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16 pages, 6212 KiB

Open AccessArticle

Modulation of Glutamate Transporter EAAT1 and Inward-Rectifier Potassium Channel K_ir4.1 Expression in Cultured Spinal Cord Astrocytes by Platinum-Based Chemotherapeutics

by Markus Leo, Linda-Isabell Schmitt, Rebecca Steffen, Andrea Kutritz, Christoph Kleinschnitz and Tim Hagenacker

Int. J. Mol. Sci. 2021, 22(12), 6300; https://doi.org/10.3390/ijms22126300 - 11 Jun 2021

Cited by 6 | Viewed by 2660

Abstract

Platinum-based chemotherapeutics still play an essential role in cancer treatment. Despite their high effectiveness, severe side effects such as chemotherapy-induced neuropathy (CIPN) occur frequently. The pathophysiology of CIPN by platinum-based chemotherapeutics is not fully understood yet, but primarily the disturbance of dorsal root [...] Read more.

Platinum-based chemotherapeutics still play an essential role in cancer treatment. Despite their high effectiveness, severe side effects such as chemotherapy-induced neuropathy (CIPN) occur frequently. The pathophysiology of CIPN by platinum-based chemotherapeutics is not fully understood yet, but primarily the disturbance of dorsal root ganglion cells is discussed. However, there is increasing evidence of central nervous system involvement with activation of spinal cord astrocytes after treatment with chemotherapeutics. We investigated the influence of cis- or oxaliplatin on the functionality of cultured rat spinal cord astrocytes by using immunocytochemistry and patch-clamp electrophysiology. Cis- or oxaliplatin activated spinal astrocytes and led to downregulation of the excitatory amino acid transporter 1 (EAAT1) expression. Furthermore, the expression and function of potassium channel K_ir4.1 were modulated. Pre-exposure to a specific Kir4.1 blocker in control astrocytes led to a reduced immune reactivity (IR) of EAAT1 and a nearly complete block of the current density. When spinal astrocytes were pre-exposed to antibiotic minocycline, all effects of cis- or oxaliplatin were abolished. Taken together, the modulation of K_ir4.1 and EAAT1 proteins in astrocytes could be linked to the direct impact of cis- or oxaliplatin, identifying spinal astrocytes as a potential target in the prevention and treatment of chemotherapy-induced neuropathy. Full article

(This article belongs to the Special Issue Mechanisms of Chemotherapy-Induced Peripheral Neuropathy)

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16 pages, 2531 KiB

Open AccessArticle

PEA-OXA Mitigates Oxaliplatin-Induced Painful Neuropathy through NF-κB/Nrf-2 Axis

by Michela Campolo, Marika Lanza, Irene Paterniti, Alessia Filippone, Alessio Ardizzone, Giovanna Casili, Sarah A. Scuderi, Caterina Puglisi, Marzia Mare, Lorenzo Memeo, Salvatore Cuzzocrea and Emanuela Esposito

Int. J. Mol. Sci. 2021, 22(8), 3927; https://doi.org/10.3390/ijms22083927 - 10 Apr 2021

Cited by 14 | Viewed by 3542

Abstract

Chemotherapy-induced neuropathy is a common, dose-dependent adverse effect of several antineoplastics, such as oxaliplatin (L-OHP). The aim of the present work was to evaluate the potential beneficial effects of 2-pentadecyl-2-oxazoline (PEA-OXA) in a murine model of oxaliplatin-induced peripheral neuropathy (OIPN). OIPN was induced [...] Read more.

