Systemic use of argatroban reduces tumor mass, attenuates neurological deficits and prolongs survival time in rat glioma models

Hua, Ya; Tang, Lingling; Fewel, Matthew E.; Keep, Richard F.; Schallert, Timothy; Muraszko, Karin M.; Hoff, Julian T.; Xi, G.

doi:10.1007/3-211-32318-x_82

Cited by 19 publications

(15 citation statements)

References 17 publications

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“…Tissue factor and VEGF are also overexpressed and co-localized in these cell types (57). Thrombin immunoreactivity has been reported in GBM, and argatroban, a direct thrombin inhibitor, reduces glioma tumor mass and neurological deficits in a rat glioma model (32,58), leading to the suggestion that the coagulation system can be a target for the treatment of malignant glioma (59). Thus, the production and cleavage of OPN by thrombin and CPB-2 may all occur locally.…”

Section: Discussionmentioning

confidence: 99%

Thrombin-cleaved Fragments of Osteopontin Are Overexpressed in Malignant Glial Tumors and Provide a Molecular Niche with Survival Advantage

Yamaguchi

Shao

Sharif

et al. 2013

Journal of Biological Chemistry

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Background: Osteopontin (OPN) is highly expressed in glioblastoma (GBM) and possesses inflammatory activity modulated by proteolytic cleavage. Results: Cleaved OPN was increased in GBM and led to more adhesion of GBM cells. OPN conferred resistance to apoptosis in GBM cells. Conclusion: Increased osteopontin proteolysis increased GBM cell resistance to apoptosis. Significance: OPN cleavage links coagulation and inflammation providing a favorable niche for GBM development.

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Section: Discussionmentioning

confidence: 99%

Thrombin-cleaved Fragments of Osteopontin Are Overexpressed in Malignant Glial Tumors and Provide a Molecular Niche with Survival Advantage

Yamaguchi

Shao

Sharif

et al. 2013

Journal of Biological Chemistry

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“…A limited number of studies have reported that Argatroban can reduce tumor growth of glioma cells [12] and experimental metastasis of colon cancer [11] or melanoma cells [10], although these studies varied in terms of their injection route and dose of Argatroban. Notably, the dose of Argatroban used in the present study (9 mg/kg/day by subcutaneous injection) can be considered a sub-therapeutic (i.e.…”

Section: Discussionmentioning

confidence: 99%

“…From a therapeutic perspective, there are several clinically available agents that can inhibit thrombin, including the broad-spectrum anticoagulants heparin and warfarin, and the thrombinspecific inhibitors hirudin, Refludan, Desirudin, and Argatroban [8,9]. Although some of these therapeutics have been demonstrated to have an inhibitory effect on malignant and metastatic behavior in experimental studies [10][11][12][13][14], their main clinical application has been for management of coagulation disorders/complications rather than for prevention of cancer progression [8,9].…”

Section: Introductionmentioning

confidence: 99%

The thrombin inhibitor Argatroban reduces breast cancer malignancy and metastasis via osteopontin-dependent and osteopontin-independent mechanisms

Schulze

Hedley

Goodale

et al. 2007

Breast Cancer Res Treat

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Osteopontin (OPN) has been clinically and experimentally associated with breast cancer metastasis. Proteolytic cleavage of OPN by thrombin has been reported to increase its biologic activity. The purpose of this study was to determine if inhibition of thrombin could reduce the malignancy-promoting effects of OPN on breast cancer cell behavior in vitro and in vivo. MDA-MB-468 human breast cancer cells were stably transfected to overexpress OPN (468-OPN) or a control vector (468-CON) and compared for functional differences in malignant/metastatic behavior in response to treatment with the thrombin-specific inhibitor Argatroban. Western blot analysis revealed that both 468-CON and 468-OPN cells produce thrombin and the thrombin-related protein tissue factor, and express very low levels of thrombin receptor (PAR-1). In vitro assays demonstrated that Argatroban treatment (25 microg/ml) of 468-OPN cells resulted in decreased cell growth, colony-forming ability, adhesion, and migration relative to untreated controls (P < 0.05), but did not have a significant effect on 468-CON cells. Following mammary fat pad injection, treatment with Argatroban (9 mg/kg/day) increased the in vivo tumor latency of both 468-CON and 468-OPN cells, and reduced primary tumor growth of 468-OPN cells (relative to untreated controls; P < 0.05). Furthermore, Argatroban treatment significantly decreased lymphatic metastasis of both 468-CON (P < 0.04) and 468-OPN (P < 0.01) cells relative to untreated controls. These novel findings indicate that inhibition of thrombin can reduce malignant and metastatic behavior of MDA-MB-468 breast cancer cells using both OPN-dependent and OPN-independent mechanisms, and suggest that thrombin inhibitors such as Argatroban may hold potential as therapeutic agents to combat breast cancer progression.

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“…Argatroban, a thrombin antagonist, was shown to reduce edema, tumor growth, and tumor-related neurological deficits in rat glioma models. 23,31 Attention has also been directed toward corticotropinreleasing factor, a polypeptide that regulates adrenocorticotropin hormone release from the pituitary gland, which in turn regulates hydrocortisone secretion from the adrenal gland. Corticotropin-releasing factor has also been studied in conjunction with intracerebral gliomas and has been found to reduce BBB permeability in a tumor model 90 and to improve neurological function in patients suffering brain metastasis.…”

Section: Management Of Brain Tumor Edemamentioning

confidence: 99%

Mechanisms of tumor-related brain edema

Stummer¹

2007

FOC

112

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✓Cerebral edema contributes strongly to symptoms associated with brain tumors. Although the introduction of corticosteroids has greatly simplified treatment of patients with newly diagnosed tumors, these drugs are associated with marked side effects during the long-term treatment that is often necessary in the recurrences. Therefore, a better understanding of mechanisms related to the evolution and clearance of tumor-related edema with the aid of modern imaging and molecular methodology is clearly necessary. Recently, researchers have focused on molecular mechanisms of edema development and have demonstrated alternative routes—such as the inhibition of vascular endothelial growth factor receptor inhibitors—to be explored for treating edema. In this review the author focuses on established and current concepts regarding the pathophysiology of cerebral edema and its treatment.

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Systemic use of argatroban reduces tumor mass, attenuates neurological deficits and prolongs survival time in rat glioma models

Cited by 19 publications

References 17 publications

Thrombin-cleaved Fragments of Osteopontin Are Overexpressed in Malignant Glial Tumors and Provide a Molecular Niche with Survival Advantage

Thrombin-cleaved Fragments of Osteopontin Are Overexpressed in Malignant Glial Tumors and Provide a Molecular Niche with Survival Advantage

The thrombin inhibitor Argatroban reduces breast cancer malignancy and metastasis via osteopontin-dependent and osteopontin-independent mechanisms

Mechanisms of tumor-related brain edema

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