Apigenin inhibits endothelial-cell proliferation in G2/M phase whereas it stimulates smooth-muscle cells by inhibiting P21 and P27 expression

Trochon, Véronique; Blot, Emmanuel; Cymbalista, Florence; Engelmann, C; Tang, Ruoping; Thomaidis, Annick; Vasse, Marc; Soria, Jeannette; Lű, He; Soria, Claudine

doi:10.1002/(sici)1097-0215(20000301)85:5<691::aid-ijc15>3.0.co;2-q

Cited by 48 publications

(30 citation statements)

References 29 publications

(34 reference statements)

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“…This becomes evident most clearly in their differential effects on cell cycle progression. Apigenin has been studied extensively as a potential dietary chemopreventive agent and several studies [5,[25][26][27], including this one, have shown apigenin to induce cell cycle arrest in the G2/M phase. However, the methylated analog 5,7,4'-TMF as well as 5,7-DMF clearly induced arrest of most cells in the G1 phase (Fig.…”

Section: Discussionmentioning

confidence: 99%

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Cancer chemopreventive properties of orally bioavailable flavonoids—Methylated versus unmethylated flavones

Walle

Kawamori

et al. 2007

Biochemical Pharmacology

197

175

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Poor oral bioavailability has been a major limitation for the successful use of dietary flavonoids as cancer chemopreventive agents. In this study, we examined fully methylated flavones as promising improved agents. In the humanoral SCC-9 cancer cells, 5,7-dimethoxyflavone and 5,7,4'-trimethoxyflavone were both ten times more potent inhibitors of cell proliferation (IC 50 values 5-8 μM) than the corresponding unmethylated analogs chrysin and apigenin. Flow cytometry indicated that both methylated flavones arrested the SCC-9 cells in the G1 phase with a concomitant decrease in the S phase, dramatically different from the unmethylated analogs, which promoted G2/M phase arrest. Both methylated compounds inhibited the proliferation of two other cancer cell lines with very little effect on two immortalized normal cell lines. Examination of additional flavone structures indicated that methylated flavones in general have antiproliferative properties. Finally, we demonstrated that 5,7-dimethoxyflavone, in contrast to its unmethylated analog chrysin, was well absorbed and had high oral bioavailability as well as tissue accumulation in vivo in the rat. Thus, fully methylated flavones appear to have great potential as cancer chemopreventive/ chemotherapeutic agents, in particular in oral cancer.

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Section: Discussionmentioning

confidence: 99%

“…1) on cell proliferation. Both chrysin and in particular apigenin have been extensively studied in the past [5,[25][26][27]. Several other flavones were investigated as well to get a preliminary feel for chemical structureactivity relationships.…”

Section: Introductionmentioning

confidence: 99%

Cancer chemopreventive properties of orally bioavailable flavonoids—Methylated versus unmethylated flavones

Walle

Kawamori

et al. 2007

Biochemical Pharmacology

197

175

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“…Both apigenin and emodin have been reported to arrest cell cycle progression and proliferation of cancer cells (Kamei et al, 1998;Trochon et al, 2000). Since pharmacologic inhibition of CK2 reduces c-myc protein, which may play a role in cell cycle progression (Bosc et al, 1999;Pinna and Meggio, 1997), we expected that the CK2 inhibitors would reduce proliferation of the CK2a lymphoma cell lines.…”

Section: Ck2 Inhibition Reduces Lymphoma Cell Proliferationmentioning

confidence: 98%

Functional interaction of protein kinase CK2 and c-Myc in lymphomagenesis

2002

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Protein kinase CK2 (formerly casein kinase II) is frequently upregulated in human cancers, and transgenic expression of CK2a in lymphocytes is oncogenic. Lymphomagenesis is dramatically acclerated by coexpression of a c-myc transgene, suggestive of a synergistic interaction between the kinase and the transcription factor. Since c-myc can be phosphorylated by CK2, we hypothesized that the synergy between CK2 and c-myc might be due to a functional interaction of the two molecules. Pharmacologic inhibition of CK2 activity in cell lines established from CK2a transgenic T cell lymphomas reduces their proliferation and concomitantly with this, the steady state levels of c-myc protein decline. This is caused by acclerated c-myc protein turnover, which occurs in a proteasome-dependent manner. Transfection of cells with sense or anti-sense CK2 constructs modulates c-myc protein levels in concert with the alteration in CK2 activity, validating the findings obtained using the kinase inhibitors. Thus, CK2 is a critical regulator of c-myc protein stability and of the proliferation of these T cell lymphomas.

