Abstract
Given the role of macrophage-derived high mobility group box 1 (HMGB1) in chemotherapy-induced peripheral neuropathy (CIPN) caused by paclitaxel, we analyzed the role of HMGB1 and macrophages in the CIPN caused by bortezomib, a proteasome-inhibiting chemotherapeutic agent used for the treatment of multiple myeloma. Repeated administration of bortezomib caused CIPN accompanied by early-stage macrophage accumulation in the dorsal root ganglion. This CIPN was prevented by an anti-HMGB1-neutralizing antibody, thrombomodulin alfa capable of accelerating thrombin-dependent degradation of HMGB1, antagonists of the receptor for advanced glycation end-products (RAGE) and C-X-C motif chemokine receptor 4 (CXCR4), known as HMGB1-targeted membrane receptors, or macrophage depletion with liposomal clodronate, as reported in a CIPN model caused by paclitaxel. In macrophage-like RAW264.7 cells, bortezomib as well as MG132, a well-known proteasome inhibitor, caused HMGB1 release, an effect inhibited by caspase inhibitors but not inhibitors of NF-κB and p38 MAP kinase, known to mediate paclitaxel-induced HMGB1 release from macrophages. Bortezomib increased cleaved products of caspase-8 and caused nuclear fragmentation or condensation in macrophages. Repeated treatment with the caspase inhibitor prevented CIPN caused by bortezomib in mice. Our findings suggest that bortezomib causes caspase-dependent release of HMGB1 from macrophages, leading to the development of CIPN via activation of RAGE and CXCR4.
Highlights
Chemotherapy-induced peripheral neuropathy (CIPN) frequently occurs in cancer patients undergoing chemotherapy with platinum agents, taxanes, vinca alkaloids, proteasome inhibitors, etc
We have demonstrated that high mobility group box 1 (HMGB1), one of the damageassociated molecular patterns (DAMPs), plays a role in the development and maintenance of CIPN in rodents treated with paclitaxel, vincristine, or oxaliplatin [2,4,5,6,7]
We show, for the first time to our knowledge, that bortezomib directly stimulates HMGB1 release from macrophages in a manner dependent on caspase, which is different from the mechanism for paclitaxelinduced HMGB1 release form macrophages, contributing to the development of CIPN in mice treated with bortezomib
Summary
Chemotherapy-induced peripheral neuropathy (CIPN) frequently occurs in cancer patients undergoing chemotherapy with platinum agents, taxanes, vinca alkaloids, proteasome inhibitors, etc. We have demonstrated that high mobility group box 1 (HMGB1), one of the damageassociated molecular patterns (DAMPs), plays a role in the development and maintenance of CIPN in rodents treated with paclitaxel, vincristine, or oxaliplatin [2,4,5,6,7]. Thrombomodulin (TM), an endothelial membrane protein, accelerates thrombin-dependent degradation of extracellular HMGB1, an effect being reproduced by recombinant human soluble TM (TMα) that is composed of TM’s extracellular domains and clinically used as a therapeutic agent for disseminated intravascular coagulation (DIC) in Japan [11]. We have shown that TMα as well as an anti-HMGB1-neutralizing antibody prevents CIPN in rodents treated with paclitaxel, vincristine, or oxaliplatin [4,5,6]. Of importance is that the clinical efficacy of TMα in preventing CIPN has been demonstrated in colorectal cancer patients undergoing oxaliplatin-based chemotherapy [12]. The endogenous TM/thrombin system appears to function to degrade HMGB1 in mice treated with oxaliplatin, thereby suppressing CIPN development
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