Recombinant thrombomodulin suppresses tumor growth of pancreatic cancer by blocking thrombin-induced PAR1 and NF-κB activation

Abstract

Thrombomodulin, an anticoagulant that inhibits thrombin-induced growth factor promotion, also has an anti-inflammatory effect. Furthermore, thrombomodulin inhibits nuclear factor-kappa B activation, which plays a crucial role in cancer progression. We assessed the antitumor activity of recombinant thrombomodulin for pancreatic cancer. A xenograft orthotopic model was established in mice by implantation of human pancreatic cancer cells. The animals were treated with intraperitoneal injection of recombinant thrombomodulin 5 times a week for 4weeks. Nuclear factor-kappa B activation was evaluated by measuring nuclear localization of the p65. Efficacy of recombinant thrombomodulin on the signal transduction of nuclear factor-kappa B was measured invitro under preconditioning with thrombin or epidermal growth factor. Tumor growth was suppressed by recombinant thrombomodulin (P<.05). Recombinant thrombomodulin inhibited the expression of IκB kinase β (P<.05) and pIκBα (P<.01), as well as the activation of nuclear factor-kappa B NF-κB (P<.001). Furthermore, recombinant thrombomodulin inhibited thrombin-induced protease activate receptor 1 and nuclear factor-kappa B activation invitro (P<.05). The number of Ki67-positive cells was decreased by recombinant thrombomodulin (P<.01). Recombinant thrombomodulin also suppressed body weight loss associated with pancreatic cancer (P<.05). No obvious adverse effects were observed. Recombinant thrombomodulin significantly suppressed tumor growth against human pancreatic cancer by blocking thrombin-induced nuclear factor-kappa B activation without adverse effects.