Synthesis and in Vitro and in Vivo Antitumor Activity of 2-Phenylpyrroloquinolin-4-ones

Ferlin, María Grazia; Chiarelotto, Gianfranco; Gasparotto, V.; Via, Lisa Dalla; Pezzi, Vincenzo; Barzon, Luisa; Palù, Giorgio; Castagliuolo, Ignazio

doi:10.1021/jm049387x

Cited by 69 publications

(60 citation statements)

References 52 publications

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“…[8][9][10][11][12] It was reported that the synthesized 2-phenylpyrroloquinolin-4-ones inhibited the growth of hepatocellular carcinoma both in vitro and in vivo 14 and that the 20-fluoro-7-methylenedioxy-2-phenyl-4-quinolone (CHM-1) acted as an anti-invasive agent in hepatocellular carcinoma cells. 15 However, there is no available information on effects of CHM-1 on human osterogenic sarcoma cells.…”

Section: Introductionmentioning

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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Section: Introductionmentioning

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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“…We also showed the 2-phenyl-4-quinolone series inhibited tubulin polymerization by binding to tubulin at the colchicine-binding site and was exerted as antimitotic agents (11 -15). Recently, some 2-phenylpyrroloquinolin-4-ones were synthesized from the 2-phenyl-4-quinolone and have been shown to inhibit the growth of hepatocellular carcinoma both in vitro and in vivo (17). Notably, 2 ¶-fluoro-6,7-methylenedioxy-2-phenyl-4-quinolone (CHM-1) has been identified from 6,7-substituted 2-phenyl-4-quinolone derivatives in our laboratory as an anti-invasive agent in hepatocellular carcinoma cells (18).…”

Section: Introductionmentioning

confidence: 99%

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

Wang

Pan

Huang

et al. 2008

Molecular Cancer Therapeutics

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Hepatocellular carcinoma is highly chemoresistant to currently available chemotherapeutic agents. In this study, 2 ¶-fluoro-6,7-methylenedioxy-2-phenyl-4-quinolone (CHM-1), a synthetic 6,7-substituted 2-phenyl-4-quinolone, was identified as a potent and selective antitumor agent in human hepatocellular carcinoma. CHM-1 induced growth inhibition of HA22T, Hep3B, and HepG2 cells in a concentration-dependent manner but did not obviously impair the viability of normal cells at the IC 50 for liver cancer cells. CHM-1-induced apoptosis was also characterized by immunofluorescence microscopy. CHM-1 interacted with tubulin at the colchicine-binding site, markedly inhibited tubulin polymerization both in vitro and in vivo, and disrupted microtubule organization. CHM-1 caused cell cycle arrest at G 2 -M phase by activating Cdc2/cyclin B1 complex activity. CHM-1-induced cell death, activation of Cdc2 kinase activity, and elevation of MPM2 phosphoepitopes were profoundly attenuated by roscovitine, a specific cyclin-dependent kinase inhibitor. CHM-1 did not modulate the caspase cascade, and the pan-caspaseinhibitor z-VAD-fmk did not abolish CHM-1-induced cell death. However, CHM-1 induced the translocation of apoptosis-inducing factor (AIF) from mitochondria to the nucleus. Small interfering RNA targeting of AIF substantially attenuated CHM-1-induced AIF translocation. Importantly, CHM-1 inhibited tumor growth and prolonged the lifespan in mice inoculated with HA22T cells. In conclusion, we show that CHM-1 exhibits a novel antimitotic antitumor activity against human hepatocellular carcinoma both in vitro and in vivo via a caspase-independent pathway. CHM-1 is a promising chemotherapeutic agent worthy of further development into a clinical trial candidate for treating cancer, especially hepatocellular carcinoma. [Mol Cancer Ther 2008;7(2):350 -60]

