JOURNAL ARTICLE

A novel oncotherapy strategy, direct thrombin inhibitors suppress progression, dissemination and spontaneous metastasis in non-small cell lung cancer

Bing Zhao, Mengfang Wu, Zhihuang Hu, Tianfa Wang, Jin Chao Yu, Yixin Ma, Qi Wang, Yanling Zhang, Di Chen, Tianyu Li, Yaran Li, Min Yu, Huijie Wang, Wei Mo
British Journal of Pharmacology 2021 January 22
33481255

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.

Full Text Links

Find Full Text Links for this Article

Discussion

You are not logged in. Sign Up or Log In to join the discussion.

Trending Papers

Remove bar
Read by QxMD icon Read
33481255
×

Save your favorite articles in one place with a free QxMD account.

×

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"