Thrombomodulin alfa prevents oxaliplatin-induced neuropathic symptoms through activation of thrombin-activatable fibrinolysis inhibitor and protein C without affecting anti-tumor activity

• Published in: European journal of pharmacology Vol. 880; p. 173196
• Main Authors: Minami, Tatsuro, Takeda, Mineko, Sata, Minako, Kato, Hiroki, Yano, Kazuo, Sakai, Takumi, Tsujita, Ryuichi, Kawasaki, Koh, Ito, Akitoshi
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 05.08.2020
• Subjects: Analgesics - pharmacology; Analgesics - therapeutic use; Animals; Antineoplastic Agents - adverse effects; Antineoplastic Agents - therapeutic use; Carboxypeptidase B2 - metabolism; Cell Line, Tumor; Chemotherapy-induced peripheral neuropathy; Colonic Neoplasms - drug therapy; Colonic Neoplasms - pathology; Female; Humans; Hyperalgesia; Hyperalgesia - chemically induced; Hyperalgesia - drug therapy; Hyperalgesia - metabolism; Male; Mice, Inbred BALB C; Mice, Nude; Neuralgia - chemically induced; Neuralgia - drug therapy; Neuralgia - metabolism; Oxaliplatin; Oxaliplatin - adverse effects; Oxaliplatin - therapeutic use; Peripheral Nervous System Diseases - chemically induced; Peripheral Nervous System Diseases - drug therapy; Peripheral Nervous System Diseases - metabolism; Protein C; Protein C - metabolism; Rats, Sprague-Dawley; Recombinant Proteins - pharmacology; Recombinant Proteins - therapeutic use; Thrombin-activatable fibrinolysis inhibitor; Thrombomodulin; Thrombomodulin - genetics; Thrombomodulin - therapeutic use; Touch; Protein C; Oxaliplatin; Thrombomodulin; Thrombin-activatable fibrinolysis inhibitor; Chemotherapy-induced peripheral neuropathy; Hyperalgesia
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2020.173196

Oxaliplatin, a platinum-based chemotherapeutic agent, is widely used to treat colorectal cancer, but it induces peripheral neuropathy as a serious dose-limiting side effect. Recently, thrombomodulin alfa, a recombinant human soluble thrombomodulin, was reported to prevent oxaliplatin-induced peripheral neuropathy in a clinical phase 2 study. Here we conducted preclinical pharmacology studies. Rats were given oxaliplatin (6 mg/kg) intravenously to induce mechanical hyperalgesia associated with peripheral neuropathy. Single intravenous administration of thrombomodulin alfa (0.1, 0.3, 1 mg/kg) dose dependently prevented the development of oxaliplatin-induced mechanical hyperalgesia, with no sex difference in the efficacy. The preventative effect of thrombomodulin alfa on mechanical hyperalgesia was attenuated by antithrombin or carboxypeptidase inhibitor. In addition, carboxypeptidase B, a homolog of activated thrombin-activatable fibrinolysis inhibitor (TAFI) and human-derived activated protein C, prevented mechanical hyperalgesia, whereas antithrombin or other anti-coagulants did not. These results suggest that thrombomodulin alfa prevents sensory symptoms of oxaliplatin-induced peripheral neuropathy through the activation of TAFI and protein C by modulating thrombin activity, but the effects are independent of an anticoagulant effect. On the other hand, thrombomodulin alfa did not affect the anti-cancer activity of oxaliplatin on human colon cancer cell lines or mice transplanted with HCT116 cells. These results indicate that thrombomodulin alfa prevents sensory symptoms of oxaliplatin-induced peripheral neuropathy without affecting the anti-tumor activity of oxaliplatin. Therefore, thrombomodulin alfa is a promising drug to prevent the symptoms of oxaliplatin-induced peripheral neuropathy. •Thrombomodulin alfa prevents oxaliplatin-induced peripheral neuropathy.•Activated thrombin-activatable fibrinolysis inhibitor and protein C contributed.•Thrombin-dependent prevention was independent of anticoagulation.•No impact of thrombomodulin on the anti-tumor activity of oxaliplatin was seen.