loading page

A novel oncotherapy strategy, direct thrombin inhibitors suppress progression, dissemination and spontaneous metastasis in non-small cell lung cancer
  • +11
  • Zhao Bing,
  • Mengfang Wu,
  • Zhihuang Hu,
  • Tianfa Wang,
  • Jinchao Yu,
  • Yixin Ma,
  • Qi Wang,
  • Yanling Zhang,
  • Di Chen,
  • Tianyu Li,
  • Yaran Li,
  • Min Yu,
  • Huijie Wang,
  • Wei Mo
Zhao Bing
Fudan University
Author Profile
Mengfang Wu
Fudan University
Author Profile
Zhihuang Hu
Fudan University Shanghai Cancer Center
Author Profile
Tianfa Wang
Fudan University
Author Profile
Jinchao Yu
Fudan University
Author Profile
Yixin Ma
Fudan University
Author Profile
Qi Wang
Fudan University
Author Profile
Yanling Zhang
Fudan University
Author Profile
Di Chen
Fudan University
Author Profile
Tianyu Li
Fudan University
Author Profile
Yaran Li
Fudan University School of Basic Medical Sciences
Author Profile
Min Yu
Fudan University
Author Profile
Huijie Wang
Fudan University Shanghai Cancer Center
Author Profile
Wei Mo
Fudan University
Author Profile

Abstract

Background and Purpose: Cancer cachexia and cancer-associated thrombosis are potentially fatal outcomes of advanced cancer. Nevertheless, thrombin expression in NSCLC primary tumor tissues and the association between prognosis of NSCLC patients remain largely unknown. Experimental Approach: Clinical pathological analysis was performed to determine the relationship between thrombin and tumor progression. Effect of r-hirudin and DTIP on cancer progression were evaluated. Western blotting, immunohistochemistry, and immunofluorescence were used to explore the inhibition mechanism of r-hirudin and DTIP. Therapeutic effect of combination of DTIP and chemotherapy was determined. Key Results: We illustrated thrombin expression in NSCLC tissues is closely related to clinicopathological features and the prognosis of patients. Thrombin deficiency inhibited tumor progression. The novel thrombin inhibitors, r-hirudin and DTIP, inhibited cell invasion and metastasis in vitro. They inhibited tumor growth and metastasis in orthotopic lung cancer model; inhibited cells invasion and prolonged survival after injection tumor cells via tail vein; they also inhibited angiogenesis and spontaneous metastases from subcutaneously inoculated tumors. The promotional activity of thrombin in invasion and metastasis was abolished in PAR-1 deficient-NSCLC cells. r-hirudin and DTIP inhibit tumor progression through the thrombin-PAR-1-mediated RhoA and NF-κB signaling cascades via inhibiting the MMP9 and IL6 expression. DTIP potentiated chemotherapy-induced growth and metastatic inhibition and inhibited chemotherapy-induced resistance in mice. Conclusions and Implications: Thrombin makes a substantial contribution, together with PAR-1, to NSCLC malignancy. We concluded the anticoagulants, r-hirudin and DTIP, could be expanded for anti-tumor therap. Combination therapy of DTIP and chemotherapy might achieve a better therapeutic effect.

Peer review status:UNDER REVIEW

27 Aug 2020Submitted to British Journal of Pharmacology
28 Aug 2020Assigned to Editor
28 Aug 2020Submission Checks Completed
10 Sep 2020Reviewer(s) Assigned