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“…It was reported that the 2-phenylpyrroloquinolin-4-ones have antitumor activity in vitro and in vivo (22). In our previous study, we had speculated that CHM-1, which was identified from a synthetic 6,7-substituted 2-phenyl-4-quinolone derivative, potently inhibits hepatocyte growth factor-induced cell invasion in the human hepatocellular carcinoma cell line, SK-Hep-1, and exhibits a novel antimitotic antitumor activity against human hepatocellular carcinoma both in vitro and in vivo (23,24).…”

mentioning

confidence: 99%

CHM-1, a New Vascular Targeting Agent, Induces Apoptosis of Human Umbilical Vein Endothelial Cells via p53-mediated Death Receptor 5 Up-regulation

Tsai

Pan

Sun

et al. 2010

Journal of Biological Chemistry

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CHM-1 (2-fluoro-6,7-methylenedioxy-2-phenyl-4-quinolone) has been identified as a potent antitumor agent in human hepatocellular carcinoma; however, its role in tumor angiogenesis is unclear. This study investigated the effects of CHM-1 and the mechanisms by which it exerts its antiangiogenic and vascular disrupting properties. Using a xenograft model antitumor assay, we found that CHM-1 significantly inhibits tumor growth and microvessel formation. Flow cytometry, immunofluorescence microscopy, and cell death enzyme-linked immunosorbent assay kit revealed that CHM-1 inhibits growth of human umbilical vein endothelial cells (HUVEC) by induction of apoptotic cell death in a concentration-dependent manner. CHM-1 also suppresses HUVEC migration and capillary-like tube formation. We were able to correlate CHM-1-induced apoptosis in HUVEC with the cleavage of procaspase-3, -7, and -8, as well as with the cleavage of poly(ADP-ribose) polymerase by Western blotting assay. Such sensitization was achieved through up-regulation of death receptor 5 (DR5) but not DR4 or Fas. CHM-1 was also capable of increasing the expression level of p53, and most importantly, the induction of DR5 by CHM-1 was abolished by p53 small interfering RNA. Taken together, the results of this study indicate that CHM-1 exhibits vascular targeting activity associated with the induction of DR5-mediated endothelial cell apoptosis through p53 up-regulation, which suggests its potential as an antivascular and antitumor therapeutic agent.In neoplasm, malignant angiogenesis and tumor mortality are highly associated with each other. Almost every step of aggressive tumor growth and metastatic dissemination relies on a functional vascular network to provide tumor cells with oxygen and nutrients and to remove waste products associated with tumor metabolism, a crucial hallmark of cancer (1). Nowadays, several antiangiogenic strategies have been developed to inhibit tumor growth and metastasis. In addition to the indirect interference of proangiogenic communication between the tumor and endothelial cell compartments, several recent reports have suggested that the induction of apoptosis in proliferation of endothelial cells may represent a potential therapeutic strategy in the treatment of neovascularization-related diseases (2-4). For instance, numerous natural angiogenic inhibitors, such as endostatin, angiostatin, and thrombospondin-1, act in part through selective triggering apoptosis in endothelial cells, resulting in vascular regression (5, 6). Several antitubulin-binding agents (e.g. CA-4-phosphate, ZD6126, and TZT-1027) and flavonoids (5,6-dimethylxanthenone-4-acetic acid) have demonstrated the ability to induce apoptosis of tumor vascular endothelial cells, leading to the rapid collapse and obstruction of tumor vessels and ultimately causing a tumor vascular shutdown effect (7).Apoptosis is an intracellular suicide program possessing morphologic characteristics and biochemical features, including chromatin condensation, nuclear DNA fragmentation, cell s...

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Synthesis and in Vitro and in Vivo Antitumor Activity of 2-Phenylpyrroloquinolin-4-ones

Cited by 69 publications

References 52 publications

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

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

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

CHM-1, a New Vascular Targeting Agent, Induces Apoptosis of Human Umbilical Vein Endothelial Cells via p53-mediated Death Receptor 5 Up-regulation

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