Abstract
Chemotherapy-induced peripheral neuropathy (CIPN), one of major dose-limiting side effects of first-line chemotherapeutic agents such as paclitaxel, oxaliplatin, vincristine, and bortezomib is resistant to most of existing medicines. The molecular mechanisms of CIPN have not been fully understood. High mobility group box 1 (HMGB1), a nuclear protein, is a damage-associated molecular pattern protein now considered to function as a pro-nociceptive mediator once released to the extracellular space. Most interestingly, HMGB1 plays a key role in the development of CIPN. Soluble thrombomodulin (TMα), known to degrade HMGB1 in a thrombin-dependent manner, prevents CIPN in rodents treated with paclitaxel, oxaliplatin, or vincristine and in patients with colorectal cancer undergoing oxaliplatin-based chemotherapy. In this review, we describe the role of HMGB1 and its upstream/downstream mechanisms in the development of CIPN and show drug candidates that inhibit the HMGB1 pathway, possibly useful for prevention of CIPN.
Highlights
We have shown that the inactivation of high mobility group box 1 (HMGB1) with HMGB1-nAb or TMα and pharmacological blockade of receptors for advance glycosylation end products (RAGE), CXCR4, or TLR4 prevent Chemotherapy-induced peripheral neuropathy (CIPN) in rodents treated with oxaliplatin (Figure 2B and Table 1) [10]
Peripheral TLR4 appears to be involved in the CIPN caused by oxaliplatin, because systemic administration of Lipopolysaccharide of Rhodobacter sphaeroides (LPS-RS) as well as TAK-242 exhibited a preventive effect in this CIPN model (Figure 2B and Table 1)
Our study has demonstrated that repeated administration of different anticoagulants aggravates CIPN and increases plasma HMGB1 levels in mice treated with a sub-effective dose of oxaliplatin [10], suggesting that the endothelial
Summary
The mechanisms for development and maintenance of CIPN have not been fully understood, preclinical studies have provided evidence for some possible mechanisms for CIPN [2], such as neuroimmune interactions [3], mitochondrial dysfunction [4], reactive oxygen species (ROS) accumulation [5], and transcriptional or functional upregulation of cation channels [6,7] in the spinal cord, dorsal root ganglion (DRG), and peripheral sensory neurons. We have shown that the HMGB1-nAb strongly prevents the development of CIPN in rodents [8,9,10].
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