YC-1 [3-(5′-Hydroxymethyl-2′-furyl)-1-benzyl Indazole] Exhibits a Novel Antiproliferative Effect and Arrests the Cell Cycle in G<sub>0</sub>-G<sub>1</sub> in Human Hepatocellular Carcinoma Cells

Wang, Shih‐Wei; Pan, Shiow Lin; Guh, Jih‐Hwa; Chen, Hui-Ling; Dong, Hao; Chang, Ya Ling; Kuo, Sheng Chu; Lee, Fang Yu; Teng, Che-Ming

doi:10.1124/jpet.104.077230

Cited by 46 publications

(31 citation statements)

References 38 publications

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“…Because both HIF-1a inhibition and S-phase arrest were induced by YC-1 at <5 Amol/L, we believe that these effects are responsible for tumor growth inhibition by YC-1. However, a recent report (22) showed that YC-1 at >50 Amol/L induced G 1 -phase arrest in hepatoma cell lines. This concentration is much higher (10 fold) than the tumor levels of YC-1 in vivo.…”

Section: Discussionmentioning

confidence: 94%

YC-1 Induces S Cell Cycle Arrest and Apoptosis by Activating Checkpoint Kinases

Yeo

Ryu²,

Chun³

et al. 2006

Cancer Research

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Hypoxia-inducible factor-1A (HIF-1A) seems central to tumor growth and progression because it up-regulates genes essential for angiogenesis and the hypoxic adaptation of cancer cells, which is why HIF-1A inhibition is viewed as a cancer therapy strategy. Paradoxically, HIF-1A also leads to cell cycle arrest or the apoptosis of cancer cells. Thus, the possibility cannot be ruled out that HIF-1A inhibitors unlock cell cycle arrest under hypoxic conditions and prevent cell death, which would limit the anticancer effect of HIF-1A inhibitors. Previously, we reported on the development of YC-1 as an anticancer agent that inhibits HIF-1A. In the present study, we evaluated the effects of YC-1 on hypoxia-induced cell cycle arrest and cell death. It was found that YC-1 does not reverse the antiproliferative effect of hypoxia, but rather that it induces S-phase arrest and apoptosis at therapeutic concentrations that inhibit HIF-1A and tumor growth; however, YC-1 did not stimulate cyclic guanosine 3 ¶,5 ¶-monophosphate production in this concentration range. It was also found that YC-1 activates the checkpoint kinase-mediated intra-S-phase checkpoint, independently of ataxia-telangiectasia mutated kinase or ataxia-telangiectasia mutated and Rad3-related kinase. These results imply that YC-1 does not promote the regrowth of hypoxic tumors because of its cell cycle arrest effect. Furthermore, YC-1 may induce the combined anticancer effects of HIF-1A inhibition and cell growth inhibition. (Cancer Res 2006; 66(12): 6345-52)

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Section: Discussionmentioning

confidence: 94%

YC-1 Induces S Cell Cycle Arrest and Apoptosis by Activating Checkpoint Kinases

Yeo

Ryu²,

Chun³

et al. 2006

Cancer Research

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“…This S-phase arrest was not peculiar to a single cell type as it occurred in both HT29 and HCT116 colorectal cancer cell lines. At similar concentrations, YC-1 has been reported to induce G 0 /G 1 arrest in human hepatocellular carcinoma (23) and human umbilical vein endothelial cells (24). The mechanism by which YC-1 induces cell cycle arrest at different phases in different cell types is unknown but may depend on the individual cell type and/or culture conditions, including culture density and serum concentration.…”

Section: Discussionmentioning

confidence: 97%

Sulindac independently modulates extracellular signal–regulated kinase 1/2 and cyclic GMP–dependent protein kinase signaling pathways

Rice

Peters

Beard

et al. 2006

Molecular Cancer Therapeutics

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Colorectal cancer is the second leading cause of cancer mortality in the United States. Substantial human and animal data support the ability of nonsteroidal antiinflammatory drugs to cause regression of existing colon tumors and prevent new tumor formation. The mechanism by which the nonsteroidal anti-inflammatory drug sulindac prevents tumor growth is poorly understood and seems complex as sulindac can modulate several growth-related signaling pathways. Sulindac metabolites simultaneously (a) increase cellular cyclic GMP and subsequently activate cyclic GMP -dependent protein kinase (PKG); (b) activate c-jun NH 2 -terminal kinase (JNK); (c) inhibit extracellular signal -regulated kinase 1/2 (ERK1/2); and (d) decrease B-catenin protein expression at times and doses consistent with apoptosis. The purpose of this study was to determine if PKG, ERK1/2, JNK, and B-catenin are independent targets for sulindac in vitro. Pharmacologic activation of PKG with YC-1 increases JNK phosphorylation and induces apoptosis in colon cancer cells without modulating ERK1/2 phosphorylation or B-catenin protein expression. Inhibition of ERK1/2 with U0126 induces apoptosis but fails to activate JNK phosphorylation or down-regulate B-catenin protein expression. Cotreatment with U0126 and YC-1 synergistically increases apoptosis in colorectal cancer cells and recapitulates the effects of sulindac treatment on ERK1/2, JNK, and B-catenin. These results indicate that sulindac metabolites modulate ERK1/2 and PKG pathways independently in colon cancer cells and suggest that the full apoptotic effect of sulindac is mediated by more than one pathway. Using similar combinatorial approaches in vivo may provide more effective, less toxic chemopreventive and chemotherapeutic strategies. Such therapies could dramatically reduce the incidence and death rate from colorectal cancer. [Mol Cancer Ther 2006;5(3):746 -54]

