Shirai Yoshihiro, Uwagawa Tadashi, Shiba Hiroaki, Shimada Yohta, Horiuchi Takashi, Saito Nobuhiro, Furukawa Kenei, Ohashi Toya, Yanaga Katsuhiko
Department of Surgery, The Jikei University, School of Medicine, Tokyo, Japan; Division of Gene Therapy, Research Center for Medical Science, The Jikei University, School of Medicine, Tokyo, Japan.
Department of Surgery, The Jikei University, School of Medicine, Tokyo, Japan; Division of Clinical Oncology and Hematology, and Department of Internal Medicine, The Jikei University, School of Medicine, Tokyo, Japan.
Surgery. 2017 Jun;161(6):1675-1682. doi: 10.1016/j.surg.2016.12.008. Epub 2017 Jan 13.
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 4 weeks. 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 in vitro 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 in vitro (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.
血栓调节蛋白是一种抗凝剂，可抑制凝血酶诱导的生长因子促进作用，还具有抗炎作用。此外，血栓调节蛋白可抑制核因子-κB的激活，而核因子-κB在癌症进展中起关键作用。我们评估了重组血栓调节蛋白对胰腺癌的抗肿瘤活性。
通过植入人胰腺癌细胞在小鼠中建立异种移植原位模型。动物每周腹腔注射重组血栓调节蛋白5次，共4周。通过测量p65的核定位来评估核因子-κB的激活。在凝血酶或表皮生长因子预处理下，体外测量重组血栓调节蛋白对核因子-κB信号转导的功效。
重组血栓调节蛋白抑制肿瘤生长（P <.05）。重组血栓调节蛋白抑制IκB激酶β（P <.05）和pIκBα（P <.01）的表达，以及核因子-κB NF-κB的激活（P <.001）。此外，重组血栓调节蛋白在体外抑制凝血酶诱导的蛋白酶激活受体1和核因子-κB的激活（P <.05）。重组血栓调节蛋白使Ki67阳性细胞数量减少（P <.01）。重组血栓调节蛋白还抑制了与胰腺癌相关的体重减轻（P <.05）。未观察到明显的不良反应。
重组血栓调节蛋白通过阻断凝血酶诱导的核因子-κB激活，显著抑制人胰腺癌的肿瘤生长，且无不良反应。
