1. Chemotherapy-Induced Peripheral Neuropathy

Taxanes (i.e., paclitaxel, docetaxel), proteasome/angiogenesis inhibitors (bortezomib/thalidomide), vinca alkaloids (i.e., vincristine, vinorelbine), and platinum-based drugs (i.e., cisplatin, oxaliplatin) are the most common systemic anticancer treatments used as first-line chemotherapy for a variety of cancers, including breast, lung, colorectal and gastric cancers, and multiple myeloma [1]. While systemic chemotherapeutics offer potentially curative effects for cancer patients, they also confer a variety of neurotoxicities which can lead to dose reductions. In extreme cases, it can lead to cessation of chemotherapy treatment entirely [2]. Particularly, platinum-based chemotherapeutic agents, such as cisplatin, are well known to cause systemic neuronal toxicity leading to diffuse, bilateral degenerative changes in peripheral sensation and an altered perception of cold, heat, and pain. Clinically, chemotherapy-induced peripheral neuropathy (CIPN) is typically characterized by a subacute development of numbness, paresthesia, and occasional pain. Symptoms usually follow a “stocking and glove” distribution, first affecting the fingers and toes before migrating proximally to involve the arms and legs, respectively. Decreased sensitivity to vibration in the toes and loss of ankle jerk reflexes are the first observable signs of cisplatin-induced peripheral neuropathy. Despite loss of reflexes and proprioception impairment, pinprick, temperature sensation, and motor strength are initially maintained or less severely affected. Autonomic neuropathy was previously reported in multiple case reports; however, neuropathy rarely affects the autonomic nervous system. With prolonged treatment, patients develop significant burning, shooting, or electric-shock-like pain in the same distribution [3–5]. Signs also include generalized loss of deep tendon reflexes and worsening proximal impairment in vibration sensation. Rarely, patients may develop Lhermitte’s sign—an electric-shock-like sensation radiating cervico-caudally along the spine that can involve the arms, legs, or both and is provoked by neck flexion or rotation. It has been described in patients with direct tumor involvement of the spinal cord, in relation to radiotherapy, and with cisplatin treatment, and is believed to result from a transient demyelination of the posterior columns [6]. These painful symptoms of CIPN may persist well beyond discontinuation of treatment, sometimes permanently, and ultimately impede the quality of life of cancer patients. Prevalence of CIPN is also high. Rates have been reported as high as 84% in patients receiving cisplatin treatments [7]. Importantly, the likelihood of developing cisplatin-induced peripheral neuropathy is dose- and duration-dependent. Onset of the toxicity is expected to occur following cisplatin treatment at 250–350 mg/m², and cumulative doses of 500-600 mg/m² result in development of CIPN in almost all patients [8]. As cancer prevalence continues to increase, and along with it the use of chemotherapy, CIPN has become an urgent, unresolved medical problem for which there are no effective treatments or preventive measures available [3,9–11].

2. Platinum-Based Chemotherapy Agents: Mechanism of Action in Cancer Control and CIPN

Since cisplatin gained approval by the US Food and Drug Administration in the late 1970s for the treatment of testicular, ovarian, and bladder cancer, additional platinum-based chemotherapeutics have been developed, and clinical indications have grown to include several cancer types [12]. In fact, platinum-based drugs continue to be some of the mostly widely used anticancer treatments. However, despite over 40 years of research and identification of DNA as the major cellular target early on, the mechanisms involved in platinum-based therapy and related toxicity remain to be fully elucidated. Toxicity profiles and dose-limiting side effects differ between platinum drugs. Of the three agents currently used in the United States—cisplatin, carboplatin, and oxaliplatin—cisplatin and oxaliplatin have a higher neurotoxic potential than carboplatin. This difference in neurotoxicity reflects the reactivity of a specific platinum drug, specifically the lability of leaving groups as they bind different biomolecules, and determines the severity of the toxicity. Consequently, more labile drugs are more toxic. This lability is conferred by the positive charge created on metal ions with vacant d-orbitals which allows the ions to bind electronegative sites on proteins and nucleic acids [13]. All three agents inhibit normal DNA function through the formation of monoadducts and DNA crosslinks, processes that are exploited in anticancer therapy due to inherent differences between healthy tissue and cancer cells. Much of tumors’ sensitivity to platinum-based chemotherapeutics comes from differences in the DNA damage response (DDR) [14,15], as the majority of cancers are defective in at least one DDR pathway [16]. Of the four major repair pathways—double-strand break (DSB) repair, base excision repair, nucleotide excision repair (NER), and mismatch repair—NER is particularly relevant to platinum agents as discussed below.