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“…In addition, the anticancer properties of apigenin in animals have been demonstrated by inhibition of tumor initiation induced by various carcinogens [21,22]. Apigenin has been shown to suppress angiogenesis in melanoma and carcinoma of the breast, skin, and colon [23][24][25][26]. Apigenin is a potent inhibitor of several protein tyrosine kinases, including epidermal growth factor receptor and Src tyrosine kinase [27,28].…”

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confidence: 99%

Apigenin-induced prostate cancer cell death is initiated by reactive oxygen species and p53 activation

Shukla

Gupta

2008

Free Radical Biology and Medicine

141

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Apigenin, a plant flavone, potentially activates wild-type p53 and induces apoptosis in cancer cells. We conducted detailed studies to understand its mechanism of action. Exposure of human prostate cancer 22Rv1 cells, harboring wild-type p53, to growth-suppressive concentrations (10-80 μM) of apigenin resulted in the stabilization of p53 by phosphorylation on critical serine sites, p14 ARFmediated downregulation of MDM2 protein, inhibition of NF-κB/p65 transcriptional activity, and induction of p21/WAF-1 in a dose-and time-dependent manner. Apigenin at these doses resulted in ROS generation, which was accompanied by rapid glutathione depletion, disruption of mitochondrial membrane potential, cytosolic release of cytochrome c, and apoptosis. Interestingly, we observed accumulation of a p53 fraction to the mitochondria, which was rapid and occurred between 1 and 3 h after apigenin treatment. All these effects were significantly blocked by pretreatment of cells with the antioxidant N-acetylcysteine, p53 inhibitor pifithrin-α, and enzyme catalase. Apigenin-mediated p53 activation and apoptosis were further attenuated by p53 antisense oligonucleotide treatment. Exposure of cells to apigenin led to a decrease in the levels of Bcl-XL and Bcl-2 and increase in Bax, triggering caspase activation. Treatment with the caspase inhibitors Z-VAD-FMK and DEVD-CHO partially rescued these cells from apigenin-induced apoptosis. In vivo, apigenin administration demonstrated p53-mediated induction of apoptosis in 22Rv1 tumors. These results indicate that apigenin-induced apoptosis in 22Rv1 cells is initiated by a ROS-dependent disruption of the mitochondrial membrane potential through transcriptional-dependent and -independent p53 pathways. KeywordsReactive oxygen species; Apoptosis; p53; Prostate cancer; Apigenin; Free radicals Cancer prevention is profoundly dependent on the p53 tumor suppressor protein, as it functions in regulating cellular growth and protecting cells from malignant transformation [1,2]. Several studies have demonstrated the anticancer activities of p53, and in fact, p53 is the most *Corresponding author. Department of Urology, Case Western Reserve University, Cleveland, OH 44106, USA. Fax: +1 216 368 0213. E-mail address: sanjay.gupta@case.edu (S. Gupta). This article appeared in a journal published by Elsevier. The attached copy is furnished to the author for internal non-commercial research and education use, including for instruction at the authors institution and sharing with colleagues. Other uses, including reproduction and distribution, or selling or licensing copies, or posting to personal, institutional or third party websites are prohibited. In most cases authors are permitted to post their version of the article (e.g. in Word or Tex form) to their personal website or institutional repository. Authors requiring further information regarding Elsevier's archiving and manuscript policies are encouraged to visit: http://www.elsevier.com/copyright NIH Public Access NIH-PA Author ManuscriptNIH-PA A...

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Apigenin inhibits endothelial-cell proliferation in G2/M phase whereas it stimulates smooth-muscle cells by inhibiting P21 and P27 expression

Cited by 48 publications

References 29 publications

Cancer chemopreventive properties of orally bioavailable flavonoids—Methylated versus unmethylated flavones

Cancer chemopreventive properties of orally bioavailable flavonoids—Methylated versus unmethylated flavones

Functional interaction of protein kinase CK2 and c-Myc in lymphomagenesis

Apigenin-induced prostate cancer cell death is initiated by reactive oxygen species and p53 activation

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