Apigenin induces cell cycle arrest and p21/WAF1 expression in a p53-independent pathway

Takagaki, Nobumasa; Sowa, Yoshihiro; Oki, Teruki; Nakanishi, Ryoko; Yogosawa, Shingo; Sakai, Toshiyuki

doi:10.3892/ijo.26.1.185

Cited by 70 publications

(69 citation statements)

References 28 publications

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“…Similar studies in cell culture have shown that apigenin activates the WAF1/p21 promoter dependent on p53-binding elements (34). In addition, apigenin has been shown to stimulate expression of WAF1/p21 mRNA and protein in a p53-independent manner (35). Therefore, apigenin seems to be capable of exerting its effect on cancer cells with or without p53 mutations.…”

Section: Discussionmentioning

confidence: 64%

Molecular targets for apigenin-induced cell cycle arrest and apoptosis in prostate cancer cell xenograft

Shukla

Gupta

2006

Molecular Cancer Therapeutics

112

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Apigenin (4V ,5,7-trihydroxyflavone) is a promising chemopreventive agent abundantly present in fruits and vegetables that has been shown to promote cell cycle arrest and apoptosis in various malignant cell lines. To determine whether pharmacologic intervention with apigenin has a direct growth inhibitory effect on human prostate tumors implanted in athymic nude mice, we examined cell cycle regulatory molecules as precise molecular targets of apigenin action. Apigenin feeding by gavage to these mice at doses of 20 and 50 Mg/mouse/d in 0.2 mL of a vehicle containing 0.5% methyl cellulose and 0.025% Tween 20 resulted in significant decreases in tumor volume and mass of androgen-sensitive 22Rv1 and androgen-insensitive PC-3-implanted cells. Oral intake of apigenin resulted in dose-dependent (a) increase in the protein expression of WAF1/p21, KIP1/p27, INK4a/p16, and INK4c/p18; (b) down-modulation of the protein expression of cyclins D1, D2, and E; and cyclin-dependent kinases (cdk), cdk2, cdk4, and cdk6; (c) decrease in retinoblastoma phosphorylation at serine 780; (d) increase in the binding of cyclin D1 toward WAF1/p21 and KIP1/p27; and (e) decrease in the binding of cyclin E toward cdk2 in both types of tumors. In addition, apigenin feeding resulted in stabilization of p53 by phosphorylation at serine 15 in 22Rv1 tumors, which seems to exhibit p53-dependent growth inhibitory responses. Apigenin intake by these mice also resulted in induction of apoptosis, which positively correlated with serum and tumor apigenin levels. Taken together, this is the first systematic in vivo study showing the involvement of cell cycle regulatory proteins as potential molecular targets of apigenin. [Mol Cancer Ther 2006;5(4):843 -52]

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Section: Discussionmentioning

confidence: 64%

Molecular targets for apigenin-induced cell cycle arrest and apoptosis in prostate cancer cell xenograft

Shukla

Gupta

2006

Molecular Cancer Therapeutics

112

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“…Exposure of p53-mutant cancer cells to apigenin results in inhibition of cell growth and alteration of the cell cycle as demonstrated in a study in which apigenin treatment resulted in growth-inhibition and G2/M phase arrest in two p53-mutant cancer cell lines, HT-29 and MG63 (91). These effects were associated with a marked increase in the protein expression of p21/WAF1 in a dose-and time-dependent manner.…”

Section: Apigenin and Cancermentioning

confidence: 81%

Apigenin and cancer chemoprevention: Progress, potential and promise (Review)

