CHM-1, a novel synthetic quinolone with potent and selective antimitotic antitumor activity against human hepatocellular carcinoma <i>in vitro</i> and <i>in vivo</i>

Wang, Shih‐Wei; Pan, Shiow Lin; Huang, Yu; Guh, Jih‐Hwa; Chiang, Po Cheng; Huang, Deng-Yuan; Kuo, Sheng Chu; Lee, Kuo Hsiung̀; Teng, Che-Ming

doi:10.1158/1535-7163.mct-07-2000

Cited by 55 publications

(42 citation statements)

References 33 publications

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“…Many reports have demonstrated that microtubule inhibitor induced M-phase arrest and inappropriate accumulation of B-type cyclins were associated with the initiation of apoptotic pathways (24,25). In the present study, HAC-Y6 arrested the growth of cancer cells at the The endogenous level of the mitotic spindle checkpoint protein BubR1 directly correlated with the cellular response to microtubule disruption.…”

Section: Discussionsupporting

confidence: 57%

Induction of apoptosis by HAC-Y6, a novel microtubule inhibitor, through activation of the death receptor 4 signaling pathway in human hepatocellular carcinoma cells

et al. 2010

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Abstract. The present data showed that a novel synthesized compound, 6-acetyl-9-(3,4,5-trimethoxybenzyl)-9H-pyrido [2,3-b]indole (HAC-Y6), exhibited potent antitumor activity against human hepatocellular carcinoma (HCC) cells in vitro. Western blot and immunofluorescence experiments showed that HAC-Y6 depolymerized microtubules similarly to the effects of colchicine. HAC-Y6-treatment in Hep3B cells resulted in the accumulation of the G2/M phase and induced apoptosis. In addition, HAC-Y6-treatment influenced the expression of cell cycle and apoptosis related proteins in Hep3B cells. HAC-Y6 exposure increased caspases-3, -8, -9 and Bax protein levels, while reducing levels of Bcl-2 family proteins. Moreover, Bid, a substrate of caspase-8, was also activated by HAC-Y6. Treatment of cells caused the upregulation of the death receptor 4 (DR4) and phosphorylation of p38. Taken together, we show that HAC-Y6 exhibited its antitumor activity by disrupting microtubule assembly, causing cell cycle arrest and apoptosis through both extrinsic and intrinsic pathways in Hep3B cells. Therefore, the novel compound HAC-Y6 is a promising microtubule inhibitor that has great potential for treatment of HCC.

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Section: Discussionsupporting

confidence: 57%

Induction of apoptosis by HAC-Y6, a novel microtubule inhibitor, through activation of the death receptor 4 signaling pathway in human hepatocellular carcinoma cells

et al. 2010

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“…28 There are no published reports on effects of CHM-1 on human osterogenic sarcoma cells. Therefore, U-2 OS human osterogenic sarcoma cells were used in the current study.…”

Section: Discussionmentioning

confidence: 99%

Novel quinolone CHM‐1 induces apoptosis and inhibits metastasis in a human osterogenic sarcoma cell line

Hsu

Yang

Kuo

et al. 2009

Journal Orthopaedic Research

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Novel 2-phenyl-4-quinolone compounds have potent cytotoxic effects on different human cancer cell lines. In this study, we examined anticancer activity and mechanisms of 20-fluoro-6,7-methylenedioxy-2-phenyl-4-quinolone (CHM-1) in human osterogenic sarcoma U-2 OS cells. CHM-1-induced apoptosis was determined by flow cytometric analysis, DAPI staining, Comet assay, and caspase inhibitors. CHM-1-inhibited cell migration and invasion was assessed by a wound healing assay, gelatin zymography, and a Transwell assay. The mechanisms of CHM-1 effects on apoptosis and metastasis signaling pathways were studied using Western blotting and gene expression. CHM-1 induced G2/M arrest and apoptosis at an IC(50) (3 microM) in U-2 OS cells and caspase-3, -8, and -9 were activated. Caspase inhibitors increased cell viability after exposure to CHM-1. CHM-1-induced apoptosis was associated with enhanced ROS generation, DNA damage, decreased DeltaPsi(m) levels, and promotion of mitochondrial cytochrome c release. CHM-1 stimulated mRNA expression of caspase-3, -8, and -9, AIF, and Endo G. In addition, CHM-1 inhibited cell metastasis at a low concentration (<3 microM). CHM-1 inhibited the cell metastasis through the inhibition of MMP-2, -7, and -9. CHM-1 also decreased the levels of MAPK signaling pathways before leading to the inhibition of MMPs. In summary, CHM-1 is a potent inducer of apoptosis, which plays a role in the anticancer activity of CHM-1.

