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Ahlström FH, Viisanen H, Karhinen L, Velagapudi V, Blomqvist KJ, Lilius TO, Rauhala PV, Kalso EA. Gene expression in the dorsal root ganglion and the cerebrospinal fluid metabolome in polyneuropathy and opioid tolerance in rats. IBRO Neurosci Rep 2024; 17:38-51. [PMID: 38933596 PMCID: PMC11201153 DOI: 10.1016/j.ibneur.2024.05.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Revised: 05/13/2024] [Accepted: 05/20/2024] [Indexed: 06/28/2024] Open
Abstract
First-line pharmacotherapy for peripheral neuropathic pain (NP) of diverse pathophysiology consists of antidepressants and gabapentinoids, but only a minority achieve sufficient analgesia with these drugs. Opioids are considered third-line analgesics in NP due to potential severe and unpredictable adverse effects in long-term use. Also, opioid tolerance and NP may have shared mechanisms, raising further concerns about opioid use in NP. We set out to further elucidate possible shared and separate mechanisms after chronic morphine treatment and oxaliplatin-induced and diabetic polyneuropathies, and to identify potential diagnostic markers and therapeutic targets. We analysed thermal nociceptive behaviour, the transcriptome of dorsal root ganglia (DRG) and the metabolome of cerebrospinal fluid (CSF) in these three conditions, in rats. Several genes were differentially expressed, most following oxaliplatin and least after chronic morphine treatment, compared with saline-treated rats. A few genes were differentially expressed in the DRGs in all three models (e.g. Csf3r and Fkbp5). Some, e.g. Alox15 and Slc12a5, were differentially expressed in both diabetic and oxaliplatin models. Other differentially expressed genes were associated with nociception, inflammation, and glial cells. The CSF metabolome was most significantly affected in the diabetic rats. Interestingly, we saw changes in nicotinamide metabolism, which has been associated with opioid addiction and withdrawal, in the CSF of morphine-tolerant rats. Our results offer new hypotheses for the pathophysiology and treatment of NP and opioid tolerance. In particular, the role of nicotinamide metabolism in opioid addiction deserves further study.
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Affiliation(s)
- Fredrik H.G. Ahlström
- Department of Pharmacology, Faculty of Medicine, Biomedicum 1, University of Helsinki, Haartmaninkatu 8, 00014, Finland
- Individualized Drug Therapy Research Programme, Faculty of Medicine, Biomedicum 1, University of Helsinki, Haartmaninkatu 8, 00014, Finland
| | - Hanna Viisanen
- Department of Pharmacology, Faculty of Medicine, Biomedicum 1, University of Helsinki, Haartmaninkatu 8, 00014, Finland
- Individualized Drug Therapy Research Programme, Faculty of Medicine, Biomedicum 1, University of Helsinki, Haartmaninkatu 8, 00014, Finland
| | - Leena Karhinen
- Department of Pharmacology, Faculty of Medicine, Biomedicum 1, University of Helsinki, Haartmaninkatu 8, 00014, Finland
| | - Vidya Velagapudi
- Metabolomics Unit, Institute for Molecular Medicine Finland FIMM, University of Helsinki, P.O. Box 20, FI-00014, Finland
| | - Kim J. Blomqvist
- Department of Pharmacology, Faculty of Medicine, Biomedicum 1, University of Helsinki, Haartmaninkatu 8, 00014, Finland
- Individualized Drug Therapy Research Programme, Faculty of Medicine, Biomedicum 1, University of Helsinki, Haartmaninkatu 8, 00014, Finland
| | - Tuomas O. Lilius
- Department of Pharmacology, Faculty of Medicine, Biomedicum 1, University of Helsinki, Haartmaninkatu 8, 00014, Finland
- Individualized Drug Therapy Research Programme, Faculty of Medicine, Biomedicum 1, University of Helsinki, Haartmaninkatu 8, 00014, Finland
- Department of Clinical Pharmacology, University of Helsinki and Helsinki University Hospital, Tukholmankatu 8C, 00014, Finland
- Department of Emergency Medicine and Services, University of Helsinki and HUS Helsinki University Hospital, Haartmaninkatu 4, Helsinki 00290, Finland
| | - Pekka V. Rauhala
- Department of Pharmacology, Faculty of Medicine, Biomedicum 1, University of Helsinki, Haartmaninkatu 8, 00014, Finland
- Individualized Drug Therapy Research Programme, Faculty of Medicine, Biomedicum 1, University of Helsinki, Haartmaninkatu 8, 00014, Finland
| | - Eija A. Kalso
- Department of Pharmacology, Faculty of Medicine, Biomedicum 1, University of Helsinki, Haartmaninkatu 8, 00014, Finland
- SleepWell Research Programme, Faculty of Medicine, , University of Helsinki, Haartmaninkatu 3, 00014, Finland
- Department of Anaesthesiology and Intensive Care Medicine, Helsinki University Hospital and University of Helsinki, HUS, Stenbäckinkatu 9, P.O. Box 440, 00029, Finland
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Ünel ÇÇ, Eroğlu E, Özatik O, Erol K. Chlorogenic acid co-administration alleviates cisplatin-induced peripheral neuropathy in rats. Fundam Clin Pharmacol 2024; 38:523-537. [PMID: 37996998 DOI: 10.1111/fcp.12970] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 10/06/2023] [Accepted: 11/02/2023] [Indexed: 11/25/2023]
Abstract
BACKGROUND Chemotherapy-induced peripheral neuropathy (CIPN) is still an unresolved problem in cisplatin (CIS) use. OBJECTIVES This study investigates possible anti-neuropathic effect of chlorogenic acid (CGA) against CIS-induced CIPN in rats while also investigating the contribution of nitric oxide (NO) to this phenomenon. METHODS Initially, CGA (250-1000 μM) was tested by MTT assay on primary DRG neurons. Subsequently, CIPN was induced in Sprague-Dawley rats by 3 mg/kg intraperitoneal injections of CIS once/week for 5 weeks. CGA (100 mg/kg) was co-administered with CIS, both alone and in combination with l-arginine (LARG) or l-nitro-arginine-methyl-ester (LNAME), to elucidate the contribution of nitrergic system to anti-neuropathic effects. Mechanical allodynia, thermal hyperalgesia, and cold plate tests were performed to test CIPN. Rotarod, footprint analysis, and activitymeter were used to evaluate motor coordination and performance. Tumor necrosis factor alpha (TNF-α) was measured as a marker of inflammation. Histological evaluations of DRG and sciatic nerves (SNs) were performed utilizing toluidine blue staining. Two-way analysis of variance and Kruskal-Wallis following Tukey's test were used as statistical analysis. RESULTS Higher concentration of CGA (1000 μM) exhibited protective effect against in vitro neurotoxicity. Neither LARG nor LNAME exerted significant change in this effect. Co-administration of CGA alleviated histological abnormalities and neuropathic effects induced by CIS. Ameliorative effect of CGA was not changed in mechanical allodynia but attenuated in cold allodynia, and motor activity/coordination tests by LARG and LNAME. Neuropathic effects of CIS remained unchanged with LARG and LNAME in behavioral experiments. CONCLUSION The study identified CGA as candidate agent in mitigating CIPN. NO seems to play a modulatory role in this effect.