Chemotherapy-induced neuropathy is a common, dose-dependent adverse effect of several antineoplastics, such as oxaliplatin (L-OHP). The aim of the present work was to evaluate the potential beneficial effects of 2-pentadecyl-2-oxazoline (PEA-OXA) in a murine model of oxaliplatin-induced peripheral neuropathy (OIPN). OIPN was induced by an intraperitoneally injection of L-OHP in rats on five consecutive days (D0–4) for a final cumulative dose of 10 mg/kg. PEA-OXA and ultramicronized palmitoylethanolamide (PEAum), both 10 mg/kg, were given orally 15–20 min prior (L-OHP) and sacrifice was made on day 25. Our results demonstrated that PEA-OXA, more than PEAum, reduced the development of hypersensitivity in rats; this was associated with the reduction in hyperactivation of glia cells and the increased production of proinflammatory cytokines in the dorsal horn of the spinal cord, accompanied by an upregulation of neurotrophic factors in the dorsal root ganglia (DRG). Moreover, we showed that PEA-OXA reduced L-OHP damage via a reduction in NF-κB pathway activation and a modulation of Nrf-2 pathways. Our findings identify PEA-OXA as a therapeutic target in chemotherapy-induced painful neuropathy, through the biomolecular signaling NF-κB/Nrf-2 axis, thanks to its abilities to counteract L-OHP damage. Therefore, we can consider PEA-OXA as a promising adjunct to chemotherapy to reduce chronic pain in patients. Full article

(This article belongs to the Special Issue Mechanisms of Chemotherapy-Induced Peripheral Neuropathy)

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Review

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13 pages, 939 KiB

Open AccessReview

Mechanisms, Characteristics, and Treatment of Neuropathic Pain and Peripheral Neuropathy Associated with Dinutuximab in Neuroblastoma Patients

by Stefano Mastrangelo, Serena Rivetti, Silvia Triarico, Alberto Romano, Giorgio Attinà, Palma Maurizi and Antonio Ruggiero

Int. J. Mol. Sci. 2021, 22(23), 12648; https://doi.org/10.3390/ijms222312648 - 23 Nov 2021

Cited by 12 | Viewed by 3013

Abstract

Prognosis of metastatic neuroblastoma is very poor. Its treatment includes induction chemotherapy, surgery, high-dose chemotherapy, radiotherapy, and maintenance with retinoic acid, associated with the anti-GD2 monoclonal antibody (ch14.18) dinutuximab. Immunotherapy determined a significant improvement in survival rate and is also utilized in relapsed [...] Read more.

Prognosis of metastatic neuroblastoma is very poor. Its treatment includes induction chemotherapy, surgery, high-dose chemotherapy, radiotherapy, and maintenance with retinoic acid, associated with the anti-GD2 monoclonal antibody (ch14.18) dinutuximab. Immunotherapy determined a significant improvement in survival rate and is also utilized in relapsed and resistant neuroblastoma patients. Five courses of dinutuximab 100 mg/m² are usually administered as a 10-day continuous infusion or over 5 consecutive days every 5 weeks. Dinutuximab targets the disialoganglioside GD2, which is highly expressed on neuroblastoma cells and minimally present on the surface of normal human neurons, peripheral pain fibers, and skin melanocytes. Anti GD2 antibodies bind to surface GD2 and determine the lysis of neuroblastoma cells induced by immune response via the antibody-dependent cellular cytotoxicity and the complement-dependent cytotoxicity. Dinutuximab has significant side effects, including neuropathic pain, peripheral neuropathy, hypersensitivity reactions, capillary leak syndrome, photophobia, and hypotension. The most important side effect is neuropathic pain, which is triggered by the same antibody–antigen immune response, but generates ectopic activity in axons, which results in hyperalgesia and spontaneous pain. Pain can be severe especially in the first courses of dinutuximab infusion, and requires the administration of gabapentin and continuous morphine infusion. This paper will focus on the incidence, mechanisms, characteristics, and treatment of neuropathic pain and peripheral neuropathy due to dinutuximab administration in neuroblastoma patients. Full article

(This article belongs to the Special Issue Mechanisms of Chemotherapy-Induced Peripheral Neuropathy)

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27 pages, 380 KiB

Open AccessReview

Preclinical and Clinical Evidence of Therapeutic Agents for Paclitaxel-Induced Peripheral Neuropathy

by Takehiro Kawashiri, Mizuki Inoue, Kohei Mori, Daisuke Kobayashi, Keisuke Mine, Soichiro Ushio, Hibiki Kudamatsu, Mayako Uchida, Nobuaki Egashira and Takao Shimazoe