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“…In preliminarily studies, we demonstrated that treatment with high concentrations (Ͼ50 M) of YC-1 results in growth inhibition of hepatocellular carcinoma cells (HA22T) (Wang et al, 2005) or apoptosis of prostate cancer cells (PC-3) and leukemia cancer cells (HL-60 and CCRF-CEM) in culture (data not shown). Thus, the growth-inhibitory action of YC-1 at low concentration is considered to be a more specific effect on endothelial cells that are stimulated by angiogenic growth factors.…”

Section: Discussionmentioning

confidence: 99%

YC-1 [3-(5′-Hydroxymethyl-2′-furyl)-1-benzyl Indazole] Inhibits Endothelial Cell Functions Induced by Angiogenic Factors in Vitro and Angiogenesis in Vivo Models

Pan

Guh

Peng

et al. 2005

J Pharmacol Exp Ther

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Angiogenesis is a process that involves endothelial cell proliferation, migration, invasion, and tube formation, and inhibition of these processes has implications for angiogenesis-mediated disorders. The purpose of this study was to evaluate the antiangiogenic efficacy of YC-1 [3-(5Ј-hydroxymethyl-2Ј-furyl)-1-benzyl indazole] in well characterized in vitro and in vivo systems. YC-1 inhibited the ability of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in a dose-dependent manner to induce proliferation, migration, and tube formation in human umbilical vascular endothelial cells; these outcomes were evaluated using [ 3 H]thymidine incorporation, transwell chamber, and Matrigel-coated slide assays, respectively. YC-1 inhibited VEGF-and bFGF-induced p42/p44 mitogen-activated protein kinase and Akt phosphorylation as well as protein kinase C␣ translocation using Western blot analysis. The effect of YC-1 on angiogenesis in vivo was evaluated using the mouse Matrigel implant model. YC-1 administered orally in doses of 1 to 100 mg/kg/day inhibited VEGF-and bFGF-induced neovascularization in a dose-dependent manner over 7 days. These results indicate that YC-1 has antiangiogenic activity at very low doses. Moreover, in transplantable murine tumor models, YC-1 administered orally displayed a high degree of antitumor activity (treatment-to-control life span ratio Ͼ 175%) without cytotoxicity. YC-1 may be useful for treating angiogenesis-dependent human diseases such as cancer.

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YC-1 [3-(5′-Hydroxymethyl-2′-furyl)-1-benzyl Indazole] Exhibits a Novel Antiproliferative Effect and Arrests the Cell Cycle in G₀-G₁ in Human Hepatocellular Carcinoma Cells

Cited by 46 publications

References 38 publications

YC-1 Induces S Cell Cycle Arrest and Apoptosis by Activating Checkpoint Kinases

YC-1 Induces S Cell Cycle Arrest and Apoptosis by Activating Checkpoint Kinases

Sulindac independently modulates extracellular signal–regulated kinase 1/2 and cyclic GMP–dependent protein kinase signaling pathways

YC-1 [3-(5′-Hydroxymethyl-2′-furyl)-1-benzyl Indazole] Inhibits Endothelial Cell Functions Induced by Angiogenic Factors in Vitro and Angiogenesis in Vivo Models

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YC-1 [3-(5′-Hydroxymethyl-2′-furyl)-1-benzyl Indazole] Exhibits a Novel Antiproliferative Effect and Arrests the Cell Cycle in G0-G1 in Human Hepatocellular Carcinoma Cells

Cited by 46 publications

References 38 publications

YC-1 Induces S Cell Cycle Arrest and Apoptosis by Activating Checkpoint Kinases

YC-1 Induces S Cell Cycle Arrest and Apoptosis by Activating Checkpoint Kinases

Sulindac independently modulates extracellular signal–regulated kinase 1/2 and cyclic GMP–dependent protein kinase signaling pathways

YC-1 [3-(5′-Hydroxymethyl-2′-furyl)-1-benzyl Indazole] Inhibits Endothelial Cell Functions Induced by Angiogenic Factors in Vitro and Angiogenesis in Vivo Models

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YC-1 [3-(5′-Hydroxymethyl-2′-furyl)-1-benzyl Indazole] Exhibits a Novel Antiproliferative Effect and Arrests the Cell Cycle in G₀-G₁ in Human Hepatocellular Carcinoma Cells