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Affiliation(s)
- Çiğdem Çengelli Ünel
- Faculty of Medicine, Department of Medical Pharmacology, Eskisehir Osmangazi University, Eskisehir, Turkey
| | - Ezgi Eroğlu
- Department of Clinical Research, Turkish Medicines and Medical Devices Agency, Ankara, Turkey
| | - Orhan Özatik
- Faculty of Medicine, Department of Histology and Embryology, Kutahya Health Sciences University, Kutahya, Turkey
| | - Kevser Erol
- Faculty of Medicine, Department of Pharmacology, Bahçeşehir University, Istanbul, Turkey
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Biagioni C, Traini C, Faussone‐Pellegrini MS, Idrizaj E, Baccari MC, Vannucchi MG. Prebiotics counteract the morphological and functional changes secondary to chronic cisplatin exposition in the proximal colon of mice. J Cell Mol Med 2024; 28:e18161. [PMID: 38445787 PMCID: PMC10915824 DOI: 10.1111/jcmm.18161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 01/05/2024] [Accepted: 01/18/2024] [Indexed: 03/07/2024] Open
Abstract
Cisplatin is an antimitotic drug able to cause acute and chronic gastrointestinal side effects. Acute side effects are attributable to mucositis while chronic ones are due to neuropathy. Cisplatin has also antibiotic properties inducing dysbiosis which enhances the inflammatory response, worsening local damage. Thus, a treatment aimed at protecting the microbiota could prevent or reduce the toxicity of chemotherapy. Furthermore, since a healthy microbiota enhances the effects of some chemotherapeutic drugs, prebiotics could also improve this drug effectiveness. We investigated whether chronic cisplatin administration determined morphological and functional alterations in mouse proximal colon and whether a diet enriched in prebiotics had protective effects. The results showed that cisplatin caused lack of weight gain, increase in kaolin intake, decrease in stool production and mucus secretion. Prebiotics prevented increases in kaolin intake, changes in stool production and mucus secretion, but had no effect on the lack of weight gain. Moreover, cisplatin determined a reduction in amplitude of spontaneous muscular contractions and of Connexin (Cx)43 expression in the interstitial cells of Cajal, changes that were partially prevented by prebiotics. In conclusion, the present study shows that daily administration of prebiotics, likely protecting the microbiota, prevents most of the colonic cisplatin-induced alterations.
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Affiliation(s)
- Cristina Biagioni
- Research Unit of Histology and Embryology, Department of Experimental and Clinical MedicineUniversity of FlorenceFlorenceItaly
| | - Chiara Traini
- Research Unit of Histology and Embryology, Department of Experimental and Clinical MedicineUniversity of FlorenceFlorenceItaly
| | | | - Eglantina Idrizaj
- Section of Physiological Sciences, Department of Experimental and Clinical MedicineUniversity of FlorenceFlorenceItaly
| | - Maria Caterina Baccari
- Section of Physiological Sciences, Department of Experimental and Clinical MedicineUniversity of FlorenceFlorenceItaly
| | - Maria Giuliana Vannucchi
- Research Unit of Histology and Embryology, Department of Experimental and Clinical MedicineUniversity of FlorenceFlorenceItaly
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Ali M, Aziz T. The Combination of Zinc and Melatonin Enhanced Neuroprotection and Attenuated Neuropathy in Oxaliplatin-Induced Neurotoxicity. Drug Des Devel Ther 2022; 16:3447-3463. [PMID: 36217449 PMCID: PMC9547652 DOI: 10.2147/dddt.s385914] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Accepted: 09/22/2022] [Indexed: 11/23/2022] Open
Abstract
Objective The present study was designed to investigate the possible synergistic effects of melatonin with zinc in the prevention and treatment of oxaliplatin-induced neurotoxicity in rats. Methodology Forty-eight male Wistar albino rats were used and randomly allocated into six groups: The negative control group, oxaliplatin group, zinc + oxaliplatin group, melatonin + oxaliplatin group, zinc + melatonin + oxaliplatin prevention-approach group, and zinc + melatonin + oxaliplatin treatment-approach group. The thermal nociceptive/hyperalgesia tests were performed. Brain tissue homogenate was used for measuring GFAP, NCAM, TNF α, MAPK 14, NF-kB, GPX, and SOD. Brain tissue was sent for histopathological and immunohistochemistry studies. Results The combination therapies showed improvement in the behavioral tests. A significant increase in GPX and SOD with a significant decrease in GFAP levels resulted in the prevention approach. TNF α decreased significantly in the treatment approach. No significant changes were seen in NCAM, NFkB, and MAPK-14. The histopathological findings support the biochemical results. Additionally, immunohistochemistry revealed a significant attenuation of p53 and a non-significant decrease in Bcl2 levels in the combination groups. Conclusion The combination of zinc with melatonin for the prevention approach was effective in attenuating neurotoxicity induced by oxaliplatin. The proposed mechanisms are boosting the antioxidant system and attenuating the expression of p53, GFAP, and TNF-α.
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Affiliation(s)
- Mayyadah Ali
- Hiwa Cancer Hospital, Sulaimani, Kurdistan Region, Iraq
| | - Tavga Aziz
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Sulaimani, Sulaimani, Kurdistan Region, Iraq,Correspondence: Tavga Aziz, Tel +9647701523544, Email
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Hadi H, Safari R. Synthesis and experimental/theoretical evaluation of an efficient Calix[4]arene based sensor for selective detection of Pt 2+ ion. Mol Phys 2022. [DOI: 10.1080/00268976.2022.2108516] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/15/2022]
Affiliation(s)
- Hamid Hadi
- Faculty of Science, Department of Chemistry (Physical Chemistry Group), University of Lorestan, Khorramabad, Iran
- Faculty of Science, Department of Chemistry (Physical Chemistry Group), University of Qom, Qom, Iran
| | - Reza Safari
- Faculty of Science, Department of Chemistry (Physical Chemistry Group), University of Qom, Qom, Iran
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Saward JB, Ellis EG, Cobden AL, Caeyenberghs K. Mapping cognitive deficits in cancer patients after chemotherapy: An Activation Likelihood Estimation meta-analysis of task-related fMRI studies. Brain Imaging Behav 2022; 16:2320-2334. [PMID: 35366180 PMCID: PMC9581855 DOI: 10.1007/s11682-022-00655-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/26/2022] [Indexed: 12/23/2022]
Abstract
Recent neuroimaging studies have reported alterations in brain activation during cognitive tasks in cancer patients who have undergone chemotherapy treatment. However, the location of these altered brain activation patterns after chemotherapy varies considerably across studies. The aim of the present meta-analysis was to quantitatively synthesise this body of evidence using Activation Likelihood Estimation to identify reliable regions of altered brain activation in cancer patients treated with chemotherapy, compared to healthy controls and no chemotherapy controls. Our systematic search identified 12 studies that adopted task-related fMRI on non-central nervous system cancer patients who received chemotherapy relative to controls. All studies were included in the analyses and were grouped into four contrasts. Cancer patients treated with chemotherapy showed reduced activation in the left superior parietal lobe/precuneus (family-wise error corrected p < .05) compared to no chemotherapy controls. No significant clusters were found in three of our contrasts. The majority of studies did not support an association between altered brain activation and cognitive performance after chemotherapy. Findings point towards a possible chemotherapy-induced alteration, which could inform targeted treatment strategies. With continued work in this field using homogenous task-related protocols and cancer populations, fMRI may be used as a biomarker of cognitive deficits in the future.
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Affiliation(s)
- Jacqueline B Saward
- Cognitive Neuroscience Unit, School of Psychology, Deakin University, Melbourne Burwood Campus, 221 Burwood Highway, Burwood, VIC, 3125, Australia.
