Rho-kinase inhibitors as therapeutics: from pan inhibition to isoform selectivity

Hahmann, C.; Schroeter, Thomas

doi:10.1007/s00018-009-0189-x

Cited by 132 publications

(112 citation statements)

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“…Also, we showed that the distribution patterns of ROCK1 and ROCK2 differed in both porcine oocytes and embryos by using immunostaining employing specific antibodies. Although ROCK1 and ROCK2 share structural similarities, being 65% homologous in terms of amino acid sequence (92% homologous in the kinase domains), the two proteins may play distinct roles in cell differentiation and adhesion (Lock & Hotchin 2009, Hahmann & Schroeter 2010. In a previous study in mitotic cells, Values with different superscripts (*, †, ‡) indicate that the numbers are significantly different (P!0.05).…”

Section: Discussionmentioning

confidence: 99%

“…Thus, we proposed the hypothesis that LPA enhanced embryo development by activating ROCKs. Y27632, a specific inhibitor of Rho-kinases (Ishizaki et al 2000, Hahmann & Schroeter 2010, has been widely used to study enzyme function. Therefore, employing either Y27632, a specific inhibitor of ROCKs, or LPA, an activator of ROCKs, we explored the distribution and function of ROCK1 and ROCK2 during porcine oocyte maturation and embryonic cleavage.…”

Section: Introductionmentioning

confidence: 99%

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Distinct roles of ROCK1 and ROCK2 during development of porcine preimplantation embryos

et al. 2014

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Cell-to-cell contact mediated by cell adhesion is fundamental to the compaction process that ensures blastocyst quality during embryonic development. In this study, we first showed that Rho-associated coiled-coil protein kinases (ROCK1 and ROCK2) were expressed both in porcine oocytes and IVF preimplantation embryos, playing different roles in oocytes maturation and embryo development. The amount of mRNA encoding ROCK1 and the protein concentration clearly increased between the eight-cell and morula stages, but decreased significantly when blastocysts were formed. Conversely, ROCK2 was more abundant in the blastocyst compared with other embryonic stages. Moreover, immunostaining showed that ROCK1 protein distribution changed as the embryo progressed through cleavage and compaction to the morula stage. Initially, the protein was predominantly associated with the plasma membrane but later became cytoplasmic. By contrast, ROCK2 protein was localized in both the cytoplasm and the spindle rotation region during oocyte meiosis, but in the cytoplasm and nucleus as the embryo developed. In addition, ROCK2 was present in the trophectoderm cells of the blastocyst. Treatment with 15 mM Y27632, a specific inhibitor of ROCKs, completely blocked further development of early four-cell stage embryos. Moreover, we did not detect the expression of ROCK1 but did detect ROCK2 expression in blastocysts. Moreover, lysophosphatidic acid an activator of ROCKs significantly improved the rates of blastocyst formation. These data demonstrate that ROCKs are required for embryo development to the blastocyst stage. Together, our results indicate that ROCK1 and ROCK2 may exert different biological functions during the regulation of compaction and in ensuring development of porcine preimplantation embryos to the blastocyst stage.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Distinct roles of ROCK1 and ROCK2 during development of porcine preimplantation embryos

et al. 2014

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“…The stimulation of Rho signaling by PCP results in downstream activation of the serine/threonine Rho-associated coiled coil-containing protein kinases (ROCK)1 and ROCK2 (9). ROCK1 and ROCK2 phosphorylate downstream substrates such as myosin light chain and LIM kinases 1/2, which further regulate a range of cellular functions primarily through rearrangement of the actin cytoskeleton (10,11). ROCK is dysregulated in a variety of cancers, including prostate, breast, and lung cancers, with ROCK overexpression contributing to metastasis by enhancing tumor cell invasion and motility (11).…”