Int. J. Mol. Sci. 2021, 22(16), 8733; https://doi.org/10.3390/ijms22168733 - 13 Aug 2021

Cited by 15 | Viewed by 3329

Abstract

Paclitaxel is an essential drug in the chemotherapy of ovarian, non-small cell lung, breast, gastric, endometrial, and pancreatic cancers. However, it frequently causes peripheral neuropathy as a dose-limiting factor. Animal models of paclitaxel-induced peripheral neuropathy (PIPN) have been established. The mechanisms of PIPN [...] Read more.

Paclitaxel is an essential drug in the chemotherapy of ovarian, non-small cell lung, breast, gastric, endometrial, and pancreatic cancers. However, it frequently causes peripheral neuropathy as a dose-limiting factor. Animal models of paclitaxel-induced peripheral neuropathy (PIPN) have been established. The mechanisms of PIPN development have been elucidated, and many drugs and agents have been proven to have neuroprotective effects in basic studies. In addition, some of these drugs have been validated in clinical studies for their inhibitory PIPN effects. This review summarizes the basic and clinical evidence for therapeutic or prophylactic effects for PIPN. In pre-clinical research, many reports exist of neuropathy inhibitors that target oxidative stress, inflammatory response, ion channels, transient receptor potential (TRP) channels, cannabinoid receptors, and the monoamine nervous system. Alternatively, very few drugs have demonstrated PIPN efficacy in clinical trials. Thus, enhancing translational research to translate pre-clinical research into clinical research is important. Full article

(This article belongs to the Special Issue Mechanisms of Chemotherapy-Induced Peripheral Neuropathy)

13 pages, 1067 KiB

Open AccessReview

Vincristine-Induced Peripheral Neuropathy (VIPN) in Pediatric Tumors: Mechanisms, Risk Factors, Strategies of Prevention and Treatment

by Silvia Triarico, Alberto Romano, Giorgio Attinà, Michele Antonio Capozza, Palma Maurizi, Stefano Mastrangelo and Antonio Ruggiero

Int. J. Mol. Sci. 2021, 22(8), 4112; https://doi.org/10.3390/ijms22084112 - 16 Apr 2021

Cited by 73 | Viewed by 11530

Abstract

Vincristine-induced peripheral neurotoxicity (VIPN) is a very common side effect of vincristine chemotherapy among pediatric patients with cancer. Neuropathy may be sensory, motor and/or autonomic, with consequent reduction, delay or discontinuation of vincristine-chemotherapy, but also pain, disability, reduced quality of life of patients [...] Read more.

Vincristine-induced peripheral neurotoxicity (VIPN) is a very common side effect of vincristine chemotherapy among pediatric patients with cancer. Neuropathy may be sensory, motor and/or autonomic, with consequent reduction, delay or discontinuation of vincristine-chemotherapy, but also pain, disability, reduced quality of life of patients and an increase in medical costs. Vincristine acts out its antineoplastic function by altering the normal assembly and disassembly of microtubules, with their consequent mitosis block and death. Vincristine leads to VIPN through a complex mechanism of damage, which occurs not only on the microtubules, but also on the endothelium and the mitochondria of nerve cells. Furthermore, both patient-related risk factors (age, race, ethnicity and genetic polymorphisms) and treatment-related risk factors (dose, time of infusion and drug–drug interactions) are involved in the pathogenesis of VIPN. There is a lack of consensus about the prophylaxis and treatment of VIPN among pediatric oncologic patients, despite several molecules (such as gabapentin, pyridoxine and pyridostigmine, glutamic acid and glutamine) having been already investigated in clinical trials. This review describes the molecular mechanisms of VIPN and analyzes the risk factors and the principal drugs adopted for the prophylaxis and treatment of VIPN in pediatric patients with cancer. Full article

