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