Multiple mechanisms underlying neurotoxicity resulting from platinum-based chemotherapy have been proposed, yet treatment modalities remain elusive. Bodies of sensory neurons within the dorsal root ganglia (DRG) are believed to be the primary target of platinum agents [17–19], although Schwann cells, Langerhans cells, and macrophages could also play a role [20–22]. Increasing evidence shows hypersensitivity to mechanical and thermal stimuli commonly develops after preferential damage to DRG sensory fibers. This may be particularly relevant to CIPN due, in part, to the lack of the blood-brain barrier in the peripheral nervous system and the consequent exposure of its neurons to endogenous and exogenous agents, such as metabolites, inflammatory molecules, and environmental contaminants. Moreover, cisplatin has been demonstrated to preferentially bind to DNA in DRG neurons with a high propensity for platinum adduct formation. In addition to DNA injury, oxidative stress, and mitochondrial dysfunction [23–25], dysregulation of intracellular signaling pathways [26–28], voltage-gated ion channel dysfunction [29–31], and neuroinflammation [32] are among the proposed underlying mechanisms of CIPN.

Cisplatin’s effect on both healthy and cancer cells begins with its cellular uptake. Uptake and accumulation of systemically-administered cisplatin and its metabolites in the DRG allow for platinum-DNA adduct formation and are considered fundamental steps in neurotoxicity development. Preferential accumulation of cisplatin in the DRG results from the presence of an abundant fenestrated capillary network and the absence of the blood-brain barrier [30]. Together, these characteristics of the peripheral nervous system allow for easy access to sensory neurons by exogenous toxins.

Various transport mechanisms have been identified that might allow for uptake of cisplatin into DRG neurons. Two different types of neuronal membrane transporters: volume-regulated anion channel (VRAC), organic cation transporter-2 (OCT2), and copper transporter-1 (CTR1) have been shown to be particularly relevant, and their overexpression in neurons could contribute to the development or exacerbation of neurotoxicity. VRAC mediates anion and osmolyte fluxes to account for cell swelling and changes in tonicity and ionic strength within the cell [33]. It is composed of LRRC8 family members that assemble to form the channel. LRRC8A, an obligatory subunit of VRAC [34], has been shown to play a key role in cisplatin uptake in human embryonic kidney cells as demonstrated by a 70% reduction in cisplatin accumulation following disruption of LRRC8A [35]. Interestingly, DRG neurons have also been shown to express LRRC8A-encoding mRNA, and VRAC currents are inducible within the DRG [36]. Although the specific role VRAC, and specifically the LRRC8A subunit, play in cisplatin-mediated neurotoxicity has not yet been studied, literature suggests a dynamic relationship might exist. Similarly, OCT2 has been extensively studied in the uptake of cisplatin by renal proximal tubular cells leading to cisplatin-induced nephrotoxicity [37–39]. OCT2 is also highly expressed in the DRG. Neurons overexpressing mouse OCT2 and human OCT2 have demonstrated a 16- to 35-fold increase in the cellular oxaliplatin accumulation, resulting in a significant increase in DNA platination products and neurotoxicity [40]. Moreover, genetic and pharmacological inhibition of OCT2 has been shown to protect rats from oxaliplatin-induced peripheral neuropathy [41]. Finally, CTR1 is the primary copper influx transporter for cisplatin and has been localized in the DRG of normal rats as well as rats treated with cisplatin [42]. In vivo studies have demonstrated the CTR1-dependent uptake of cisplatin into DRG neurons and the resulting neuronal atrophy [43].