(This article belongs to the Special Issue Mechanisms of Chemotherapy-Induced Peripheral Neuropathy)

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19 pages, 649 KiB

Open AccessReview

Modulation by Ozone Therapy of Oxidative Stress in Chemotherapy-Induced Peripheral Neuropathy: The Background for a Randomized Clinical Trial

by Bernardino Clavo, Gregorio Martínez-Sánchez, Francisco Rodríguez-Esparragón, Delvys Rodríguez-Abreu, Saray Galván, David Aguiar-Bujanda, Juan A. Díaz-Garrido, Silvia Cañas, Laura B. Torres-Mata, Himar Fabelo, Teresa Téllez, Norberto Santana-Rodríguez, Leandro Fernández-Pérez and Gustavo Marrero-Callico

Int. J. Mol. Sci. 2021, 22(6), 2802; https://doi.org/10.3390/ijms22062802 - 10 Mar 2021

Cited by 16 | Viewed by 5522

Abstract

(1) Background: Chemotherapy-induced peripheral neuropathy (CIPN) decreases the quality of life of patients and can lead to a dose reduction and/or the interruption of chemotherapy treatment, limiting its effectiveness. Potential pathophysiological mechanisms involved in the pathogenesis of CIPN include chronic oxidative stress and [...] Read more.

(1) Background: Chemotherapy-induced peripheral neuropathy (CIPN) decreases the quality of life of patients and can lead to a dose reduction and/or the interruption of chemotherapy treatment, limiting its effectiveness. Potential pathophysiological mechanisms involved in the pathogenesis of CIPN include chronic oxidative stress and subsequent increase in free radicals and proinflammatory cytokines. Approaches for the treatment of CIPN are highly limited in their number and efficacy, although several antioxidant-based therapies have been tried. On the other hand, ozone therapy can induce an adaptive antioxidant and anti-inflammatory response, which could be potentially useful in the management of CIPN. (2) Methods: The aims of this works are: (a) to summarize the potential mechanisms that could induce CIPN by the most relevant drugs (platinum, taxanes, vinca alkaloids, and bortezomib), with particular focus on the role of oxidative stress; (b) to summarize the current situation of prophylactic and treatment approaches; (c) to describe the action mechanisms of ozone therapy to modify oxidative stress and inflammation with its potential repercussions for CIPN; (d) to describe related experimental and clinical reports with ozone therapy in chemo-induced neurologic symptoms and CIPN; and (e) to show the main details about an ongoing focused clinical trial. (3) Results: A wide background relating to the mechanisms of action and a small number of experimental and clinical reports suggest that ozone therapy could be useful to prevent or improve CIPN. (4) Conclusions: Currently, there are no clinically relevant approaches for the prevention and treatment of stablished CIPN. The potential role of ozone therapy in this syndrome merits further research. Randomized controlled trials are ongoing. Full article

(This article belongs to the Special Issue Mechanisms of Chemotherapy-Induced Peripheral Neuropathy)

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22 pages, 449 KiB

Open AccessReview

Peripheral Neuropathy under Oncologic Therapies: A Literature Review on Pathogenetic Mechanisms

by Mariarita Laforgia, Carmelo Laface, Concetta Calabrò, Simona Ferraiuolo, Valentina Ungaro, Domenico Tricarico, Cosmo Damiano Gadaleta, Patrizia Nardulli and Girolamo Ranieri

Int. J. Mol. Sci. 2021, 22(4), 1980; https://doi.org/10.3390/ijms22041980 - 17 Feb 2021

Cited by 28 | Viewed by 3864

Abstract

Peripheral neurologic complications are frequent adverse events during oncologic treatments and often lead to dose reduction, administration delays with time elongation of the therapeutic plan and, not least, worsening of patients’ quality of life. Experience skills are required to recognize symptoms and clinical [...] Read more.