| | - Elizabeth G Ellis
- Cognitive Neuroscience Unit, School of Psychology, Deakin University, Melbourne Burwood Campus, 221 Burwood Highway, Burwood, VIC, 3125, Australia
| | - Annalee L Cobden
- Cognitive Neuroscience Unit, School of Psychology, Deakin University, Melbourne Burwood Campus, 221 Burwood Highway, Burwood, VIC, 3125, Australia
| | - Karen Caeyenberghs
- Cognitive Neuroscience Unit, School of Psychology, Deakin University, Melbourne Burwood Campus, 221 Burwood Highway, Burwood, VIC, 3125, Australia
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Behrouzi A, Xia H, Thompson EL, Kelley MR, Fehrenbacher JC. Oxidative DNA Damage and Cisplatin Neurotoxicity Is Exacerbated by Inhibition of OGG1 Glycosylase Activity and APE1 Endonuclease Activity in Sensory Neurons. Int J Mol Sci 2022; 23:ijms23031909. [PMID: 35163831 PMCID: PMC8836551 DOI: 10.3390/ijms23031909] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 02/01/2022] [Accepted: 02/03/2022] [Indexed: 02/04/2023] Open
Abstract
Cisplatin can induce peripheral neuropathy, which is a common complication of anti-cancer treatment and negatively impacts cancer survivors during and after completion of treatment; therefore, the mechanisms by which cisplatin alters sensory neuronal function to elicit neuropathy are the subject of much investigation. Our previous work suggests that the DNA repair activity of APE1/Ref-1, the rate-limiting enzyme of the base excision repair (BER) pathway, is critical for neuroprotection against cisplatin. A specific role for 8-oxoguanine DNA glycosylase-1 (OGG1), the glycosylase that removes the most common oxidative DNA lesion, and putative coordination of OGG1 with APE1/Ref-1 in sensory neurons, has not been investigated. We investigated whether inhibiting OGG1 glycosylase activity with the small molecule inhibitor, TH5487, and/or APE1/Ref-1 endonuclease activity with APE Repair Inhibitor III would alter the neurotoxic effects of cisplatin in sensory neuronal cultures. Sensory neuron function was assessed by calcitonin gene-related peptide (CGRP) release, as a marker of sensitivity and by neurite outgrowth. Cisplatin altered neuropeptide release in an inverse U-shaped fashion, with low concentrations enhancing and higher concentrations diminishing CGRP release. Pretreatment with BER inhibitors exacerbated the functional effects of cisplatin and enhanced 8oxo-dG and adduct lesions in the presence of cisplatin. Our studies demonstrate that inhibition of OGG1 and APE1 endonuclease activity enhances oxidative DNA damage and exacerbates neurotoxicity, thus limiting oxidative DNA damage in sensory neurons that might alleviate cisplatin-induced neuropathy.
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Affiliation(s)
- Adib Behrouzi
- Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (A.B.); (H.X.); (E.L.T.); (M.R.K.)
| | - Hanyu Xia
- Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (A.B.); (H.X.); (E.L.T.); (M.R.K.)
| | - Eric L. Thompson
- Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (A.B.); (H.X.); (E.L.T.); (M.R.K.)
| | - Mark R. Kelley
- Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (A.B.); (H.X.); (E.L.T.); (M.R.K.)
- Department of Pediatrics, Indiana University Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Jill C. Fehrenbacher
- Department of Pharmacology and Toxicology, Stark Neuroscience Research Institute, Indiana University Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Correspondence: ; Tel.: +1-317-274-8360
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Perše M. Cisplatin Mouse Models: Treatment, Toxicity and Translatability. Biomedicines 2021; 9:1406. [PMID: 34680523 PMCID: PMC8533586 DOI: 10.3390/biomedicines9101406] [Citation(s) in RCA: 68] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 09/26/2021] [Accepted: 10/05/2021] [Indexed: 02/06/2023] Open
Abstract
Cisplatin is one of the most widely used chemotherapeutic drugs in the treatment of a wide range of pediatric and adult malignances. However, it has various side effects which limit its use. Cisplatin mouse models are widely used in studies investigating cisplatin therapeutic and toxic effects. However, despite numerous promising results, no significant improvement in treatment outcome has been achieved in humans. There are many drawbacks in the currently used cisplatin protocols in mice. In the paper, the most characterized cisplatin protocols are summarized together with weaknesses that need to be improved in future studies, including hydration and supportive care. As demonstrated, mice respond to cisplatin treatment in similar ways to humans. The paper thus aims to illustrate the complexity of cisplatin side effects (nephrotoxicity, gastrointestinal toxicity, neurotoxicity, ototoxicity and myelotoxicity) and the interconnectedness and interdependence of pathomechanisms among tissues and organs in a dose- and time-dependent manner. The paper offers knowledge that can help design future studies more efficiently and interpret study outcomes more critically. If we want to understand molecular mechanisms and find therapeutic agents that would have a potential benefit in clinics, we need to change our approach and start to treat animals as patients and not as tools.
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Affiliation(s)
- Martina Perše
- Medical Experimental Centre, Institute of Pathology, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia
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9
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van’t Sant LJ, White JJ, Hoeijmakers JHJ, Vermeij WP, Jaarsma D. In vivo 5-ethynyluridine (EU) labelling detects reduced transcription in Purkinje cell degeneration mouse mutants, but can itself induce neurodegeneration. Acta Neuropathol Commun 2021; 9:94. [PMID: 34020718 PMCID: PMC8139001 DOI: 10.1186/s40478-021-01200-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Accepted: 05/12/2021] [Indexed: 12/20/2022] Open
Abstract
Fluorescent staining of newly transcribed RNA via metabolic labelling with 5-ethynyluridine (EU) and click chemistry enables visualisation of changes in transcription, such as in conditions of cellular stress. Here, we tested whether EU labelling can be used to examine transcription in vivo in mouse models of nervous system disorders. We show that injection of EU directly into the cerebellum results in reproducible labelling of newly transcribed RNA in cerebellar neurons and glia, with cell type-specific differences in relative labelling intensities, such as Purkinje cells exhibiting the highest levels. We also observed EU-labelling accumulating into cytoplasmic inclusions, indicating that EU, like other modified uridines, may introduce non-physiological properties in labelled RNAs. Additionally, we found that EU induces Purkinje cell degeneration nine days after EU injection, suggesting that EU incorporation not only results in abnormal RNA transcripts, but also eventually becomes neurotoxic in highly transcriptionally-active neurons. However, short post-injection intervals of EU labelling in both a Purkinje cell-specific DNA repair-deficient mouse model and a mouse model of spinocerebellar ataxia 1 revealed reduced transcription in Purkinje cells compared to controls. We combined EU labelling with immunohistology to correlate altered EU staining with pathological markers, such as genotoxic signalling factors. These data indicate that the EU-labelling method provided here can be used to identify changes in transcription in vivo in nervous system disease models.
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Wei G, Gu Z, Gu J, Yu J, Huang X, Qin F, Li L, Ding R, Huo J. Platinum accumulation in oxaliplatin-induced peripheral neuropathy. J Peripher Nerv Syst 2021; 26:35-42. [PMID: 33462873 PMCID: PMC7986112 DOI: 10.1111/jns.12432] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 10/29/2020] [Accepted: 10/30/2020] [Indexed: 12/16/2022]
Abstract
Oxaliplatin-induced peripheral neuropathy (OIPN) is a common and dose-limiting toxic effect that markedly limits the use of oxaliplatin and affects the quality of life. Although it is common, the underlying mechanisms of OIPN remain ambiguous. Recent studies have shown that the platinum accumulation in peripheral nervous system, especially in dorsal root ganglion, is a significant mechanism of OIPN. Several specific transporters, including organic cation transporters, high-affinity copper uptake protein1 (CTR1), ATPase copper transporting alpha (ATP7A) and multidrug and toxin extrusion protein 1 (MATE1), could be associated with this mechanism. This review summarizes the current research progress about the relationship between platinum accumulation and OIPN, as well as suggests trend for the future research.