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“…We used an established method to measure soluble (depolymerized) and assembled (polymerized) tubulin (Wang et al, 2008). U937, HL-60, K562, and KG-1 cells (5 ϫ 10 7 /flask) were seeded into the 75-T flask.…”

Section: Methodsmentioning

confidence: 99%

MJ-29 Inhibits Tubulin Polymerization, Induces Mitotic Arrest, and Triggers Apoptosis via Cyclin-Dependent Kinase 1-Mediated Bcl-2 Phosphorylation in Human Leukemia U937 Cells

Yang

Hour

Huang

et al. 2010

J Pharmacol Exp Ther

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139

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We investigated the signaling pathways associated with microtubule interaction and apoptosis in U937 cells in vitro and in the U937 xenograft model in vivo by using 6-pyrrolidinyl-2-(2-hydroxyphenyl)-4-quinazolinone (MJ-29). MJ-29 induced growth inhibition and cell death of leukemia cell lines (U937, HL-60, K562, and KG-1) in a doseand time-dependent manner but did not obviously impair the viability of normal cells (peripheral blood mononuclear cells and human umbilical vein endothelial cells). MJ-29 interacted with ␣-and ␤-tubulin, inhibited tubulin polymerization both in vitro and in vivo, and disrupted microtubule organization. MJ-29 caused mitotic arrest by activating cyclin-dependent kinase 1 (CDK1)/cyclin B complex activity. MJ-29-induced growth inhibition and activation of CDK1 activity were significantly attenuated by roscovitine (CDK inhibitor) and CDK1 small interfering RNA (siRNA). Furthermore, MJ-29-induced Bcl-2 phosphorylation was also significantly attenuated by CDK1 siRNA. MJ-29 caused an increase in the protein levels of cytosolic cytochrome c, apoptotic protease-activating factor-1, procaspase-9, and apoptosis-inducing factor. MJ-29-promoted activation of caspase-9 and caspase-3 during apoptosis was significantly attenuated by caspase-9 and caspase-3 inhibitors. It is noteworthy that in BALB/ c nu/nu mice bearing U937 xenograft tumors MJ-29 inhibited tumor growth in vivo. The terminal deoxynucleotidyl transferase-mediated d-UTP nick end-labeling-positive apoptotic cells of tumor sections significantly increased in MJ-29-treated mice compared with the control group. In conclusion, our results suggest that MJ-29 induces mitotic arrest and apoptosis in U937 cells via CDK1-mediated Bcl-2 phosphorylation and inhibits the in vivo tumor growth of U937 xenograft mice.

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CHM-1, a novel synthetic quinolone with potent and selective antimitotic antitumor activity against human hepatocellular carcinoma in vitro and in vivo

Cited by 55 publications

References 33 publications

Induction of apoptosis by HAC-Y6, a novel microtubule inhibitor, through activation of the death receptor 4 signaling pathway in human hepatocellular carcinoma cells

Induction of apoptosis by HAC-Y6, a novel microtubule inhibitor, through activation of the death receptor 4 signaling pathway in human hepatocellular carcinoma cells

Novel quinolone CHM‐1 induces apoptosis and inhibits metastasis in a human osterogenic sarcoma cell line

MJ-29 Inhibits Tubulin Polymerization, Induces Mitotic Arrest, and Triggers Apoptosis via Cyclin-Dependent Kinase 1-Mediated Bcl-2 Phosphorylation in Human Leukemia U937 Cells

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