Neurotoxicity

Taxanes are part of the group of chemotherapeutic agents known as microtubule-stabilizing agents (MTSAs) [28]. Unlike vinca alkaloids, which induce the disassembly of microtubules, paclitaxel inhibits this action, leading to the polymerization of tubulin and the formation of extraordinarily stable and dysfunctional microtubules [29]. Properly functioning microtubules are required for axonal transport and therefore also neuron survival [30].

2.5. Bortezomib-Induced Neurotoxicity

Bortezomib-related neurotoxicity may occur through mechanisms of indirect overstabilization of microtubules [31]. Other mechanisms, such as mitochondrial toxicity, endoplasmic reticulum stress in Schwann cells, and inhibition of transcription, transport, and cytoplasmic translation of mRNAs due to accumulation of ubiquitin-conjugated proteins, are also taken into account [32][33].

2.6. Thalidomide-Induced Neurotoxicity

For thalidomide, the antitumor mechanisms are suspected to be the cause of its neurotoxicity. TNF-α inhibition and NF-B activation blockade cause neurotrophin and receptor dysregulation, resulting in cell death. The antiangiogenic effect of thalidomide leads to hypoxia and ischemia of nerve fibers [34].


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