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Affiliation(s)
- Guoli Wei
- Department of Oncology, Affiliated Hospital of Integrated Traditional Chinese and Western MedicineNanjing University of Chinese MedicineNanjingChina
- Graduate schoolNanjing University of Chinese MedicineNanjingChina
- Department of OncologyJiangsu Province Academy of Traditional Chinese MedicineNanjingChina
| | - Zhancheng Gu
- Department of Oncology, Affiliated Hospital of Integrated Traditional Chinese and Western MedicineNanjing University of Chinese MedicineNanjingChina
- Graduate schoolNanjing University of Chinese MedicineNanjingChina
| | - Jialin Gu
- Department of Oncology, Affiliated Hospital of Integrated Traditional Chinese and Western MedicineNanjing University of Chinese MedicineNanjingChina
- Graduate schoolNanjing University of Chinese MedicineNanjingChina
| | - Jialin Yu
- Department of Oncology, Affiliated Hospital of Integrated Traditional Chinese and Western MedicineNanjing University of Chinese MedicineNanjingChina
- Department of OncologyJiangsu Province Academy of Traditional Chinese MedicineNanjingChina
| | - Xiaofei Huang
- Department of Oncology, Affiliated Hospital of Integrated Traditional Chinese and Western MedicineNanjing University of Chinese MedicineNanjingChina
- Graduate schoolNanjing University of Chinese MedicineNanjingChina
- Department of OncologyJiangsu Province Academy of Traditional Chinese MedicineNanjingChina
| | - Fengxia Qin
- Department of Oncology, Affiliated Hospital of Integrated Traditional Chinese and Western MedicineNanjing University of Chinese MedicineNanjingChina
- Graduate schoolNanjing University of Chinese MedicineNanjingChina
- Department of OncologyJiangsu Province Academy of Traditional Chinese MedicineNanjingChina
| | - Lingchang Li
- Department of Oncology, Affiliated Hospital of Integrated Traditional Chinese and Western MedicineNanjing University of Chinese MedicineNanjingChina
- Department of OncologyJiangsu Province Academy of Traditional Chinese MedicineNanjingChina
| | - Rong Ding
- Department of Oncology, Affiliated Hospital of Integrated Traditional Chinese and Western MedicineNanjing University of Chinese MedicineNanjingChina
- Department of OncologyJiangsu Province Academy of Traditional Chinese MedicineNanjingChina
| | - Jiege Huo
- Department of Oncology, Affiliated Hospital of Integrated Traditional Chinese and Western MedicineNanjing University of Chinese MedicineNanjingChina
- Department of OncologyJiangsu Province Academy of Traditional Chinese MedicineNanjingChina
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Abstract
Platinum (Pt) compounds entered the clinic as anticancer agents when cisplatin was approved in 1978. More than 40 years later, even in the era of precision medicine and immunotherapy, Pt drugs remain among the most widely used anticancer drugs. As Pt drugs mainly target DNA, it is not surprising that recent insights into alterations of DNA repair mechanisms provide a useful explanation for their success. Many cancers have defective DNA repair, a feature that also sheds new light on the mechanisms of secondary drug resistance, such as the restoration of DNA repair pathways. In addition, genome-wide functional screening approaches have revealed interesting insights into Pt drug uptake. About half of cisplatin and carboplatin but not oxaliplatin may enter cells through the widely expressed volume-regulated anion channel (VRAC). The analysis of this heteromeric channel in tumour biopsies may therefore be a useful biomarker to stratify patients for initial Pt treatments. Moreover, Pt-based approaches may be improved in the future by the optimization of combinations with immunotherapy, management of side effects and use of nanodelivery devices. Hence, Pt drugs may still be part of the standard of care for several cancers in the coming years.
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Affiliation(s)
- Sven Rottenberg
- Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
- Bern Center for Precision Medicine, University of Bern, Bern, Switzerland
| | - Carmen Disler
- Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, Bern, Switzerland
| | - Paola Perego
- Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
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St. Germain DC, O’Mara AM, Robinson JL, Torres AD, Minasian LM. Chemotherapy‐induced peripheral neuropathy: Identifying the research gaps and associated changes to clinical trial design. Cancer 2020; 126:4602-4613. [DOI: 10.1002/cncr.33108] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2019] [Revised: 06/11/2020] [Accepted: 06/17/2020] [Indexed: 12/25/2022]
Affiliation(s)
| | - Ann M. O’Mara
- Division of Cancer Prevention National Cancer Institute Bethesda Maryland
| | - Jennifer L. Robinson
- Department of Behavioral and Community Health University of Maryland College Park Maryland
| | | | - Lori M. Minasian
- Division of Cancer Prevention National Cancer Institute Bethesda Maryland
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Koryakina O, Bazarnyi V, Fechina L, Kostromina P, Maksimova A. Features of the chemokine profile of blood plasma by neurotoxic complications of acute lymphoblastic leukemia in children: preliminary report. BIO WEB OF CONFERENCES 2020. [DOI: 10.1051/bioconf/20202202003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
The article presents an assessment of the neurotoxicity of chemotherapy in children with acute lymphoblastic leukemia receiving specific treatment according to the protocols used in pediatric oncological practice. An analysis of the neurological state with the determination of the chemokine profile of blood plasma was performed in 21 children aged 3 to 17 at the Regional Children’s Clinical Hospital in Yekaterinburg and the Central Research Laboratory of the Ural State Medical University in 2019. In the study group of children, neurotoxic complications were recorded in 42.9% of cases. At the same time, the appearance of neurological symptoms in most patients (77.7%) was observed during co chemotherapy at the stages of reinduction during consolidating treatment with a predominant clinical picture of chemo-induced polyneuropathy. In a comparative analysis of the indicators of the chemokine profile in groups of children, depending on the formation of neurotoxic complications during chemotherapy, we selected the chemokines CXCL10 (IP-10) and CXCL12 (SDF-1α) as possible prognostic biomarkers of damage to the nervous system.
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Workel HH, van Rooij N, Plat A, Spierings DC, Fehrmann RSN, Nijman HW, de Bruyn M. Transcriptional Activity and Stability of CD39+CD103+CD8+ T Cells in Human High-Grade Endometrial Cancer. Int J Mol Sci 2020; 21:E3770. [PMID: 32471032 PMCID: PMC7312498 DOI: 10.3390/ijms21113770] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 05/21/2020] [Accepted: 05/22/2020] [Indexed: 12/13/2022] Open
Abstract
Tumor-infiltrating CD8+ T cells (TIL) are of the utmost importance in anti-tumor immunity. CD103 defines tumor-resident memory T cells (TRM cells) associated with improved survival and response to immune checkpoint blockade (ICB) across human tumors. Co-expression of CD39 and CD103 marks tumor-specific TRM with enhanced cytolytic potential, suggesting that CD39+CD103+ TRM could be a suitable biomarker for immunotherapy. However, little is known about the transcriptional activity of TRM cells in situ. We analyzed CD39+CD103+ TRM cells sorted from human high-grade endometrial cancers (n = 3) using mRNA sequencing. Cells remained untreated or were incubated with PMA/ionomycin (activation), actinomycin D (a platinum-like chemotherapeutic that inhibits transcription), or a combination of the two. Resting CD39+CD103+ TRM cells were transcriptionally active and expressed a characteristic TRM signature. Activated CD39+CD103+ TRM cells differentially expressed PLEK, TWNK, and FOS, and cytokine genes IFNG, TNF, IL2, CSF2 (GM-CSF), and IL21. Findings were confirmed using qPCR and cytokine production was validated by flow cytometry of cytotoxic TIL. We studied transcript stability and found that PMA-responsive genes and mitochondrial genes were particularly stable. In conclusion, CD39+CD103+ TRM cells are transcriptionally active TRM cells with a polyfunctional, reactivation-responsive repertoire. Secondly, we hypothesize that differential regulation of transcript stability potentiates rapid responses upon TRM reactivation in tumors.
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Affiliation(s)
- Hagma H. Workel
- Department of Obstetrics and Gynaecology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands; (H.H.W.); (N.v.R.); (A.P.); (H.W.N.)
| | - Nienke van Rooij
- Department of Obstetrics and Gynaecology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands; (H.H.W.); (N.v.R.); (A.P.); (H.W.N.)
| | - Annechien Plat
- Department of Obstetrics and Gynaecology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands; (H.H.W.); (N.v.R.); (A.P.); (H.W.N.)
| | - Diana C.J. Spierings
- European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands;
| | - Rudolf S. N. Fehrmann
- Department of Medical Oncology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands;
| | - Hans W. Nijman
- Department of Obstetrics and Gynaecology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands; (H.H.W.); (N.v.R.); (A.P.); (H.W.N.)
| | - Marco de Bruyn
- Department of Obstetrics and Gynaecology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands; (H.H.W.); (N.v.R.); (A.P.); (H.W.N.)
