Effect of Wf-536, a novel ROCK inhibitor, against metastasis of B16 melanoma

Nakajima, Masahide; Hayashi, Kazutaka; Egi, Yasuhiro; Katayama, Ken-ichi; Amano, Yusaku; Uehata, Masayoshi; Ohtsuki, M; Fujii, Akihiro; Oshita, Koh-ichi; Kataoka, Hirotoshi; Chiba, Kenji; Gotô, Nobuharu; Kondo, Takao

doi:10.1007/s00280-003-0641-9

Cited by 78 publications

(58 citation statements)

References 16 publications

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“…The results of the present study revealed that afzelin inhibited the protein expression levels of MRCKα and ROCK1, clarifying that downregulation of LIMK1 by afzelin is due to its inhibitory effect on MRCKα and ROCK1, upstream in its signaling pathway. Previous studies have demonstrated that ROCK inhibitors appear to reduce the invasive ability of tumor cells in vitro and prevent the dissemination of tumor cells in vivo in different types of cancer, particularly in prostate cancer (10,(13)(14)(15)(16)(17)38). Furthermore, LIMK1, MRCKα and ROCK1 are proteins of interest in the development of novel cancer therapies due to their involvement in regulating actin organization (7) and, in combination with other proteins, maintaining the tight regulation of normal cell growth and differentiation (8,9).…”

Section: Discussionmentioning

confidence: 99%

“…The Rho GTPase myotonic dystrophy kinase-related Cdc42-binding kinase α (MRCKα), Rho-associated coiled-coil containing protein kinase (ROCK)1 and ROCK2 are responsible for the activation of LIMK1 (9,12). Previous studies have demonstrated the ability of ROCK inhibitors to reduce the invasive ability of tumor cells in vitro and prevent the spread of tumor cells in vivo, including melanoma and fibrosarcoma cells, as well as liver, breast, lung and prostate cancer tumor cells (13)(14)(15)(16)(17) Thus, inhibitors of LIMK1, MRCKα and ROCK1/2 are considered to restore normal cell proliferation and provide a key strategy for cancer treatment (18). Therefore, the aim of the present study was to evaluate the in vitro anti-prostate cancer activity of afzelin and its effect on prostate cancer-associated kinases.…”

Section: Introductionmentioning

confidence: 99%

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Afzelin exhibits anti-cancer activity against androgen-sensitive LNCaP and androgen-independent PC-3 prostate cancer cells through the inhibition of LIM domain kinase 1

et al. 2015

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Abstract. Prostate cancer presents high occurrence worldwide. Medicinal plants are a major source of novel and potentially therapeutic molecules; therefore, the aim of the present study was to investigate the possible anti-prostate cancer activity of afzelin, a flavonol glycoside that was previously isolated from Nymphaea odorata. The effect of afzelin on the proliferation of androgen-sensitive LNCaP and androgen-independent PC-3 cells was evaluated by performing a water soluble tetrazolium salt-1 assay. In addition, the effect of afzelin on the cell cycle of the LNCaP and PC-3 prostate cancer cell lines was evaluated. Western blot analysis was performed to evaluate the effect of afzelin on the kinases responsible for the regulation of actin organization. Afzelin was identified to inhibit the proliferation of LNCaP and PC3 cells, and block the cell cycle in the G 0 phase. The anticancer activity of afzelin in these cells was determined to be due to inhibition of LIM domain kinase 1 expression. Thus, the in vitro efficacy of afzelin against prostate cancer is promising; however, additional studies on different animal models are required to substantiate its anticancer potential. IntroductionProstate cancer is the second most frequently diagnosed type of cancer and the sixth most common cause of cancer-associated mortality in males, worldwide (1). The typical treatment strategies of chemotherapy and radiotherapy have not provided significant survival benefits for patients with advanced prostate cancer, and the majority of available strategies are only palliative (2). Therefore, there is requirement for the prompt identification of novel molecules to treat the increasing number of prostate cancer cases, particularly cases that are resistant to current chemotherapeutic agents (3,4).Afzelin is a flavonol glycoside found in Nymphaea odorata, which has been identified to inhibit the growth of breast cancer cells by stimulating apoptosis (5). In addition, afzelin has been demonstrated to scavenge superoxide anion radicals in RAW264.7 cells (6). The structure of this compound is shown in Fig. 1.In eukaryotic cells, the actin cytoskeleton is essential for mediating various biological functions, including providing the structural framework of the cell, and driving cellular motility and division. In particular, dynamic reorganization of the actomyosin cytoskeleton and remodelling of the extracellular matrix drive the multistep process of tumor cell metastasis. Tumor cells are able to cross tissue boundaries into the blood and lymphatic systems and migrate to distal regions of the body. Therefore, cancer therapy has recently focused on gaining a comprehensive understanding of the biological processes that regulate actin organization (7).Rho GTPase family proteins are key regulators of the actin cytoskeleton and, with the aid of various target proteins, maintain the tight regulation of normal cell growth and differentiation (8-11). Eukaryotic cells exhibit a predisposition to rapid and uncontrollable growth following genomic a...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Afzelin exhibits anti-cancer activity against androgen-sensitive LNCaP and androgen-independent PC-3 prostate cancer cells through the inhibition of LIM domain kinase 1

et al. 2015

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“…Among these we should mention NCOA1 (nuclear receptor coactivator (1), a transcriptional coactivator belonging to the SRC family which is deregulated in breast and prostatic cancer and may potentiate gene expression by acting as a coactivator for nuclear hormone receptors and other transcription factors (TF) [44][45][46][47][48][49][50][51][52][53][54][55]; and ROCK2, a serine/threonine kinase member of the Rho pathway, involved in cell adhesion, migration, invasion, and mitosis [56][57][58][59], which may be a potential therapeutic target in human cancer cells and animal models [60][61][62][63][64][65][66][67][68].…”

