Abstract:Chemotherapy-induced peripheral neuropathy (CIPN) is a serious adverse side effect of many chemotherapeutic agents, affecting >60% of patients with cancer. Moreover, CIPN persists long into survivorship in approximately 20% to 30% of these patients. To the authors' knowledge, no drugs have been approved to date by the US Food and Drug Administration to effectively manage chemotherapy-induced neuropathic pain. The majority of the drugs tested for the management of CIPN aim at symptom relief, including pain and … Show more
“…This study is the first to provide molecular evidence that a number of neuroinflammatory mechanisms identified in preclinical models of neuropathic pain and/or PIPN (Flatters et al, 2017;Ma et al, 2018) are perturbed in cancer survivors with PIPN. As noted in a review on the role of cytokines in chemotherapy-induced peripheral neuropathy (CIPN), (Wang et al, 2012) pro-inflammatory cytokines and chemokines play a critical role in the development and maintenance of painful peripheral neuropathy.…”
A B S T R A C TPaclitaxel is a common chemotherapy drug associated with the development of chronic paclitaxel-induced peripheral neuropathy (PIPN). PIPN is associated with neuroinflammatory mechanisms in pre-clinical studies. Here, we evaluated for differential gene expression (DGE) in peripheral blood between breast cancer survivors with and without PIPN and for neuroinflammatory (NI) related signaling pathways and whole-transcriptome profiles from other experiments. Pathway impact analysis identified 8 perturbed NI related pathways. Expression profile analysis found 15 experiments having similar whole-transcriptome profiles of DGE related to neuroinflammation and PIPN. These findings suggest that perturbations in pathways associated with neuroinflammation are found in cancer survivors with PIPN.
“…This study is the first to provide molecular evidence that a number of neuroinflammatory mechanisms identified in preclinical models of neuropathic pain and/or PIPN (Flatters et al, 2017;Ma et al, 2018) are perturbed in cancer survivors with PIPN. As noted in a review on the role of cytokines in chemotherapy-induced peripheral neuropathy (CIPN), (Wang et al, 2012) pro-inflammatory cytokines and chemokines play a critical role in the development and maintenance of painful peripheral neuropathy.…”
A B S T R A C TPaclitaxel is a common chemotherapy drug associated with the development of chronic paclitaxel-induced peripheral neuropathy (PIPN). PIPN is associated with neuroinflammatory mechanisms in pre-clinical studies. Here, we evaluated for differential gene expression (DGE) in peripheral blood between breast cancer survivors with and without PIPN and for neuroinflammatory (NI) related signaling pathways and whole-transcriptome profiles from other experiments. Pathway impact analysis identified 8 perturbed NI related pathways. Expression profile analysis found 15 experiments having similar whole-transcriptome profiles of DGE related to neuroinflammation and PIPN. These findings suggest that perturbations in pathways associated with neuroinflammation are found in cancer survivors with PIPN.
“…The non‐selective character of most chemotherapeutic drugs usually initiates systemic symptoms as adverse or side effects during therapy (de Oliveira Junior et al, ). These adverse effects include cardiotoxicity, nephrotoxicity, hepatotoxicity, and peripheral neuropathy (Duwe et al, ; Ma, Kavelaars, Dougherty, & Heijnen, ; Santoni et al, ; Sharbaf et al, ). Sometimes, the adverse effects severely affect the daily quality of life for patients (X. Wu et al, ).…”
Section: Herbal Compounds With the Potential To Synergize With Antitumentioning
Traditional chemotherapy is being considered due to hindrances caused by systemic toxicity. Currently, the administration of multiple chemotherapeutic drugs with different biochemical/molecular targets, known as combination chemotherapy, has attained numerous benefits like efficacy enhancement and amelioration of adverse effects that has been broadly applied to various cancer types. Additionally, seeking natural‐based alternatives with less toxicity has become more important. Experimental evidence suggests that herbal extracts such as Solanum nigrum and Claviceps purpurea and isolated herbal compounds (e.g., curcumin, resveratrol, and matairesinol) combined with antitumoral drugs have the potential to attenuate resistance against cancer therapy and to exert chemoprotective actions. Plant products are not free of risks: Herb adverse effects, including herb–drug interactions, should be carefully considered.
Linked Articles
This article is part of a themed section on The Pharmacology of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.6/issuetoc
“…Existing first-line treatments produce only 30% pain relief in the majority of patients (1). Chemotherapy-induced peripheral neuropathy (CIPN) is the primary doselimiting side effect of cancer treatment and no drugs are approved to treat this form of neuropathic pain (2). Peripheral pain sensing neurons, called nociceptors, are the cellular origin of pain caused by neuropathies (3).…”
One Sentence SummaryCell-specific sequencing of translating mRNAs elucidates signaling pathology that can be targeted to reverse neuropathic pain
Abstract (100-125 words)Pain sensing neurons, nociceptors, are key drivers of neuropathic pain. We used translating ribosome affinity purification (TRAP) to comprehensively characterize upand down-regulated mRNA translation in Scn10a-positive nociceptors in chemotherapy-induced neuropathic pain. We provide evidence that an underlying mechanism driving these changes in gene expression is a sustained mTORC1 activation driven by MNK1-eIF4E signaling. RagA, a GTPase controlling mTORC1 activity, is identified as a novel target of MNK1-eIF4E signaling, demonstrating a new link between these distinct signaling pathways. Neuropathic pain and RagA translation are strongly attenuated by genetic ablation of eIF4E phosphorylation, MNK1 elimination or treatment with the MNK inhibitor eFT508. We reveal a novel translational circuit for the genesis of neuropathic pain with important implications for next generation neuropathic pain therapeutics.
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