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15
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Lazic A, Popović J, Paunesku T, Woloschak GE, Stevanović M. Insights into platinum-induced peripheral neuropathy-current perspective. Neural Regen Res 2020; 15:1623-1630. [PMID: 32209761 PMCID: PMC7437596 DOI: 10.4103/1673-5374.276321] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Cancer is a global health problem that is often successfully addressed by therapy, with cancer survivors increasing in numbers and living longer world around. Although new cancer treatment options are continuously explored, platinum based chemotherapy agents remain in use due to their efficiency and availability. Unfortunately, all cancer therapies affect normal tissues as well as cancer, and more than 40 specific side effects of platinum based drugs documented so far decrease the quality of life of cancer survivors. Chemotherapy-induced peripheral neuropathy is a frequent side effects of platinum-based chemotherapy agents. This cluster of complications is often so debilitating that patients occasionally have to discontinue the therapy. Sensory neurons of dorsal root ganglia are at the core of chemotherapy-induced peripheral neuropathy symptoms. In these postmitotic cells, DNA damage caused by platinum chemotherapy interferes with normal functioning. Accumulation of DNA-platinum adducts correlates with neurotoxic severity and development of sensation of pain. While biochemistry of DNA-platinum adducts is the same in all cell types, molecular mechanisms affected by DNA-platinum adducts are different in cancer cells and non-dividing cells. This review aims to raise awareness about platinum associated chemotherapy-induced peripheral neuropathy as a medical problem that has remained unexplained for decades. We emphasize the complexity of this condition both from clinical and mechanistical point of view and focus on recent findings about chemotherapy-induced peripheral neuropathy in in vitro and in vivo model systems. Finally, we summarize current perspectives about clinical approaches for chemotherapy-induced peripheral neuropathy treatment.
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Affiliation(s)
- Andrijana Lazic
- Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia
| | - Jelena Popović
- Feinberg School of Medicine, Department of Radiation Oncology, Northwestern University, Chicago, IL, USA
| | - Tatjana Paunesku
- Feinberg School of Medicine, Department of Radiation Oncology, Northwestern University, Chicago, IL, USA
| | - Gayle E Woloschak
- Feinberg School of Medicine, Department of Radiation Oncology, Northwestern University, Chicago, IL, USA
| | - Milena Stevanović
- Institute of Molecular Genetics and Genetic Engineering; Faculty of Biology; Serbian Academy of Sciences and Arts, Belgrade, Serbia
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16
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Calls A, Carozzi V, Navarro X, Monza L, Bruna J. Pathogenesis of platinum-induced peripheral neurotoxicity: Insights from preclinical studies. Exp Neurol 2019; 325:113141. [PMID: 31865195 DOI: 10.1016/j.expneurol.2019.113141] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Revised: 11/26/2019] [Accepted: 12/03/2019] [Indexed: 12/18/2022]
Abstract
One of the most relevant dose-limiting adverse effects of platinum drugs is the development of a sensory peripheral neuropathy that highly impairs the patients' quality of life. Nowadays there are no available efficacy strategies for the treatment of platinum-induced peripheral neurotoxicity (PIPN), and the only way to prevent its development and progression is by reducing the dose of the cytostatic drug or even withdrawing the chemotherapy regimen. This clinical issue has been the main focus of hundreds of preclinical research works during recent decades. As a consequence, dozens of in vitro and in vivo models of PIPN have been developed to elucidate the molecular mechanisms involved in its development and to find neuroprotective targets. The apoptosis of peripheral neurons has been identified as the main mechanism involved in PIPN pathogenesis. This mechanism of DRG sensory neurons cell death is triggered by the nuclear and mitochondrial DNA platination together with the increase of the oxidative cellular status induced by the depletion of cytoplasmic antioxidant mechanisms. However, since there has been no successful transfer of preclinical results to clinical practise in terms of therapeutic approaches, some mechanisms of PIPN pathogenesis still remain to be elucidated. This review is focused on the pathogenic mechanisms underlying PIPN described up to now, provided by the critical analysis of in vitro and in vivo models.
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Affiliation(s)
- Aina Calls
- Department of Cell Biology, Physiology and Immunology, Institute of Neurosciences, Universitat Autònoma de Barcelona, and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Bellaterra, Spain
| | - Valentina Carozzi
- Experimental Neurology Unit, School of Medicine and Surgery, University of Milan Bicocca. Italy; Milan Center For Neuroscience, Milan, Italy
| | - Xavier Navarro
- Department of Cell Biology, Physiology and Immunology, Institute of Neurosciences, Universitat Autònoma de Barcelona, and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Bellaterra, Spain
| | - Laura Monza
- Experimental Neurology Unit, School of Medicine and Surgery, University of Milan Bicocca. Italy
| | - Jordi Bruna
- Department of Cell Biology, Physiology and Immunology, Institute of Neurosciences, Universitat Autònoma de Barcelona, and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Bellaterra, Spain; Unit of Neuro-Oncology, Hospital Universitari de Bellvitge-Institut Català d'Oncologia L'Hospitalet, Institut d'Investigació Biomedica de Bellvitge (IDIBELL), Feixa Llarga s/n, 08907 Barcelona, Spain.
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17
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Lans H, Hoeijmakers JHJ, Vermeulen W, Marteijn JA. The DNA damage response to transcription stress. Nat Rev Mol Cell Biol 2019; 20:766-784. [DOI: 10.1038/s41580-019-0169-4] [Citation(s) in RCA: 127] [Impact Index Per Article: 21.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/14/2019] [Indexed: 12/30/2022]
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18
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Qi L, Luo Q, Zhang Y, Jia F, Zhao Y, Wang F. Advances in Toxicological Research of the Anticancer Drug Cisplatin. Chem Res Toxicol 2019; 32:1469-1486. [PMID: 31353895 DOI: 10.1021/acs.chemrestox.9b00204] [Citation(s) in RCA: 247] [Impact Index Per Article: 41.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Cisplatin is one of the most widely used chemotherapeutic agents for various solid tumors in the clinic due to its high efficacy and broad spectrum. The antineoplastic activity of cisplatin is mainly due to its ability to cross-link with DNA, thus blocking transcription and replication. Unfortunately, the clinical use of cisplatin is limited by its severe, dose-dependent toxic side effects. There are approximately 40 specific toxicities of cisplatin, among which nephrotoxicity is the most common one. Other common side effects include ototoxicity, neurotoxicity, gastrointestinal toxicity, hematological toxicity, cardiotoxicity, and hepatotoxicity. These side effects together reduce the life quality of patients and require lowering the dosage of the drug, even stopping administration, thus weakening the treatment effect. Few effective measures exist clinically against these side effects because the exact mechanisms of various side effects from cisplatin remain still unclear. Therefore, substantial effort has been made to explore the complicated biochemical processes involved in the toxicology of cisplatin, aiming to identify effective ways to reduce or eradicate its toxicity. This review summarizes and reviews the updated advances in the toxicological research of cisplatin. We anticipate to provide insights into the understanding of the mechanisms underlying the side effects of cisplatin and designing comprehensive therapeutic strategies involving cisplatin.