Patel

Shukla²,

Gupta³

2007

Int J Oncol

315

362

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Abstract. Cancer is one of the major public health burdens in the United States and in other developed countries, causing approximately 7 million deaths every year worldwide. Cancer rates vary dramatically in different regions and populations around the globe, especially between developing and developed nations. Changes in cancer prevalence patterns occur within regions as their populations age or become progressively urbanized. Migration has also contributed to such variations as changes in dietary habits influence cancer rates. These epidemiologic findings strongly suggest that cancer rates are influenced by environmental factors including diet, which is largely preventable. Approaches to prevent cancer include overlapping strategies viz. chemoprevention or dietary cancer prevention. Chemoprevention aims at prevention or reversal of the initiation phase of carcinogenesis or arrest at progression of carcinogenesis through the administration of naturally occurring constituents or pharmacological agents. Cancer prevention through diet may be largely achievable by increased consumption of fruits and vegetables. Considerable attention has been devoted to identifying plant-derived dietary agents which could be developed as promising chemopreventives. One such agent is apigenin. A naturally occurring plant flavone (4', 5, 7,-trihydroxyflavone) abundantly present in common fruits and vegetables including parsley, onions, oranges, tea, chamomile, wheat sprouts and some seasonings. Apigenin has been shown to possess remarkable anti-inflammatory, antioxidant and anti-carcinogenic properties. In the last few years, significant progress has been made in studying the biological effects of apigenin at cellular and molecular levels. This review examines the cancer chemopreventive effects of apigenin in an organ-specificity format, evaluating its limitations and its considerable potential for development as a cancer chemopreventive agent.

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“…Flavone also induced apoptosis in these cells. The flavonoid apigenin was also shown to induce apoptosis in HT-29 colon carcinoma cells [in which the p53 gene is also mutated [46]. Flavone and flavonoids have been shown to reactivate the expression of genes silenced by methylation, including tumor suppressor genes.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of cell proliferation, induction of apoptosis, reactivation of DLC1, and modulation of other gene expression by dietary flavone in breast cancer cell lines

Ullmannova

Popescu

2007

Cancer Detection and Prevention

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Background-Dietary flavone was previously shown to increase the expression of deleted in liver cancer-1 gene (DLC-1) in HT-29 colon carcinoma cell line (Proteomics 2004;4:2455-64). DLC-1 that encodes a Rho GTPase-activating protein, functions as a tumor suppressor gene and is frequently inactivated or down-regulated in several common cancers. Restoration of DLC-1 expression suppresses in vitro tumor cells proliferation and tumorigenicity in vivo.Methods-Here, the effect of flavone was examined in several DLC-1-deficient cell lines derived from different types human cancer using assays for cell proliferation, gene expression and transfer.Results-We show that exposure to 15μM flavone increased DLC1 expression in breast but not in liver or prostate carcinoma cells or a nonmalignant breast epithelial cell line. Flavone restored the expression of DLC1 in the breast carcinoma cell lines MDA-MB-468, MDA-MB-361, and BT20 as well as in the colon carcinoma cell line HT-29 all of which are DLC-1-negative due to promoter hypermethylation. We further show that flavone inhibited cell proliferation, induced cell cycle arrest at G2-M, increased p21 Waf1 gene expression, and caused apoptosis. Microarray analysis of these aggressive and metastatic breast carcinoma cells revealed 29 flavone-responsive genes, among which the DNA damage-inducible GADD genes were up-regulated and the proto-oncogene STMN1 and IGFBP3 were down-regulated.Conclusions-Flavone-mediated alterations of genes that regulate tumor cell proliferation, cell cycle, and apoptosis contribute to chemopreventive and antitumoral effects of flavone. Alone or in combination with demethylating agents, flavone may be an effective adjunct to chemotherapy in preventing breast cancer metastasis.

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Apigenin induces cell cycle arrest and p21/WAF1 expression in a p53-independent pathway

Cited by 70 publications

References 28 publications

Molecular targets for apigenin-induced cell cycle arrest and apoptosis in prostate cancer cell xenograft

Molecular targets for apigenin-induced cell cycle arrest and apoptosis in prostate cancer cell xenograft

Apigenin and cancer chemoprevention: Progress, potential and promise (Review)

Inhibition of cell proliferation, induction of apoptosis, reactivation of DLC1, and modulation of other gene expression by dietary flavone in breast cancer cell lines

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