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The Rho kinase inhibitor fasudil inhibits tumor progression in human and rat tumor models
The ability of cancer cells to undergo invasion and migration is a prerequisite for tumor metastasis. Rho, a Ras-related small GTPase, and the Rho-associated coiled coil–containing protein kinases (Rho kinases, ROCK1 and ROCK2) are key regulators of focal adhesion, actomyosin contraction, and thus c...
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Published in: | Molecular cancer therapeutics 2006-09, Vol.5 (9), p.2158-2164 |
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Main Authors: | , , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | The ability of cancer cells to undergo invasion and migration is a prerequisite for tumor metastasis. Rho, a Ras-related small
GTPase, and the Rho-associated coiled coil–containing protein kinases (Rho kinases, ROCK1 and ROCK2) are key regulators of
focal adhesion, actomyosin contraction, and thus cell motility. Inhibitors of this pathway have been shown to inhibit tumor
cell motility and metastasis. Here, we show that fasudil [1-(5-isoquinolinesulfonyl)-homopiperazine], an orally available
inhibitor of Rho kinases, and its metabolite 1-(hydroxy-5-isoquinoline sulfonyl-homopiperazine) (fasudil-OH) modify tumor
cell morphology and inhibit tumor cell migration and anchorage-independent growth. In addition, we show that fasudil inhibited
tumor progression in three independent animal models. In the MM1 peritoneal dissemination model, tumor burden and ascites
production were reduced by >50% ( P < 0.05). In the HT1080 experimental lung metastasis model, fasudil decreased lung nodules by ∼40% ( P < 0.05). In the orthotopic breast cancer model with MDA-MB-231, there were 3-fold more tumor-free mice in the fasudil-treated
group versus saline control group ( P < 0.01). Fasudil has been approved for the treatment of cerebral vasospasm and associated cerebral ischemic symptoms. In
patients, fasudil is well tolerated without any serious adverse reactions. Therefore, the concept of Rho kinase inhibition
as an antimetastatic therapy for cancer can now be clinically explored. [Mol Cancer Ther 2006;5(9):2158–64] |
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ISSN: | 1535-7163 1538-8514 |
DOI: | 10.1158/1535-7163.MCT-05-0440 |