期刊
BRITISH JOURNAL OF PHARMACOLOGY
卷 179, 期 22, 页码 5056-5073出版社
WILEY
DOI: 10.1111/bph.15384
关键词
combination therapy; direct thrombin inhibitors; metastasis; non‐ small cell lung cancer; thrombin
资金
- China Postdoctoral Science Foundation [2018M641936]
- Science and Technology Commission of Shanghai Municipality [16431904600]
- National Natural Science Foundation of China [81673498, 81902995]
Thrombin expression in NSCLC tissues is closely related to clinicopathological features and patient prognosis. Thrombin deficiency inhibits tumor progression. Novel thrombin inhibitors, r-hirudin and DTIP, inhibit cancer cell invasion and metastasis, and combination with chemotherapy shows potential for improving therapeutic effects.
Background and Purpose Cancer cachexia and cancer-associated thrombosis are potentially fatal outcomes of advanced cancer. Nevertheless, thrombin expression in non-small cell lung cancer (NSCLC) primary tumour 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 tumour progression. Effects of r-hirudin and direct thrombin inhibitor peptide (DTIP) on cancer progression were evaluated. Western blotting, immunohistochemistry, and immunofluorescence were used to explore the inhibition mechanism of r-hirudin and DTIP. The therapeutic effect of the combination of DTIP and chemotherapy was determined. Key Results Thrombin expression in NSCLC tissues was closely related to clinicopathological features and the prognosis of patients. Thrombin deficiency inhibited tumour progression. The novel thrombin inhibitors, r-hirudin and DTIP, inhibited cell invasion and metastasis in vitro. They inhibited tumour growth and metastasis in orthotopic lung cancer model, inhibited cell invasion, and prolonged survival after injection of tumour cells via the tail vein. They also inhibited angiogenesis and spontaneous metastases from subcutaneously inoculated tumours. The promotion by thrombin of invasion and metastasis was abolished in PAR-1-deficient NSCLC cells. r-hirudin and DTIP inhibited tumour progression through the thrombin-PAR-1-mediated RhoA and NF-kappa B signalling cascades via inhibiting 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. The anti-coagulants, r-hirudin and DTIP, could be used in anti-tumour therapy and a combination of DTIP and chemotherapy might improve therapeutic effects.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据