Peripheral neurologic complications are frequent adverse events during oncologic treatments and often lead to dose reduction, administration delays with time elongation of the therapeutic plan and, not least, worsening of patients’ quality of life. Experience skills are required to recognize symptoms and clinical evidences and the collaboration between different health professionals, in particular oncologists and hospital pharmacists, grants a correct management of this undesirable occurrence. Some classes of drugs (platinates, vinca alkaloids, taxanes) typically develop this kind of side effect, but the genesis of chemotherapy-induced peripheral neuropathy is not linked to a single mechanism. This paper aims from one side at summarizing and explaining all the scattering mechanisms of chemotherapy-induced peripheral neuropathy through a detailed literature revision, on the other side at finding new approaches to possible treatments, in order to facilitate the collaboration between oncologists, hematologists and hospital pharmacists. Full article

(This article belongs to the Special Issue Mechanisms of Chemotherapy-Induced Peripheral Neuropathy)

15 pages, 570 KiB

Open AccessReview

The Role of Nucleotide Excision Repair in Cisplatin-Induced Peripheral Neuropathy: Mechanism, Prevention, and Treatment

by Scarlett Acklin and Fen Xia

Int. J. Mol. Sci. 2021, 22(4), 1975; https://doi.org/10.3390/ijms22041975 - 17 Feb 2021

Cited by 10 | Viewed by 2954

Abstract

Platinum-based chemotherapy-induced peripheral neuropathy (CIPN) is one of the most common dose-limiting effects of cancer treatment and results in dose reduction and discontinuation of life-saving chemotherapy. Its debilitating effects are often permanent and lead to lifelong impairment of quality of life in cancer [...] Read more.

Platinum-based chemotherapy-induced peripheral neuropathy (CIPN) is one of the most common dose-limiting effects of cancer treatment and results in dose reduction and discontinuation of life-saving chemotherapy. Its debilitating effects are often permanent and lead to lifelong impairment of quality of life in cancer patients. While the mechanisms underlying the toxicity are not yet fully defined, dorsal root ganglia sensory neurons play an integral role in symptom development. DNA-platinum adducts accumulate in these cells and inhibit normal cellular function. Nucleotide excision repair (NER) is integral to the repair of platinum adducts, and proteins involved in its mechanism serve as potential targets for future therapeutics. This review aims to highlight NER’s role in cisplatin-induced peripheral neuropathy, summarize current clinical approaches to the toxicity, and discuss future perspectives for the prevention and treatment of CIPN. Full article

(This article belongs to the Special Issue Mechanisms of Chemotherapy-Induced Peripheral Neuropathy)

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25 pages, 398 KiB

Open AccessReview

Therapeutic Agents for Oxaliplatin-Induced Peripheral Neuropathy; Experimental and Clinical Evidence

by Takehiro Kawashiri, Keisuke Mine, Daisuke Kobayashi, Mizuki Inoue, Soichiro Ushio, Mayako Uchida, Nobuaki Egashira and Takao Shimazoe

Int. J. Mol. Sci. 2021, 22(3), 1393; https://doi.org/10.3390/ijms22031393 - 30 Jan 2021

Cited by 17 | Viewed by 5246

Abstract

Oxaliplatin is an essential drug in the chemotherapy of colorectal, gastric, and pancreatic cancers, but it frequently causes peripheral neuropathy as a dose-limiting factor. So far, animal models of oxaliplatin-induced peripheral neuropathy have been established. The mechanisms of development of neuropathy induced by [...] Read more.