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Affiliation(s)
- Luyu Qi
- Beijing National Laboratory for Molecular Sciences; National Centre for Mass Spectrometry in Beijing; CAS Key Laboratory of Analytical Chemistry for Living Biosystems , Institute of Chemistry, Chinese Academy of Sciences , Beijing 100190 , P.R. China.,University of Chinese Academy of Sciences , Beijing 100049 , P.R. China
| | - Qun Luo
- Beijing National Laboratory for Molecular Sciences; National Centre for Mass Spectrometry in Beijing; CAS Key Laboratory of Analytical Chemistry for Living Biosystems , Institute of Chemistry, Chinese Academy of Sciences , Beijing 100190 , P.R. China.,University of Chinese Academy of Sciences , Beijing 100049 , P.R. China
| | - Yanyan Zhang
- Beijing National Laboratory for Molecular Sciences; National Centre for Mass Spectrometry in Beijing; CAS Key Laboratory of Analytical Chemistry for Living Biosystems , Institute of Chemistry, Chinese Academy of Sciences , Beijing 100190 , P.R. China
| | - Feifei Jia
- Beijing National Laboratory for Molecular Sciences; National Centre for Mass Spectrometry in Beijing; CAS Key Laboratory of Analytical Chemistry for Living Biosystems , Institute of Chemistry, Chinese Academy of Sciences , Beijing 100190 , P.R. China
| | - Yao Zhao
- Beijing National Laboratory for Molecular Sciences; National Centre for Mass Spectrometry in Beijing; CAS Key Laboratory of Analytical Chemistry for Living Biosystems , Institute of Chemistry, Chinese Academy of Sciences , Beijing 100190 , P.R. China
| | - Fuyi Wang
- Beijing National Laboratory for Molecular Sciences; National Centre for Mass Spectrometry in Beijing; CAS Key Laboratory of Analytical Chemistry for Living Biosystems , Institute of Chemistry, Chinese Academy of Sciences , Beijing 100190 , P.R. China.,University of Chinese Academy of Sciences , Beijing 100049 , P.R. China.,Basic Medical College , Shandong University of Chinese Traditional Medicine , Jinan 250355 , P.R. China
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19
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Slyskova J, Sabatella M, Ribeiro-Silva C, Stok C, Theil AF, Vermeulen W, Lans H. Base and nucleotide excision repair facilitate resolution of platinum drugs-induced transcription blockage. Nucleic Acids Res 2019; 46:9537-9549. [PMID: 30137419 PMCID: PMC6182164 DOI: 10.1093/nar/gky764] [Citation(s) in RCA: 77] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2018] [Accepted: 08/20/2018] [Indexed: 12/21/2022] Open
Abstract
Sensitivity and resistance of cells to platinum drug chemotherapy are to a large extent determined by activity of the DNA damage response (DDR). Combining chemotherapy with inhibition of specific DDR pathways could therefore improve treatment efficacy. Multiple DDR pathways have been implicated in removal of platinum-DNA lesions, but it is unclear which exact pathways are most important to cellular platinum drug resistance. Here, we used CRISPR/Cas9 screening to identify DDR proteins that protect colorectal cancer cells against the clinically applied platinum drug oxaliplatin. We find that besides the expected homologous recombination, Fanconi anemia and translesion synthesis pathways, in particular also transcription-coupled nucleotide excision repair (TC-NER) and base excision repair (BER) protect against platinum-induced cytotoxicity. Both repair pathways are required to overcome oxaliplatin- and cisplatin-induced transcription arrest. In addition to the generation of DNA crosslinks, exposure to platinum drugs leads to reactive oxygen species production that induces oxidative DNA lesions, explaining the requirement for BER. Our findings highlight the importance of transcriptional integrity in cells exposed to platinum drugs and suggest that both TC-NER and BER should be considered as targets for novel combinatorial treatment strategies.
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Affiliation(s)
- Jana Slyskova
- Department of Molecular Genetics, Erasmus MC, Erasmus University Medical Center Rotterdam, 3000 CA Rotterdam, The Netherlands
| | - Mariangela Sabatella
- Department of Molecular Genetics, Erasmus MC, Erasmus University Medical Center Rotterdam, 3000 CA Rotterdam, The Netherlands
| | - Cristina Ribeiro-Silva
- Department of Molecular Genetics, Erasmus MC, Erasmus University Medical Center Rotterdam, 3000 CA Rotterdam, The Netherlands
- Oncode Institute, Erasmus MC, Erasmus University Medical Center Rotterdam, 3000 CA Rotterdam, The Netherlands
| | - Colin Stok
- Department of Molecular Genetics, Erasmus MC, Erasmus University Medical Center Rotterdam, 3000 CA Rotterdam, The Netherlands
| | - Arjan F Theil
- Department of Molecular Genetics, Erasmus MC, Erasmus University Medical Center Rotterdam, 3000 CA Rotterdam, The Netherlands
- Oncode Institute, Erasmus MC, Erasmus University Medical Center Rotterdam, 3000 CA Rotterdam, The Netherlands
| | - Wim Vermeulen
- Department of Molecular Genetics, Erasmus MC, Erasmus University Medical Center Rotterdam, 3000 CA Rotterdam, The Netherlands
- Oncode Institute, Erasmus MC, Erasmus University Medical Center Rotterdam, 3000 CA Rotterdam, The Netherlands
| | - Hannes Lans
- Department of Molecular Genetics, Erasmus MC, Erasmus University Medical Center Rotterdam, 3000 CA Rotterdam, The Netherlands
- Oncode Institute, Erasmus MC, Erasmus University Medical Center Rotterdam, 3000 CA Rotterdam, The Netherlands
- To whom correspondence should be addressed. Tel: +31 10 7038169; Fax: +31 10 7044743;
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20
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Alberti P. Platinum-drugs induced peripheral neurotoxicity: clinical course and preclinical evidence. Expert Opin Drug Metab Toxicol 2019; 15:487-497. [DOI: 10.1080/17425255.2019.1622679] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Paola Alberti
- NeuroMI (Milan Center for Neuroscience), Milan, Italy
- School of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy
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21
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Sheehan K, Lee J, Chong J, Zavala K, Sharma M, Philipsen S, Maruyama T, Xu Z, Guan Z, Eilers H, Kawamata T, Schumacher M. Transcription factor Sp4 is required for hyperalgesic state persistence. PLoS One 2019; 14:e0211349. [PMID: 30811405 PMCID: PMC6392229 DOI: 10.1371/journal.pone.0211349] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Accepted: 01/11/2019] [Indexed: 12/14/2022] Open
Abstract
Understanding how painful hypersensitive states develop and persist beyond the initial hours to days is critically important in the effort to devise strategies to prevent and/or reverse chronic painful states. Changes in nociceptor transcription can alter the abundance of nociceptive signaling elements, resulting in longer-term change in nociceptor phenotype. As a result, sensitized nociceptive signaling can be further amplified and nocifensive behaviors sustained for weeks to months. Building on our previous finding that transcription factor Sp4 positively regulates the expression of the pain transducing channel TRPV1 in Dorsal Root Ganglion (DRG) neurons, we sought to determine if Sp4 serves a broader role in the development and persistence of hypersensitive states in mice. We observed that more than 90% of Sp4 staining DRG neurons were small to medium sized, primarily unmyelinated (NF200 neg) and the majority co-expressed nociceptor markers TRPV1 and/or isolectin B4 (IB4). Genetically modified mice (Sp4+/-) with a 50% reduction of Sp4 showed a reduction in DRG TRPV1 mRNA and neuronal responses to the TRPV1 agonist-capsaicin. Importantly, Sp4+/- mice failed to develop persistent inflammatory thermal hyperalgesia, showing a reversal to control values after 6 hours. Despite a reversal of inflammatory thermal hyperalgesia, there was no difference in CFA-induced hindpaw swelling between CFA Sp4+/- and CFA wild type mice. Similarly, Sp4+/- mice failed to develop persistent mechanical hypersensitivity to hind-paw injection of NGF. Although Sp4+/- mice developed hypersensitivity to traumatic nerve injury, Sp4+/- mice failed to develop persistent cold or mechanical hypersensitivity to the platinum-based chemotherapeutic agent oxaliplatin, a non-traumatic model of neuropathic pain. Overall, Sp4+/- mice displayed a remarkable ability to reverse the development of multiple models of persistent inflammatory and neuropathic hypersensitivity. This suggests that Sp4 functions as a critical control point for a network of genes that conspire in the persistence of painful hypersensitive states.
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Affiliation(s)
- Kayla Sheehan
- Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, California, United States of America
| | - Jessica Lee
- Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, California, United States of America
| | - Jillian Chong
- Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, California, United States of America
| | - Kathryn Zavala
- Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, California, United States of America
| | - Manohar Sharma
- Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, California, United States of America
| | - Sjaak Philipsen
- Department of Cell Biology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Tomoyuki Maruyama
- Department of Anesthesiology, Wakayama Medical University, Wakayama, Japan
| | - Zheyun Xu
- Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, California, United States of America
| | - Zhonghui Guan
- Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, California, United States of America
| | - Helge Eilers
- Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, California, United States of America
| | - Tomoyuki Kawamata
- Department of Anesthesiology, Wakayama Medical University, Wakayama, Japan
| | - Mark Schumacher
- Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, California, United States of America
- * E-mail:
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22
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Notch1 inhibition enhances DNA damage induced by cisplatin in cervical cancer. Exp Cell Res 2019; 376:27-38. [PMID: 30690027 DOI: 10.1016/j.yexcr.2019.01.014] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2018] [Revised: 01/22/2019] [Accepted: 01/24/2019] [Indexed: 12/20/2022]
Abstract
The expression of Notch1 plays an important role in the occurrence and development of various tumors. Previous studies have shown that Notch1 plays a negative regulatory role in response to radiation-induced DNA damage responses. It also has been reported that Notch1 was highly expressed in cervical cancer. It is well known that the first-line chemotherapy drug for treating cervical cancer, cisplatin, targets double-stranded DNA and induces apoptosis in the cells. However, the tolerability of cisplatin is an issue to overcome in the treatment of cervical cancer. Cisplatin has been reported to induce the up-regulation of Notch1 intracellular domain (NICD) through the γ-proteolytic enzyme complex, a complex that mediates Notch1 activation. Therefore, whether Notch1 is highly expressed in the cells or cisplatin induced high expression of NICD in cervical cancer has not been specifically discussed in these studies. More importantly, whether the inhibition of Notch1 activation would enhance DNA damage induced by cisplatin and/or cellular apoptosis mediated via ATM/CHK2/P53 pathway has not been reported in cervical cancer. In this study, we observed an enhanced DNA damage and cellular apoptosis via the ATM/CHK2/P53 pathway(s) in HeLa and SiHa cells treated with cisplatin combined with DAPT of Notch1 inhibitor. Our findings provide an alternative therapeutic strategy for the treatment of cervical cancer in the clinic.
