Antiproliferative effect of esculetin on vascular smooth muscle cells: possible roles of signal transduction pathways

Huang, Hung‐Tse; Lai, Mei-Wen; Wang, Huei-Rong; Chung, Yi-Ling; Hsieh, Li-En; Chen, Ching-Chow

doi:10.1016/0014-2999(93)90090-5

Cited by 47 publications

(35 citation statements)

References 17 publications

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“…Previous studies have shown the inhibitory effect of esculetin on cell proliferation in many cell lines (31)(32)(33)(34)37). The present study also shows that esculetin inhibits the growth of colon cancer HCT116 cells in a time-and dosedependent manner, as is evident by cell viability and DNA synthesis.…”

Section: Discussionsupporting

confidence: 85%

“…Esculetin, a naturally-occurring coumarin compound, has been shown to have many pharmacological effects associated with cell proliferation (28)(29)(30)(31)(32)(33). It is known to inhibit cancer cell proliferation in both in vitro and in vivo models (34,37).…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have reported the suppression of xanthine oxidase activity, antioxidant activity, platelet aggregation, the inhibition of human leukemia cell growth and anti-atherogenic activity (28)(29)(30)(31)(32)(33). Although the inhibition of cell growth by esculetin has been observed in cancer cells (34), the mechanism by which esculetin is involved in the cross-link between the Ras/ERK1/2 signaling pathway and cell cycle regulation is not well understood.…”

Section: Introductionmentioning

confidence: 99%

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Esculetin inhibits cell proliferation through the Ras/ERK1/2 pathway in human colon cancer cells

Park

Park²,

Lim³

et al. 2010

Oncol Rep

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Abstract. Esculetin, a phenolic compound, has been shown to inhibit the growth of colon tumors in animal studies. However, the roles of signaling pathways and cell cycle regulation in the esculetin-induced inhibition of cancer cell growth, remain to be elucidated. The present study suggests a novel mechanism for the Ras/ERK1/2 pathway in esculetintreated human colon cancer HCT116 cells. The treatment of cells with esculetin resulted in significant growth inhibition and G1 phase cell cycle arrest, which led to the downregulation of cyclin and cyclin-dependent kinase (CDK) expressions. This G1 phase cell cycle arrest was associated with the up-regulation of p27KIP expression. In addition, ERK1/2 was activated by esculetin. The pre-treatment of cells with the MEK1/2-specific inhibitor, PD98059, blocked the p27KIP expression induced by esculetin. Blockage of the ERK1/2 function consistently prevented the inhibition of cell proliferation and decreased G1 phase cell cycle protein levels. Furthermore, Ras activation was increased by the esculetin treatment. Transient transfection of the dominant negative Ras (RasN17) mutant gene abolished both the ERK1/2 activity and p27KIP expression induced by esculetin. Finally, the overexpression of RasN17 suppressed the esculetininduced reduction in cell proliferation and cell cycle proteins. In conclusion, these results indicate that the Ras/ERK1/2 pathway is mediated by the p27KIP1 induction, leading to a reduction in cyclin/CDK complexes in the esculetin-induced inhibition of colon cancer cell growth. Overall, these findings indicate that the molecular action of esculetin has therapeutic potential for the treatment of colon malignancies.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Esculetin inhibits cell proliferation through the Ras/ERK1/2 pathway in human colon cancer cells

Park

Park²,

Lim³

et al. 2010

Oncol Rep

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“…At 3 -30 µM, esculetin exerts antiproliferative activity in several in vitro models including MDA-MB-231 human breast cancer cells [47,122], human T-lymphoid leukaemia cells [120] and vascular smooth muscle cells [121]. In vascular smooth muscle cells, esculetin (2 or 20 µM) was further shown to completely block cell invasiveness stimulated by linoleic acid, while completely suppressing Type IV collagenase (metalloproteinase-9) mRNA expression [121].…”

