Integrated Medicine for Chemotherapy-Induced Peripheral Neuropathy.
Ontology highlight
ABSTRACT:
SUBMITTER: Tsai CH
PROVIDER: S-EPMC8430591 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most frequent side effects caused by antineoplastic agents, with a prevalence from 19% to over 85%. Clinically, CIPN is a mostly sensory neuropathy that may be accompanied by motor and autonomic changes of varying intensity and duration. Due to its high prevalence among cancer patients, CIPN constitutes a major problem for both cancer patients and survivors as well as for their health care providers, especially because, at the moment, there is no single effective method of preventing CIPN; moreover, the possibilities of treating this syndrome are very limited. There are six main substance groups that cause damage to peripheral sensory, motor and autonomic neurons, which result in the development of CIPN: platinum-based antineoplastic agents, vinca alkaloids, epothilones (ixabepilone), taxanes, proteasome inhibitors (bortezomib) and immunomodulatory drugs (thalidomide). Among them, the most neurotoxic are platinum-based agents, taxanes, ixabepilone and thalidomide; other less neurotoxic but also commonlyused drugs are bortezomib and vinca alkaloids. This paper reviews the clinical picture of CIPN and the neurotoxicity mechanisms of the most common antineoplastic agents. A better understanding of the risk factors and underlying mechanisms of CIPN is needed to develop effective preventive and therapeutic strategies.
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Project description:Chemotherapy-induced neuropathy is a common, dose-dependent adverse effect of several antineoplastics. It can lead to detrimental dose reductions and discontinuation of treatment, and severely affects the quality of life of cancer survivors. Clinically, chemotherapy-induced peripheral neuropathy presents as deficits in sensory, motor, and autonomic function which develop in a glove and stocking distribution due to preferential effects on longer axons. The pathophysiological processes are multi-factorial and involve oxidative stress, apoptotic mechanisms, altered calcium homeostasis, axon degeneration and membrane remodeling as well as immune processes and neuroinflammation. This review focusses on the commonly used antineoplastic substances oxaliplatin, cisplatin, vincristine, docetaxel, and paclitaxel which interfere with the cancer cell cycle-leading to cell death and tumor degradation-and cause severe acute and chronic peripheral neuropathies. We discuss drug mechanism of action and pharmacokinetic disposition relevant to the development of peripheral neuropathy, the epidemiology and clinical presentation of chemotherapy-induced neuropathy, emerging insight into genetic susceptibilities as well as current understanding of the pathophysiology and treatment approaches.
| S-EPMC5450696 | biostudies-literature
Project description:Chemotherapy-induced peripheral neuropathy (CIPN) is a common cause of pain and poor quality of life for those undergoing treatment for cancer and those surviving cancer. Many advances have been made in the pre-clinical science; despite this, these findings have not been translated into novel preventative measures and treatments for CIPN. This review aims to give an update on the pre-clinical science, preventative measures, assessment and treatment of CIPN.
| S-EPMC7076330 | biostudies-literature
Project description: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 (TM?), 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.
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Project description:Chemotherapy-induced peripheral neuropathy (CIPN) is a major challenge, with increasing impact as oncological treatments, using potentially neurotoxic chemotherapy, improve cancer cure and survival. Acute CIPN occurs during chemotherapy, sometimes requiring dose reduction or cessation, impacting on survival. Around 30% of patients will still have CIPN a year, or more, after finishing chemotherapy. Accurate assessment is essential to improve knowledge around prevalence and incidence of CIPN. Consensus is needed to standardize assessment and diagnosis, with use of well-validated tools, such as the EORTC-CIPN 20. Detailed phenotyping of the clinical syndrome moves toward a precision medicine approach, to individualize treatment. Understanding significant risk factors and pre-existing vulnerability may be used to improve strategies for CIPN prevention, or to use targeted treatment for established CIPN. No preventive therapies have shown significant clinical efficacy, although there are promising novel agents such as histone deacetylase 6 (HDAC6) inhibitors, currently in early phase clinical trials for cancer treatment. Drug repurposing, eg, metformin, may offer an alternative therapeutic avenue. Established treatment for painful CIPN is limited. Following recommendations for general neuropathic pain is logical, but evidence for agents such as gabapentinoids and amitriptyline is weak. The only agent currently recommended by the American Society of Clinical Oncology is duloxetine. Mechanisms are complex with changes in ion channels (sodium, potassium, and calcium), transient receptor potential channels, mitochondrial dysfunction, and immune cell interactions. Improved understanding is essential to advance CIPN management. On a positive note, there are many potential sites for modulation, with novel analgesic approaches.
