title: Toll-like receptor 4 signaling: a common biological mechanism of regimen-related toxicities: an emerging hypothesis for neuropathy and gastrointestinal toxicity.
abstract: Regimen-related toxicities remain a priority concern within the field of supportive care in cancer. Despite this, many forms of toxicity are under reported and consequently poorly characterised. Although there have been significant improvements in our understanding of regimen-related toxicities, symptom management continues to occur independently raising concerns such as drug interactions and the tendency to emphasise management of a single symptom at the expense of others. This review focuses on two important toxicities induced by chemotherapy; neuropathy/pain and gastrointestinal toxicity, introducing the Toll-like receptor (TLR) 4 pathway as a common component of their pathobiology. Given the global observation of toxicity clusters, identification of a common initiating factor provides an excellent opportunity to simultaneously target multiple side effects of anticancer treatment. Furthermore, identification of common biological underpinnings could perhaps reduce polypharmacy and have pharmacoeconomic benefits.
authors.affiliation: Discipline of Anatomy and Pathology, School of Medical Sciences, University of Adelaide, South Australia, Australia. Electronic address: hannah.wardill@adelaide.edu.au.
authors.forename: Hannah R
authors.initials: HR
authors.lastname: Wardill
authors.affiliation: Discipline of Physiology, School of Medical Sciences, University of Adelaide, South Australia, Australia. Electronic address: ysabella.vansebille@adelaide.edu.au.
authors.forename: Ysabella Z A
authors.initials: YZ
authors.lastname: Van Sebille
authors.affiliation: Adelaide Centre for Neuroscience Research and Discipline of Anatomy and Pathology, University of Adelaide, South Australia, Australia. Electronic address: kimberley.mander@adelaide.edu.au.
authors.forename: Kimberley A
authors.initials: KA
authors.lastname: Mander
authors.affiliation: Discipline of Anatomy and Pathology, School of Medical Sciences, University of Adelaide, South Australia, Australia. Electronic address: rachel.gibson@adelaide.edu.au.
authors.forename: Rachel J
authors.initials: RJ
authors.lastname: Gibson
authors.affiliation: School of Dentistry, University of Adelaide, South Australia, Australia. Electronic address: richard.logan@adelaide.edu.au.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Logan
authors.affiliation: Discipline of Physiology, School of Medical Sciences, University of Adelaide, South Australia, Australia. Electronic address: joanne.bowen@adelaide.edu.au.
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Bowen
authors.affiliation: Brigham and Women's Hospital, Boston, MA, USA. Electronic address: ssonis@partners.org.
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Sonis
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects*; D005767:Gastrointestinal Diseases / Q000139:chemically induced* / Q000378:metabolism; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D009457:Neuroglia / Q000378:metabolism*; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D051197:Toll-Like Receptor 4 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D016328:NF-kappa B; D017382:Reactive Oxygen Species; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4
keywords: Chemotherapy; Glial activation; Gut toxicity; Neuropathy; Neurotoxicity; Toll-like receptor 4