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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

Corresponding Author:[email protected]

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Mengfang Wu
Fudan University
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Zhihuang Hu
Fudan University Shanghai Cancer Center
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Tianfa Wang
Fudan University
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Jinchao Yu
Fudan University
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Yixin Ma
Fudan University
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Qi Wang
Fudan University
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Yanling Zhang
Fudan University
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Di Chen
Fudan University
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Tianyu Li
Fudan University
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Yaran Li
Fudan University School of Basic Medical Sciences
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Min Yu
Fudan University
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Huijie Wang
Fudan University Shanghai Cancer Center
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Wei Mo
Fudan University
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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.
27 Aug 2020Submitted to British Journal of Pharmacology
28 Aug 2020Submission Checks Completed
28 Aug 2020Assigned to Editor
10 Sep 2020Reviewer(s) Assigned
19 Oct 2020Review(s) Completed, Editorial Evaluation Pending
19 Oct 2020Editorial Decision: Revise Minor
02 Dec 20201st Revision Received
02 Dec 2020Submission Checks Completed
02 Dec 2020Assigned to Editor
02 Dec 2020Reviewer(s) Assigned
13 Dec 2020Review(s) Completed, Editorial Evaluation Pending
15 Dec 2020Editorial Decision: Revise Minor
21 Dec 20202nd Revision Received
21 Dec 2020Submission Checks Completed
21 Dec 2020Assigned to Editor
27 Dec 2020Reviewer(s) Assigned
03 Jan 2021Review(s) Completed, Editorial Evaluation Pending
06 Jan 2021Editorial Decision: Revise Minor
13 Jan 20213rd Revision Received
13 Jan 2021Submission Checks Completed
13 Jan 2021Assigned to Editor
13 Jan 2021Review(s) Completed, Editorial Evaluation Pending
16 Jan 2021Editorial Decision: Accept