The selective Aurora B kinase inhibitor AZD1152 as a novel treatment for hepatocellular carcinoma

Aihara, Arihiro; Tanaka, Shinji; Yasen, Mahmut; Matsumura, Satoshi; Mitsunori, Yusuke; Murakata, Ayano; Noguchi, Norio; Kudo, Atsushi; Nakamura, Noriaki; Itō, Kōji; Arii, Shigeki

doi:10.1016/j.jhep.2009.10.013

Cited by 73 publications

(49 citation statements)

References 37 publications

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“…Human hepatoma cell lines, HepG2, Huh-7, PLC/ PRF/5 and SK-Hep1 were analyzed (15). Additionally, we used p53-deficient hepatoma cell line Hep3B as well as Hep3B transfected with wild-type p53 gene (16); named as Hep3B-p53(-) and Hep3B-p53(+), respectively.…”

Section: Methodsmentioning

confidence: 99%

Analogy between sphere forming ability and stemness of human hepatoma cells

Tanaka¹

2010

Oncol Rep

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Abstract. Increasing evidence suggests that cancers contain a small subset of cancer-initiating cells, so-called cancer stem cells (CSCs) that are capable of regenerating a tumor after chemoradiation therapy. Sphere forming ability is known to be one of properties of CSCs, but the significance remains unclear. The present study focused on sphere formation of human hepatoma cells in three-dimensional culture in order to evaluate the analogy between sphere forming ability and stemness of cancer cells in vitro. Under three-dimensional culture condition, HepG2, Hep3B and PLC/PRF/5 cells demonstrated the sphere formation while SK-Hep1 and Huh-7 cells did not. The population of G0/G1 phase increased in the spheres compared with the monolayer (67 vs. 38%). In spite of no significant difference in stem cell surface markers (CD44, CD90, CD133, EpCAM and ABCG2), remarkable upregulation of p27 CDK inhibitor was observed in sphere forming cells. Immunofluorescence analysis revealed the nuclear expression of p27 in the whole of the sphere, but weak expression of p21 only at the peripheral area. The spheres acquired chemoresistance to cisplatin compared with the monolayers (58.9 vs. 16.2 μM in IC50). This model was useful for assessment of the role of cell-cycle quiescence in the stemness and chemoresistance of cancer cells. IntroductionThere is an emerging concept of cancer stem cells (CSCs) that cancer cells do not consist of homogeneous population but include a small subpopulation of cells having the ability of self-renewal and differentiation into multiple phenotypes (1). Several unique properties of CSCs have been identified including drug-efflux ability (side population) (2,3), maintenance of quiescence, sphere formation, high tumorigenicity, and resistance to hypoxia and chemoradiation (4). After anticancer treatment that kills most cancer cells, such drugresistant CSCs might survive and finally generate new populations, resulting in cancer recurrence and metastasis. Detailed analysis on biological characteristics of CSCs are required to overcome the resistance of cancer.Recent studies revealed that the sphere formation might be essential for cancer-initiating ability of CSCs (5-7), but its significance and mechanism remain unclear. The sphereforming cells in human hepatoma were reported to associate with the expression of stemness markers such as CD90 (8,9), CD133 (10,11), EpCAM (12), ABCG2 (13) and CD44 (14). In this study, we focused on the sphere formation ability using 3D culture system to evaluate the in vitro analogy to the stemness phenotypes in human hepatoma cells. Materials and methodsCell lines. Human hepatoma cell lines, HepG2, Huh-7, PLC/ PRF/5 and SK-Hep1 were analyzed (15). Additionally, we used p53-deficient hepatoma cell line Hep3B as well as Hep3B transfected with wild-type p53 gene (16); named as Hep3B-p53(-) and Hep3B-p53(+), respectively. Culture media were the recommended media supplemented with 10% fetal bovine serum, 100 U/ml penicillin and 100 μg/ml streptomycin. All cell lines were cultivated...

