Thromb Haemost 2010; 104(05): 1044-1048
DOI: 10.1160/TH09-08-0570
Cellular Proteolysis and Oncology
Schattauer GmbH

Oral thrombostatin FM19 inhibits prostate cancer

Marvin T. Nieman
1  Division of Hematology/Oncology, Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA
,
Gretchen A. LaRusch
1  Division of Hematology/Oncology, Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA
,
Chao Fang
1  Division of Hematology/Oncology, Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA
,
Yihua Zhou
1  Division of Hematology/Oncology, Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA
,
Alvin H. Schmaier
1  Division of Hematology/Oncology, Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA
› Author Affiliations
Financial support: NIH grants HL052779, HL057346, HL065194 to Dr. Schmaier; American Heart Association Beginning Grant-in-Aid 0865441D to Dr. Nieman. Small Animal Imaging, Cytometry and Light Microscopy Core Facilities of the Comprehensive Cancer Center of Case Western Reserve University and University Hospitals of Cleveland (P30 CA43703).
Further Information

Publication History

Received: 17 August 2009

Accepted after major revision: 16 January 2010

Publication Date:
24 November 2017 (online)

Summary

Thrombin stimulates proliferation, invasion and metastasis by cleaving protease-activated receptor 1 (PAR1) on human prostate cancer cells. Current direct thrombin inhibitors pose risks for bleeding in the cancer patients. We have developed an oral reversible direct thrombin inhibitor called FM19. FM19 inhibits thrombin-induced calcium mobilisation of PC3 cells with an IC50 of 15 μM with a 95% confidence interval of 7.3–31.6 μM. Thrombin stimulation increases PC3 cell invasion threefold from 27.1 ± 11.4 to 66 ± 11.6. FM19 or bivalirudin reduces cell invasion at ≥0.1 μM (p≤0.02). After inoculation with PC3 cells, nude mice were treated with oral FM19 at 3 mg/ml in the drinking water. The treated mice did not have long bleeding times and only a 1.4-fold increase in their thrombin clotting time. However, with treatment, the mice have a reduced rate of tumour growth 0.26 ± 0.17 fold change/day vs. 0.55 ± 0.35 for untreated (p = 0.038), reduced fold change in tumour size 5.3 ± 0.47 to 8.9 ± 1.8 (untreated) (p=0.048), and reduced overall tumour weight 0.5 ± 0.31 g vs. 0.82 ± 0.32 g (untreated) (p=0.04). On microscopic examination, FM19 treatment reduces the number of large vessels in the tumours from 4.6 ± 2.1 per high-powered field in untreated samples to 1.4 ± 1.4 in treated samples (p≤0.04). These studies show FM19 reduces prostate tumour growth in vivo at a concentration below that needed for anticoagulation. These data suggest novel opportunities for oral direct thrombin inhibitors in cancer therapy.