Oxaliplatin is an essential drug in the chemotherapy of colorectal, gastric, and pancreatic cancers, but it frequently causes peripheral neuropathy as a dose-limiting factor. So far, animal models of oxaliplatin-induced peripheral neuropathy have been established. The mechanisms of development of neuropathy induced by oxaliplatin have been elucidated, and many drugs and agents have been proven to have neuroprotective effects in basic studies. In addition, some of these drugs have been validated in clinical studies for their inhibitory effects on neuropathy. In this review, we summarize the basic and clinical evidence for the therapeutic effects of oxaliplatin. In basic research, there are many reports of neuropathy inhibitors that target oxidative stress, inflammatory response, sodium channel, transient receptor potential (TRP) channel, glutamate nervous system, and monoamine nervous system. Alternatively, very few drugs have clearly demonstrated the efficacy for oxaliplatin-induced peripheral neuropathy in clinical trials. It is important to activate translational research in order to translate basic research into clinical research. Full article

(This article belongs to the Special Issue Mechanisms of Chemotherapy-Induced Peripheral Neuropathy)

14 pages, 2741 KiB

Open AccessReview

Pathological Mechanisms of Bortezomib-Induced Peripheral Neuropathy

by Shota Yamamoto and Nobuaki Egashira

Int. J. Mol. Sci. 2021, 22(2), 888; https://doi.org/10.3390/ijms22020888 - 17 Jan 2021

Cited by 58 | Viewed by 6266

Abstract

Bortezomib, a first-generation proteasome inhibitor widely used in chemotherapy for hematologic malignancy, has effective anti-cancer activity but often causes severe peripheral neuropathy. Although bortezomib-induced peripheral neuropathy (BIPN) is a dose-limiting toxicity, there are no recommended therapeutics for its prevention or treatment. One of [...] Read more.

Bortezomib, a first-generation proteasome inhibitor widely used in chemotherapy for hematologic malignancy, has effective anti-cancer activity but often causes severe peripheral neuropathy. Although bortezomib-induced peripheral neuropathy (BIPN) is a dose-limiting toxicity, there are no recommended therapeutics for its prevention or treatment. One of the most critical problems is a lack of knowledge about pathological mechanisms of BIPN. Here, we summarize the known mechanisms of BIPN based on preclinical evidence, including morphological abnormalities, involvement of non-neuronal cells, oxidative stress, and alterations of transcriptional programs in both the peripheral and central nervous systems. Moreover, we describe the necessity of advancing studies that identify the potential efficacy of approved drugs on the basis of pathological mechanisms, as this is a convincing strategy for rapid translation to patients with cancer and BIPN. Full article

(This article belongs to the Special Issue Mechanisms of Chemotherapy-Induced Peripheral Neuropathy)

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18 pages, 2356 KiB

Open AccessReview

Role of HMGB1 in Chemotherapy-Induced Peripheral Neuropathy

by Fumiko Sekiguchi and Atsufumi Kawabata

Int. J. Mol. Sci. 2021, 22(1), 367; https://doi.org/10.3390/ijms22010367 - 31 Dec 2020

Cited by 16 | Viewed by 4397

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN), one of major dose-limiting side effects of first-line chemotherapeutic agents such as paclitaxel, oxaliplatin, vincristine, and bortezomib is resistant to most of existing medicines. The molecular mechanisms of CIPN have not been fully understood. High mobility group box 1 [...] Read more.

Chemotherapy-induced peripheral neuropathy (CIPN), one of major dose-limiting side effects of first-line chemotherapeutic agents such as paclitaxel, oxaliplatin, vincristine, and bortezomib is resistant to most of existing medicines. The molecular mechanisms of CIPN have not been fully understood. High mobility group box 1 (HMGB1), a nuclear protein, is a damage-associated molecular pattern protein now considered to function as a pro-nociceptive mediator once released to the extracellular space. Most interestingly, HMGB1 plays a key role in the development of CIPN. Soluble thrombomodulin (TMα), known to degrade HMGB1 in a thrombin-dependent manner, prevents CIPN in rodents treated with paclitaxel, oxaliplatin, or vincristine and in patients with colorectal cancer undergoing oxaliplatin-based chemotherapy. In this review, we describe the role of HMGB1 and its upstream/downstream mechanisms in the development of CIPN and show drug candidates that inhibit the HMGB1 pathway, possibly useful for prevention of CIPN. Full article

(This article belongs to the Special Issue Mechanisms of Chemotherapy-Induced Peripheral Neuropathy)

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