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confidence: 99%

Rho-associated kinase is a therapeutic target in neuroblastoma

Dyberg

Fransson

Andonova

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Neuroblastoma is a peripheral neural system tumor that originates from the neural crest and is the most common and deadly tumor of infancy. Here we show that neuroblastoma harbors frequent mutations of genes controlling the Rac/Rho signaling cascade important for proper migration and differentiation of neural crest cells during neuritogenesis. RhoA is activated in tumors from neuroblastoma patients, and elevated expression of Rho-associated kinase (ROCK)2 is associated with poor patient survival. Pharmacological or genetic inhibition of ROCK1 and 2, key molecules in Rho signaling, resulted in neuroblastoma cell differentiation and inhibition of neuroblastoma cell growth, migration, and invasion. Molecularly, ROCK inhibition induced glycogen synthase kinase 3β-dependent phosphorylation and degradation of MYCN protein. Small-molecule inhibition of ROCK suppressed MYCN-driven neuroblastoma growth in TH-MYCN homozygous transgenic mice and MYCN gene-amplified neuroblastoma xenograft growth in nude mice. Interference with Rho/Rac signaling might offer therapeutic perspectives for high-risk neuroblastoma.N euroblastoma is a childhood tumor of the peripheral sympathetic nervous system, causing 6% of all childhood cancers but 9% of deaths from malignant tumors in children (1, 2). Approximately half of patients present with high-risk disease characterized by unresectable primary lesions and multiple metastases (2, 3). Although survival in this group has improved, the majority of the tumors show resistance to therapy with poor patient survival despite intensive multimodal therapy, necessitating the search for new therapeutic options (2).Compared with adult tumors, pediatric cancers exhibit significantly fewer genomic aberrations and mutations. In neuroblastoma, somatically acquired amplification of MYCN, hemizygous deletions of 1p and 11q, and gain of 17q are the most common chromosomal aberrations associated with a poor prognosis (3). Exome-and whole-genome sequencing analysis of neuroblastoma has reported an overall low somatic mutation count (12 to 18, median 15), with ALK being the most frequently mutated gene (7 to 10%) (4-6). In addition, chromothripsis, PHOX2B, and ATRX mutations have also been detected in a subset of highrisk tumors (4,5).Neuritogenesis is initiated during embryogenesis by a transient population of cells called the neural crest. During embryonic development, neural crest cells migrate throughout the embryo and eventually differentiate into multiple cell types, such as neurons and glial cells of the peripheral nervous system, pigment cells, fibroblasts, smooth muscle cells, and odontoblasts. The failure of neural crest cells to differentiate can result in development of cancers such as neuroblastoma and melanoma (7). A combination of Wingless (Wnt), bone morphogenetic protein, and fibroblast growth factor (FGF) signals is required to induce the formation of the neural crest and to initiate migration of neural crest cells by acquiring cell motility through epithelialmesenchymal transition (8). The no...

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“…Nevertheless, the current findings suggest that Rac1 inhibition may be accomplished directly in vivo because of the favorable safety profile of NSC23766, as observed in our mouse model of streptozotocin‐induced diabetes mellitus. Finally, the effects of LY27632 as ROCK1 inhibitor can be also attributed, in part, to the inhibition of ROCK2, although recent studies have demonstrated that ROCK1 and ROCK2 have distinct nonredundant functions and have different targets in different cell types 45, 46…”

Section: Discussionmentioning

confidence: 99%

Rac1 Modulates Endothelial Function and Platelet Aggregation in Diabetes Mellitus

Schiattarella

Carrizzo

Ilardi

et al. 2018

JAHA

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BackgroundVascular complications and abnormal platelet function contribute to morbidity and mortality in diabetes mellitus. We hypothesized that the Rho‐related GTPase protein, Rac1, can influence both endothelial and platelet function and might represent a potential novel therapeutic target in diabetes mellitus.Methods and ResultsWe used both in vitro and ex vivo approaches to test the effects of pharmacological inhibition of Rac1 during hyperglycemic condition. We evaluated the effect of NSC23766, a pharmacological inhibitor of Rac1, on vascular function in diabetic mice and platelet aggregation in diabetic subjects. We demonstrated that the administration of NSC23766 protects from hyperglycemia‐induced endothelial dysfunction, restoring NO levels, and reduces oxidative stress generated by nicotinamide adenine dinucleotide phosphate oxidase. Mechanistically, we identified Rho‐associated coiled‐coil serine/threonine kinase‐1 as a downstream target of Rac1. Moreover, we reported that during hyperglycemic conditions, human platelets showed hyperactivation of Rac1 and impaired NO release, which were both partially restored after NSC23766 treatment. Finally, we characterized the antiplatelet effect of NSC23766 during hyperglycemic conditions, demonstrating the additional role of Rac1 inhibition in reducing platelet aggregation in diabetic patients treated with common antiplatelet drugs.ConclusionsOur data suggest that the pharmacological inhibition of Rac1 could represent a novel therapeutic strategy to reduce endothelial dysfunction and platelet hyperaggregation in diabetes mellitus.

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Rho-kinase inhibitors as therapeutics: from pan inhibition to isoform selectivity

Cited by 132 publications

References 90 publications

Distinct roles of ROCK1 and ROCK2 during development of porcine preimplantation embryos

Distinct roles of ROCK1 and ROCK2 during development of porcine preimplantation embryos

Rho-associated kinase is a therapeutic target in neuroblastoma

Rac1 Modulates Endothelial Function and Platelet Aggregation in Diabetes Mellitus

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