Once intracellular, cisplatin binds to neuronal nuclear and mitochondrial DNA with high affinity [44]. Cisplatin’s antineoplastic effects are achieved through the formation of platination products with nuclear DNA in a highly conserved manner. 1,2-intrastrand d (GpG) (between adjacent guanine bases on the same DNA strand) and 1,2-intrastrand d (ApG) (between adenine and adjacent guanine bases on the same DNA strand) crosslinks are the most common cisplatin-induced adducts [45–47]. Unless these DNA-base crosslinks are repaired, they distort DNA’s helical conformation, interrupting replication and transcription. Due to their relatively large size, high metabolic requirements, and long axons, DRG neurons need a high level of active transcription to sustain their physiological processes. In damaged DRG neurons, signaling pathways are eventually induced by the stalling of replication forks and/or RNA polymerases and lead to cell cycle arrest, senescence, or cell death [5,45–47]. Importantly, the abundance of adducts correlates to neurotoxicity and has been shown to be three times higher following cisplatin treatment compared to equimolar oxaliplatin doses. This is congruent with in vitro studies demonstrating that cisplatin causes significantly more neuronal cell death than oxaliplatin [17]. In vivo and in vitro studies have demonstrated that cisplatin induces several apoptotic events in neuronal cells, including Bcl-2 suppression [48], activation of p53 [49], Bax translocation, mitochondrial cytochrome c release, and caspase-3 and caspase-9 activation [30]. While these effects of cisplatin on cancer cells are desired for cancer treatment, the same process needs to be avoided in normal tissue to prevent treatment toxicity.

Although cisplatin-induced DNA damage is most widely studied in nuclear DNA, mitochondrial DNA (mtDNA) is not always spared. The first description of mitochondrial dysfunction in DRG neurons as a potential mechanism for cisplatin’s neurotoxicity was published less than 10 years ago. Those studies illustrated that cisplatin binds directly to mitochondrial DNA with a similar affinity as nuclear DNA. Moreover, these cisplatin-mtDNA adducts inhibited mitochondrial transcription and resulted in mitochondrial degradation and vacuolization [50]. Identification of NER proteins in recent years have also raised the question of whether mitochondria are able to undergo DNA repair through NER. CSA, CSB, and PARP1—key NER participants—are imported into the mitochondria in response to oxidative stress and bind to mtDNA, suggesting a possible dynamic role of NER in mitochondrial DNA repair [51].

3. Nucleotide Excision Repair

The ability of DRG neurons to repair their DNA after adduct formation is an important determinant of neurotoxicity severity. Without effective DNA repair, chronic cisplatin treatment results in accumulation of DNA-platinum adducts in DRG neurons. Not surprisingly, this accumulation of DNA lesions induces early neurophysiological changes that lead to an increase in neuronal cell death [30]. NER is a major cellular pathway through which cisplatin-induced DNA intrastrand crosslinks are resolved. NER in mammalian cells requires the coordination of major protein groups and can be divided into two subpathways: global-genome NER (GG-NER) and transcription-coupled NER (TC-NER). TC-NER and GG-NER differ in the protein complexes used in the initial recognition of DNA damage. GG-NER, which promotes genomic stability and prevents mutagenesis, requires xeroderma pigmentosum group C, specifically XPC-RAD23B, and DNA damage-binding complexes to survey the genome and recognize helix-distorting DNA crosslinks. TC-NER is initiated by the stalling of RNA polymerase at DNA lesions and signals Cockayne syndrome (CS) proteins CSA and CSB to bind to lesions in the DNA, remove transcription-blocking lesions, and restore transcription. Not surprisingly, TC-NER defects are responsible for multiple genetic disorders whose symptoms include photosensitivity; intellectual, developmental, and physical disability; and the progeria-like features of CS. Both GG-NER and TC-NER rely on XPA to bind to altered nucleotides in ssDNA and facilitate DNA damage verification by the TFIIH complex, thereby launching the NER process [52–55].

This entry is adapted from the peer-reviewed paper 10.3390/ijms22041975