Section: Experimental 12-lo Inhibitorsmentioning

confidence: 97%

Potential use of lipoxygenase inhibitors for cancer chemoprevention

Steele¹,

Holmes²,

Hawk³

et al. 2000

Expert Opinion on Investigational Drugs

161

170

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Increasing evidence suggests that lipoxygenase (LO)-catalysed metabolites have a profound influence on the development and progression of human cancers. Compared with normal tissues, significantly elevated levels of LO products have been found in breast tumours, colon cancers, lung, skin and prostate cancers, as well as in cells from patients with both acute and chronic leukaemias. LO-mediated products elicit diverse biological activities needed for neoplastic cell growth, influencing growth factor and transcription factor activation, oncogene induction, stimulation of tumour cell adhesion and regulation of apoptotic cell death. Agents that block LO catalytic activity may be effective in preventing cancer by interfering with signalling events needed for tumour growth. In the past ten years, pharmaceuticals agents that specifically inhibit the 5-LO metabolic pathway have been developed to treat inflammatory diseases such as asthma, arthritis and psoriasis. Some of these compounds possess anti-oxidant properties and may be effective in preventing cancer by blocking free radical-induced genetic damage or by preventing the metabolic activation of carcinogens. Other compounds may work by negatively modulating DNA synthesis. Pharmacological profiles of potential chemopreventive agents are compiled from enzyme assays, in vitro testing (e.g., cell proliferation inhibition in human cancer cells) and in vivo animal carcinogenesis models (e.g., N-methyl-N-nitrosourea-induced rat mammary cancer, benzo(a)pyrene-induced lung tumours in strain A/J mice and hormone-induced prostate tumours in rats). In this way, compounds are identified for chemoprevention trials in human subjects. Based on currently available data, it is expected that the prevention of lung and prostate cancer will be initially studied in human trials of LO inhibitors.

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“…Esculetin has been shown to have an anti-inflammatory effect in the Croton oil ear test [1], anti-proliferative effects on vascular smooth muscle cells [2], inhibitory action on benzo[a]pyrene plus 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumorigenesis [3] and N-methyl-N-nitrosourea-induced mammary carcinoma [4], and it is a scavenger of oxygen free radicals [5,6]. It has also been shown to induce apoptosis in various cell types, including adipocytes [7][8][9].…”

Section: Introductionmentioning

confidence: 99%

Esculetin induces mitochondria-mediated apoptosis in 3T3-L1 adipocytes

2006

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Adipose tissue mass is determined by the volume and the number of adipocytes and is subjected to homeostatic regulation involving cell death mechanisms. We investigated the effects of esculetin, a coumarin compound, on apoptotic signaling in 3T3-L1 adipocytes. Esculetin treatment induced an increase in expression of Bax with a concomitant decrease of Bcl-2 in a time-dependent manner. Esculetin treatment also resulted in translocation of cytochrome c from mitochondria to cytosol and cleavage of 116 kDa poly(ADP-ribose) polymerase (PARP)-1, resulting in the accumulation of an 85 kDa cleavage product in a caspase-dependent manner. Furthermore, esculetin selectively altered the phosphorylation state of members of the MAPK superfamily, causing dephosphorylation of extracellular signal-regulating kinase 1/2 (ERK1/2) and hyperphosphorylation of c-Jun-N-terminal kinase (JNK). In addition, an inhibitor of the JNK MAP kinase pathway, SP600125, reduced esculetin-induced cytochrome c release. These results indicate that esculetin mediated adipocyte apoptosis involves the mitochondrial pathway. Esculetin thus decreases adipocyte number by initiating this apoptotic process in 3T3-L1 adipocytes.

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Antiproliferative effect of esculetin on vascular smooth muscle cells: possible roles of signal transduction pathways

Cited by 47 publications

References 17 publications

Esculetin inhibits cell proliferation through the Ras/ERK1/2 pathway in human colon cancer cells

Esculetin inhibits cell proliferation through the Ras/ERK1/2 pathway in human colon cancer cells

Potential use of lipoxygenase inhibitors for cancer chemoprevention

Esculetin induces mitochondria-mediated apoptosis in 3T3-L1 adipocytes

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