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23
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Fujita S, Hirota T, Sakiyama R, Baba M, Ieiri I. Identification of drug transporters contributing to oxaliplatin-induced peripheral neuropathy. J Neurochem 2018; 148:373-385. [PMID: 30295925 DOI: 10.1111/jnc.14607] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2018] [Revised: 06/19/2018] [Accepted: 10/01/2018] [Indexed: 12/23/2022]
Abstract
Oxaliplatin is widely used as a key drug in the treatment of colorectal cancer. However, its administration is associated with the dose-limiting adverse effect, peripheral neuropathy. Platinum accumulation in the dorsal root ganglion (DRG) is the major mechanism responsible for oxaliplatin-induced neuropathy. Some drug transporters have been identified as platinum complex transporters in kidney or tumor cells, but not yet in DRG. In the present study, we investigated oxaliplatin transporters and their contribution to peripheral neuropathy. We identified 12 platinum transporters expressed in DRG with real-time PCR, and their transiently overexpressing cells were established. After exposure to oxaliplatin, the accumulation of platinum in these overexpressing cells was evaluated using a coupled plasma mass spectrometer. Octn1/2- and Mate1-expressing cells showed the intracellular accumulation of oxaliplatin. In an animal study, peripheral neuropathy developed after the administration of oxaliplatin (4 mg/kg, intravenously, twice a week) to siRNA-injected rats (0.5 nmol, intrathecally, once a week) was demonstrated with the von Frey test. The knockdown of Octn1 in DRG ameliorated peripheral neuropathy, and decreased platinum accumulation in DRG, whereas the knockdown of Octn2 did not. Mate1 siRNA-injected rats developed more severe neuropathy than control rats. These results indicate that Octn1 and Mate1 are involved in platinum accumulation at DRG and oxaliplatin-induced peripheral neuropathy.
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Affiliation(s)
- Shunsuke Fujita
- Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
| | - Takeshi Hirota
- Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
| | - Ryo Sakiyama
- Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
| | - Misaki Baba
- Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
| | - Ichiro Ieiri
- Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
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24
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Zhuo M, Gorgun MF, Englander EW. Neurotoxicity of cytarabine (Ara-C) in dorsal root ganglion neurons originates from impediment of mtDNA synthesis and compromise of mitochondrial function. Free Radic Biol Med 2018; 121:9-19. [PMID: 29698743 PMCID: PMC5971160 DOI: 10.1016/j.freeradbiomed.2018.04.570] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Revised: 04/12/2018] [Accepted: 04/21/2018] [Indexed: 12/18/2022]
Abstract
Peripheral Nervous System (PNS) neurotoxicity caused by cancer drugs hinders attainment of chemotherapy goals. Due to leakiness of the blood nerve barrier, circulating chemotherapeutic drugs reach PNS neurons and adversely affect their function. Chemotherapeutic drugs are designed to target dividing cancer cells and mechanisms underlying their toxicity in postmitotic neurons remain to be fully clarified. The objective of this work was to elucidate progression of events triggered by antimitotic drugs in postmitotic neurons. For proof of mechanism study, we chose cytarabine (ara-C), an antimetabolite used in treatment of hematological cancers. Ara-C is a cytosine analog that terminates DNA synthesis. To investigate how ara-C affects postmitotic neurons, which replicate mitochondrial but not genomic DNA, we adapted a model of Dorsal Root Ganglion (DRG) neurons. We showed that DNA polymerase γ, which is responsible for mtDNA synthesis, is inhibited by ara-C and that sublethal ara-C exposure of DRG neurons leads to reduction in mtDNA content, ROS generation, oxidative mtDNA damage formation, compromised mitochondrial respiration and diminution of NADPH and GSH stores, as well as, activation of the DNA damage response. Hence, it is plausible that in ara-C exposed DRG neurons, ROS amplified by the high mitochondrial content shifts from physiologic to pathologic levels signaling stress to the nucleus. Combined, the findings suggest that ara-C neurotoxicity in DRG neurons originates in mitochondria and that continuous mtDNA synthesis and reliance on oxidative phosphorylation for energy needs sensitize the highly metabolic neurons to injury by mtDNA synthesis terminating cancer drugs.
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Affiliation(s)
- Ming Zhuo
- Division of Neurosurgery, Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA
| | - Murat F Gorgun
- Division of Neurosurgery, Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA
| | - Ella W Englander
- Division of Neurosurgery, Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA.
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25
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Jia M, Zhu M, Wang M, Sun M, Qian J, Ding F, Chang J, Wei Q. Genetic variants of GADD45A, GADD45B and MAPK14 predict platinum-based chemotherapy-induced toxicities in Chinese patients with non-small cell lung cancer. Oncotarget 2018; 7:25291-303. [PMID: 26993769 PMCID: PMC5041904 DOI: 10.18632/oncotarget.8052] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2015] [Accepted: 02/29/2016] [Indexed: 12/23/2022] Open
Abstract
The JNK and P38α pathways play a crucial role in tissue homeostasis, apoptosis and autophagy under genotoxic stresses, but it is unclear whether single nucleotide polymorphisms (SNPs) of genes in these pathways play a role in platinum-based chemotherapy-induced toxicities in patients with advanced non-small cell lung cancer (NSCLC). We genotyped 11 selected, independent, potentially functional SNPs of nine genes in the JNK and P38α pathways in 689 patients with advanced NSCLC treated with platinum-combination chemotherapy regimens. Associations between these SNPs and chemotherapy toxicities were tested in a discovery group of 345 patients and then validated in a replication group of 344 patients. In both discovery and validation groups as well as their pooled analysis, carriers of GADD45B rs2024144T variant allele had a significantly higher risk for severe hematologic toxicity and carriers of MAPK14 rs3804451A variant allele had a significantly higher risk for both overall toxicity and gastrointestinal toxicity. In addition, carriers of GADD45A rs581000C had a lower risk of anemia, while carriers of GADD45B rs2024144T had a significantly higher risk for leukocytopenia or agranulocytosis. The present study provides evidence that genetic variants in genes involved in the JNK and P38α pathways may predict platinum-based chemotherapy toxicity outcomes in patients with advanced NSCLC. Larger studies of other patient populations are needed to validate our findings.