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Section: Methodsmentioning

confidence: 99%

Analogy between sphere forming ability and stemness of human hepatoma cells

Tanaka¹

2010

Oncol Rep

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“…Histone H3 phosphorylation has also been at the forefront of hepatocellular carcinoma where inhibition of histone H3 phosphorylation (with an Aurora kinase inhibitor) was correlated with apoptosis of cancer cells (Aihara et al, 2010). We have reported that in vivo intraperitoneal acute ethanol promotes histone acetylation at Lys9 and phosphorylation at Ser10 and Ser28 (Aroor et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Histone H3 Phosphorylation (Ser10, Ser28) and Phosphoacetylation (K9S10) Are Differentially Associated with Gene Expression in Liver of Rats Treated In Vivo with Acute Ethanol

James¹,

Aroor²,

Lim³

et al. 2011

J Pharmacol Exp Ther

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The epigenetic histone modification by ethanol is emerging as one of the mechanisms for its deleterious effects in the liver. In this context, we have investigated the role of histone H3 phosphorylation at Ser10 (P-H3-Ser10), and Ser28 (P-H3-Ser28) in liver after acute ethanol treatment in vivo. Ethanol was administered intraperitoneally in male Sprague-Dawley rats. Ethanol dose-response (1-5 g/kg body weight) and time-course (1-4 h) experiments were conducted, and various parameters were monitored. Steatosis and necrosis (serum alanine aminotransferase) of the liver increased in 4 h, suggesting liver injury. There were differences between P-H3-Ser10 and P-H3-Ser28 at 1 h, with the latter being more sensitive to lower ethanol doses. It was noteworthy that phosphorylation of both serines disappeared at the highest dose used (5 g/kg). We also examined phosphoacetylation of histone H3 at K9S10 and observed a dramatic increase. The changes in histone H3 phosphorylation and phosphoacetylation were also accompanied with expression of early response genes (c-fos, c-jun, mitogen-activated protein kinase phosphatase-1). Chromatin immunoprecipitation assays in samples from 1.5 and 4 h of ethanol administration indicated that increased histone H3 phosphorylation at Ser28 was associated with the promoters of c-jun and plasminogen activator inhibitor-1. In conclusion, this study demonstrates for the first time that in vivo exposure of liver to acute ethanol induced phosphorylation and phosphoacetylation of histone H3, and these modifications are differentially involved in the mRNA expression of genes.

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“…In 2012, Schwartz et al (21) reported a phase I trial of barasertib in patients with malignant solid cancer, in which Grade 3 or higher pyrogenic or apyrogenic neutropenia and mild or moderate hematoxicity or gastrointestinal toxicity emerged, but all were tolerable. In a mouse model of hepatoma, Aihara et al (22) reported that AZD1152 significantly decreased the number of tumor cells and suppressed tumor proliferation.…”

Section: Clinical Applications Of Aurora Kinase Inhibitorsmentioning

confidence: 99%

Aurora kinase inhibitors: Potential molecular-targeted drugs for gynecologic malignant tumors

et al. 2013

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Abstract. Chemotherapy and surgery are important treatment strategies for gynecologic malignant tumors such as ovarian, cervical and endometrial cancer. However, many anticancer drugs currently available are cytotoxic and cause strong adverse reactions in patients. Aurora kinases have attracted increasing attention in recent years as serine/threonine kinases with various roles in cell division, including chromosomal agglutination and segregation, functions of centromeres, centrosomal maturation, spindle formation and cytokinesis. Aurora kinases are overexpressed in a number of cancers and recent studies have shown that they are involved in onco genesis and cause an aberrant increase in centrosome number, emergence of polykaryocytes and failure of cancer inhibition mechanisms. Thus, drugs that inhibit Aurora kinases are likely to exert anticancer effects in various fields, including the gynecologic field. Aurora kinase inhibitors exert antitumor effects in monotherapy and synergistic effects in combination therapy with taxane-based anticancer agents for gynecologic tumors and are likely to increase the efficacy of existing anticancer drugs. Current Aurora kinase inhibitors include ZM447439, Hesperadin, VX-680/MK-0457, AT9283 and Barasertib, and clinical trials are ongoing to verify the effects of these inhibitors.

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The selective Aurora B kinase inhibitor AZD1152 as a novel treatment for hepatocellular carcinoma

Cited by 73 publications

References 37 publications

Analogy between sphere forming ability and stemness of human hepatoma cells

Analogy between sphere forming ability and stemness of human hepatoma cells

Histone H3 Phosphorylation (Ser10, Ser28) and Phosphoacetylation (K9S10) Are Differentially Associated with Gene Expression in Liver of Rats Treated In Vivo with Acute Ethanol

Aurora kinase inhibitors: Potential molecular-targeted drugs for gynecologic malignant tumors

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