Section: Discussionmentioning

confidence: 99%

Chromosome 2p gain in monoclonal B‐cell lymphocytosis and in early stage chronic lymphocytic leukemia

et al. 2012

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Recent studies have described chromosome 2p gain as a recurrent lesion in chronic lymphocytic leukemia (CLL). We investigated the 2p gain and its relationship with common prognostic biomarkers in a prospective series of 69 clinical monoclonal B-cell lymphocytosis (cMBL) and 218 early stage (Binet A) CLL patients. The 2p gain was detected by FISH in 17 patients (6%, 16 CLL, and 1 cMBL) and further characterized by single nucleotide polymorphism-array. Overall, unfavorable cytogenetic deletions, i.e., del(11)(q23) and del(17)(p13) (P 5 0.002), were significantly more frequent in 2p gain cases, as well as unmutated status of IGHV (P < 1 3 10 24 ) and CD38 (P < 1 3 10 24 ) and ZAP-70 positive expression (P 5 0.003). Furthermore, 2p gain patients had significantly higher utilization of stereotyped B-cell receptors compared with 2p negative patients (P 5 0.009), and the incidence of stereotyped subset #1 in 2p gain patients was significantly higher than that found in the remaining CLLs (P 5 0.031). Transcriptional profiling analysis identified several genes significantly upregulated in 2p gain CLLs, most of which mapped to 2p. Among these, NCOA1 and ROCK2 are known for their involvement in tumor progression in several human cancers, whereas among those located in different chromosomes, CAV1 at 7q31.1 has been recently identified to play a critical role in CLL progression. Thus, 2p gain can be present since the early stages of the disease, particularly in those cases characterized by other poor prognosis markers. The finding of genes upregulated in the cells with 2p gain provides new insights to define the pathogenic role of this lesion. Am. J. Hematol. 88:24-31, 2013. V

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“…There is a wealth of data implicating Rho GTPases in human cancer (Sahai and Marshall, 2002;Benitah et al, 2004) further suggesting that ROCK1 and ROCK2, as key mediators of Rho signaling, may have important roles (Narumiya et al, 2009). In support of this, preclinical studies have shown beneficial effects of ROCK inhibition on tumor incidence rates, volume, invasiveness and metastasis (Itoh et al, 1999;Somlyo et al, 2000;Nakajima et al, 2003;Ying et al, 2006;Ogawa et al, 2007;Xue et al, 2008). In addition, elevated ROCK1 and/or ROCK2 expression have been detected in several human cancers, which correlated with poor outcome (Kamai et al, 2002(Kamai et al, , 2003(Kamai et al, , 2004Abe et al, 2008).…”

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confidence: 97%

Activating ROCK1 somatic mutations in human cancer

et al. 2010

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Cancer cells acquire characteristics of deregulated growth, survival and increased metastatic potential. Genetic mutations that provide a selective advantage by promoting these characteristics have been termed 'drivers,' whereas mutations that do not contribute to disease initiation/progression are termed 'passengers.' The advent of high-throughput methodologies has facilitated large-scale screening of cancer genomes and the subsequent identification of novel somatic mutations. Although this approach has generated valuable results, the data remain incomplete until the functional consequences of these mutations are determined to differentiate potential drivers from passengers. ROCK1 is an essential effector kinase downstream of Rho GTPases, an important pathway involved in cell migration. The Cancer Genome Project identified three nonsynonymous mutations in the ROCK1 gene. We now show that these somatic ROCK1 mutations lead to elevated kinase activity and drive actin cytoskeleton rearrangements that promote increased motility and decreased adhesion, characteristics of cancer progression. Mapping of the kinase-interacting regions of the carboxy terminus combined with structural modeling provides an insight into how these mutations likely affect the regulation of ROCK1. Consistent with the frequency of ROCK1 mutations in human cancer, these results support the conclusion that there is selective pressure for the ROCK1 gene to acquire 'driver' mutations that result in kinase activation.

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Effect of Wf-536, a novel ROCK inhibitor, against metastasis of B16 melanoma

Abstract: The results suggest that Wf-536 is a potentially valuable drug for preventing tumor metastasis both in monotherapy and in combination with an antineoplastic drug.

Cited by 78 publications

References 16 publications

Afzelin exhibits anti-cancer activity against androgen-sensitive LNCaP and androgen-independent PC-3 prostate cancer cells through the inhibition of LIM domain kinase 1

Afzelin exhibits anti-cancer activity against androgen-sensitive LNCaP and androgen-independent PC-3 prostate cancer cells through the inhibition of LIM domain kinase 1

Chromosome 2p gain in monoclonal B‐cell lymphocytosis and in early stage chronic lymphocytic leukemia

Activating ROCK1 somatic mutations in human cancer

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