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Affiliation(s)
- Ming Jia
- Cancer Institute, Collaborative Innovation Center for Cancer Medicine, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Meiling Zhu
- Department of Oncology, Xinhua Hospital Affiliated to Shanghai Jiaotong University, School of Medicine, Shanghai, 200092, China
| | - Mengyun Wang
- Cancer Institute, Collaborative Innovation Center for Cancer Medicine, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Menghong Sun
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
| | - Ji Qian
- State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences and Fudan Taizhou Institute of Health Sciences, Fudan University, Shanghai, 200032, China
| | - Fei Ding
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
| | - Jianhua Chang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
| | - Qingyi Wei
- Cancer Institute, Collaborative Innovation Center for Cancer Medicine, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.,Department of Medicine, Duke Cancer Institute, Duke University Medical Center, Duke University School of Medicine, Durham, North Carolina, 27710, USA
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26
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Kanat O, Ertas H, Caner B. Platinum-induced neurotoxicity: A review of possible mechanisms. World J Clin Oncol 2017; 8:329-335. [PMID: 28848699 PMCID: PMC5554876 DOI: 10.5306/wjco.v8.i4.329] [Citation(s) in RCA: 114] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2017] [Revised: 06/13/2017] [Accepted: 06/30/2017] [Indexed: 02/06/2023] Open
Abstract
Patients treated with platinum-based chemotherapy frequently experience neurotoxic symptoms, which may lead to premature discontinuation of therapy. Despite discontinuation of platinum drugs, these symptoms can persist over a long period of time. Cisplatin and oxaliplatin, among all platinum drugs, have significant neurotoxic potential. A distal dose-dependent symmetrical sensory neuropathy is the most common presentation of platinum neurotoxicity. DNA damage-induced apoptosis of dorsal root ganglion (DRG) neurons seems to be the principal cause of neurological symptoms. However, DRG injury alone cannot explain some unique symptoms such as cold-aggravated burning pain affecting distal extremities that is observed with oxaliplatin administration. In this article, we briefly reviewed potential mechanisms for the development of platinum drugs-associated neurological manifestations.
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27
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Han CH, Khwaounjoo P, Hill AG, Miskelly GM, McKeage MJ. Predicting effects on oxaliplatin clearance: in vitro, kinetic and clinical studies of calcium- and magnesium-mediated oxaliplatin degradation. Sci Rep 2017. [PMID: 28642473 PMCID: PMC5481441 DOI: 10.1038/s41598-017-04383-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
This study evaluated the impact of calcium and magnesium on the in vitro degradation and in vivo clearance of oxaliplatin. Intact oxaliplatin and Pt(DACH)Cl2 were measured in incubation solutions by HPLC-UV. A clinical study determined changes in plasma concentrations of calcium and magnesium in cancer patients and their impact on oxaliplatin clearance. Kinetic analyses modelled oxaliplatin degradation reactions in vitro and contributions to oxaliplatin clearance in vivo. Calcium and magnesium accelerated oxaliplatin degradation to Pt(DACH)Cl2 in chloride-containing solutions in vitro. Kinetic models based on calcium and magnesium binding to a monochloro-monooxalato ring-opened anionic oxaliplatin intermediate fitted the in vitro degradation time-course data. In cancer patients, calcium and magnesium plasma concentrations varied and were increased by giving calcium gluconate and magnesium sulfate infusions, but did not alter or correlate with oxaliplatin clearance. The intrinsic in vitro clearance of oxaliplatin attributed to chloride-, calcium- and magnesium-mediated degradation predicted contributions of <2.5% to the total in vivo clearance of oxaliplatin. In conclusion, calcium and magnesium accelerate the in vitro degradation of oxaliplatin by binding to a monochloro-monooxalato ring-opened anionic intermediate. Kinetic analysis of in vitro oxaliplatin stability data can be used for in vitro prediction of potential effects on oxaliplatin clearance in vivo.
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Affiliation(s)
- Catherine H Han
- Department of Pharmacology and Clinical Pharmacology and Auckland Cancer Society Research Centre, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.,Regional Cancer and Blood Services, Auckland City Hospital, Auckland, New Zealand
| | - Prashannata Khwaounjoo
- Department of Pharmacology and Clinical Pharmacology and Auckland Cancer Society Research Centre, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
| | - Andrew G Hill
- Department of Pharmacology and Clinical Pharmacology and Auckland Cancer Society Research Centre, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.,Regional Cancer and Blood Services, Auckland City Hospital, Auckland, New Zealand
| | - Gordon M Miskelly
- School of Chemical Sciences, Faculty of Science, University of Auckland, Auckland, New Zealand
| | - Mark J McKeage
- Department of Pharmacology and Clinical Pharmacology and Auckland Cancer Society Research Centre, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand. .,Regional Cancer and Blood Services, Auckland City Hospital, Auckland, New Zealand.
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28
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Translesion Synthesis DNA Polymerase Kappa Is Indispensable for DNA Repair Synthesis in Cisplatin Exposed Dorsal Root Ganglion Neurons. Mol Neurobiol 2017; 55:2506-2515. [PMID: 28391554 DOI: 10.1007/s12035-017-0507-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2017] [Accepted: 03/21/2017] [Indexed: 10/19/2022]
Abstract
In the peripheral nervous system (PNS) in the absence of tight blood barrier, neurons are at increased risk of DNA damage, yet the question of how effectively PNS neurons manage DNA damage remains largely unanswered. Genotoxins in systemic circulation include chemotherapeutic drugs that reach peripheral neurons and damage their DNA. Because neurotoxicity of platinum-based class of chemotherapeutic drugs has been implicated in PNS neuropathies, we utilized an in vitro model of Dorsal Root Ganglia (DRGs) to investigate how peripheral neurons respond to cisplatin that forms intra- and interstrand crosslinks with their DNA. Our data revealed strong transcriptional upregulation of the translesion synthesis DNA polymerase kappa (Pol κ), while expression of other DNA polymerases remained unchanged. DNA Pol κ is involved in bypass synthesis of diverse DNA lesions and considered a vital player in cellular survival under injurious conditions. To assess the impact of Pol κ deficiency on cisplatin-exposed DRG neurons, Pol κ levels were reduced using siRNA. Pol κ targeting siRNA diminished the cisplatin-induced nuclear Pol κ immunoreactivity in DRG neurons and decreased the extent of cisplatin-induced DNA repair synthesis, as reflected in reduced incorporation of thymidine analog into nuclear DNA. Moreover, Pol κ depletion exacerbated global transcriptional suppression induced by cisplatin in DRG neurons. Collectively, these findings provide the first evidence for critical role of Pol κ in DNA damage response in the nervous system and call attention to implications of polymorphisms that modify Pol κ activity, on maintenance of genomic integrity and neuronal function in exogenously challenged PNS.
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Cisplatin Toxicity in Dorsal Root Ganglion Neurons Is Relieved by Meclizine via Diminution of Mitochondrial Compromise and Improved Clearance of DNA Damage. Mol Neurobiol 2016; 54:7883-7895. [PMID: 27858292 DOI: 10.1007/s12035-016-0273-9] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2016] [Accepted: 10/30/2016] [Indexed: 01/09/2023]
Abstract
Chemotherapy-induced neurotoxicity of peripheral nervous system (PNS) hinders efficacy of cancer treatments. Mechanisms initiating PNS injury by anticancer drugs are incompletely understood delaying development of effective management strategies. To understand events triggered in PNS by cancer drugs, we exposed dorsal root ganglion (DRG) neurons to cisplatin, a drug from platinum-based class of chemotherapeutics frequently implicated in peripheral neuropathies. While cisplatin enters cancer cells and forms cisplatin/DNA crosslinks that block cell proliferation, circulating cisplatin can also reach the PNS and produce crosslinks that impede critical DNA transactions in postmitotic neurons. Cisplatin forms crosslinks with both, nuclear and mitochondrial DNA (mtDNA). Crosslinks are repairable primarily via the nucleotide excision repair (NER) pathway, which is present in nuclei but absent from mitochondrial compartment. Hence, high mitochondrial content and limited shielding by blood nerve barrier make DRG neurons particularly vulnerable to mitochondrial injury by cisplatin. We report that in DRG neurons, cisplatin elevates reactive oxygen species, depletes mtDNA, and impairs mitochondrial respiration, whereas concomitant meclizine supplementation preserves redox balance, attenuates mitochondrial compromise, and augments DNA repair. Meclizine is an antihistamine drug recently implicated in neuroprotection via modulation of energy metabolism. Our data demonstrate that in the mitochondria-rich DRG neurons, meclizine mitigates cisplatin-induced mitochondrial compromise via enhancement of pentose phosphate pathway and repletion of nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione stores. The findings suggest that meclizine-mediated preservation of redox balance sustains mitochondrial respiration and supports execution of cellular processes, including timely removal of cisplatin crosslinks from nuclear DNA, thereby attenuating cisplatin toxicity in DRG neurons. Collectively, the findings reveal potential for pharmacologic modulation of dorsal root ganglion neurons metabolism for protection against toxicity of chemotherapeutic drugs.
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