| S-EPMC6499732 | biostudies-literature
Project description:Chemotherapy-induced peripheral neuropathy is one of the most common dose-limiting side effects of cancer treatment. Currently, there is no Food and Drug Administration-approved treatment available. Histone deacetylase 6 (HDAC6) is a microtubule-associated deacetylase whose function includes regulation of α-tubulin-dependent intracellular mitochondrial transport. Here, we examined the effect of HDAC6 inhibition on established cisplatin-induced peripheral neuropathy. We used a novel HDAC6 inhibitor ACY-1083, which shows 260-fold selectivity towards HDAC6 vs other HDACs. Our results show that HDAC6 inhibition prevented cisplatin-induced mechanical allodynia, and also completely reversed already existing cisplatin-induced mechanical allodynia, spontaneous pain, and numbness. These findings were confirmed using the established HDAC6 inhibitor ACY-1215 (Ricolinostat), which is currently in clinical trials for cancer treatment. Mechanistically, treatment with the HDAC6 inhibitor increased α-tubulin acetylation in the peripheral nerve. In addition, HDAC6 inhibition restored the cisplatin-induced reduction in mitochondrial bioenergetics and mitochondrial content in the tibial nerve, indicating increased mitochondrial transport. At a later time point, dorsal root ganglion mitochondrial bioenergetics also improved. HDAC6 inhibition restored the loss of intraepidermal nerve fiber density in cisplatin-treated mice. Our results demonstrate that pharmacological inhibition of HDAC6 completely reverses all the hallmarks of established cisplatin-induced peripheral neuropathy by normalization of mitochondrial function in dorsal root ganglia and nerve, and restoration of intraepidermal innervation. These results are especially promising because one of the HDAC6 inhibitors tested here is currently in clinical trials as an add-on cancer therapy, highlighting the potential for a fast clinical translation of our findings.
| S-EPMC5435512 | biostudies-literature
Project description:Chemotherapy-induced peripheral neuropathy (CIPN) is a serious and often persistent adverse consequence of certain chemotherapeutic agents. It is a major dose-limiting factor of many first-line chemotherapies, affecting 20-50% of patients at standard doses and nearly all patients at high doses. As cancer survivorship continues to increase with improvements in early diagnosis and treatment, more patients will experience CIPN despite completing cancer treatment, which interferes with recovery, leading to chronic pain and worsening quality of life. The National Cancer Institute has identified CIPN as a priority in translational research. To date, there are no FDA-approved drugs for preventing or treating CIPN, with emerging debate on mechanisms and promising new targets. This review highlights current literature and suggests novel approaches to CIPN based on proposed mechanisms of action that aim either to confer neuroprotection against chemotherapy-induced neurotoxicity or reverse the downstream effects of painful neuropathy.
| S-EPMC8804039 | biostudies-literature
Project description:It has become increasingly clear that the innate immune system plays an essential role in the generation of many types of neuropathic pain including that which accompanies cancer treatment. In this article we review current findings of the role of the innate immune system in contributing to cancer treatment pain at the distal endings of peripheral nerve, in the nerve trunk, in the dorsal root ganglion and in the spinal dorsal horn.
| S-EPMC8190706 | biostudies-literature
Project description:Chemotherapy-induced peripheral neuropathy (CIPN) is a common dose-limiting toxicity experienced in 30-40% of patients undergoing treatment with various chemotherapeutics, including taxanes, vinca alkaloids, epothilones, proteasome inhibitors, and thalidomide. Importantly, CIPN significantly affects a patient's quality of life. Recent genetic association studies are enhancing our understanding of CIPN pathophysiology and serve as a foundation for identification of genetic biomarkers to predict toxicity risk and for the development of novel strategies for prevention and treatment.
| S-EPMC5359049 | biostudies-literature
Project description:Chemotherapy-induced peripheral neuropathy (CIPN) is a common and dose-limiting toxicity to widely used chemotherapeutics. Although the exact molecular mechanism of chemotherapy-induced peripheral neuropathy remains elusive, there is consensus that it is caused by damage to the peripheral nervous system leading to sensory symptoms. Recently developed methodologies have provided evidence of expression of drug transporters in the peripheral nervous system. In this literature review, we explore the role for drug transporters in CIPN. First, we assessed the transport of chemotherapeutics that cause CIPN (taxanes, platins, vincristine, bortezomib, epothilones, and thalidomide). Second, we cross-referenced the transporters implicated in genetic or functional studies with CIPN with their expression in the peripheral nervous system. Several drug transporters are involved in the transport of chemotherapeutics that cause peripheral neuropathy and particularly efflux transporters, such as ABCB1 and ABCC1, are expressed in the peripheral nervous system. Previous literature has linked genetic variants in efflux transporters to higher risk of peripheral neuropathy with the taxanes paclitaxel and docetaxel and the vinca alkaloid vincristine. We propose that this might be due to accumulation of the chemotherapeutics in the peripheral nervous system due to reduced neuronal efflux capacity. Thus, concomitant administration of efflux transporter inhibitors may lead to higher risk of adverse events of drugs that cause CIPN. This might prove valuable in drug development where screening new drugs for neurotoxicity might also require drug transporter consideration. There are ongoing efforts targeting drug transporters in the peripheral nervous system to reduce intraneuronal concentrations of chemotherapeutics that cause CIPN, which might ultimately protect against this dose-limiting adverse event.
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