Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0598934 (tumor growth)
58,965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Apigenin is a plant flavonoid that is thought to play a role in the prevention of carcinogenesis. However, its mechanism of action has not yet been elucidated. Because of the importance of angiogenesis in tumor growth, we investigated the effect of apigenin on endothelial and smooth-muscle cells in an in vitro model. Apigenin markedly inhibited the proliferation, and, to a lesser degree, the migration of endothelial cells, and capillary formation in vitro, independently of its inhibition of hyaluronidase activity. In contrast, it strongly stimulated vascular smooth-muscle-cell proliferation. The molecular mechanisms of apigenin activity were analyzed in these 2 types of cells. Our results show that apigenin inhibits endothelial-cell proliferation by blocking the cells in the G(2)/M phase as a result of the accumulation of the hyperphosphorylated form of the retinoblastoma protein. Apigenin stimulation of smooth-muscle cells was attributed to the reduced expression of 2 cyclin-dependent kinase inhibitors, p21 and p27, which negatively regulate the G(1)-phase cyclin-dependent kinase.
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PMID:Apigenin inhibits endothelial-cell proliferation in G(2)/M phase whereas it stimulates smooth-muscle cells by inhibiting P21 and P27 expression. 1069 50

Neuroblastoma is a pediatric tumor accounting for 15% of childhood cancer deaths and has a poor prognosis in children >1 year of age. We investigated the ability of apigenin, a nonmutagenic dietary flavonoid that has been shown to have antitumor effects in various tumor cell lines, to inhibit growth and induce apoptosis of the human neuroblastoma cell lines NUB-7, LAN-5, and SK-N-BE(2). Apigenin inhibited colony-forming ability and survival, and induced apoptosis of NUB-7 and LAN-5 cells. The presence of the C2-C3 double bond and the 4'-OH group on the flavonoid structure correlated with the growth-inhibitory potential of apigenin. Furthermore, apigenin inhibited NUB-7 xenograft tumor growth in anonobese diabetic/severe combined immunodeficiency mouse model, likely by inducing apoptosis. Apigenin did not inhibit survival of primary sympathetic neurons, suggesting that it is not toxic to nontransformed cells. The mechanism of action of apigenin seems to involve p53, as it increased the levels of p53 and the p53-induced gene products p21WAF1/CIP1 and Bax. Furthermore, apigenin (15-60 micromol/L) induced cell death and apoptosis of neuroblastoma cells expressing wild-type but not mutant p53. Apigenin increased caspase-3 activity and PARP cleavage, and Z-VAD-FMK, a broad-spectrum caspase-3 inhibitor, rescued NUB-7 cells from apigenin-mediated apoptosis indicating that apigenin induced apoptosis in acaspase-dependent manner. Overexpression of Bcl-X(L) rescued NUB-7 from apigenin-induced cell death, suggesting that Bax activity is important for the action of apigenin. Apigenin is thus a candidate therapeutic for neuroblastoma that likely acts by regulating a p53-Bax-caspase-3 apoptotic pathway.
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PMID:Induction of caspase-dependent, p53-mediated apoptosis by apigenin in human neuroblastoma. 1565 48

Apigenin (4',5,7-trihydroxyflavone), a flavone subclass of flavonoid widely distributed in many herbs, fruits, and vegetables is a substantial component of the human diet and has been shown to possess a variety of biological activities including tumor growth inhibition and chemoprevention. Recent studies in several biological systems have shown that apigenin induces tumor growth inhibition, cell cycle arrest, and apoptosis. Free radical-induced degradation of polyunsaturated fatty acid results in electrophilic products and causes severe oxidative stress. Oxidative stress induced by free radicals, nonoxidizing species, electrophiles, and associated DNA damages have been frequently coupled with carcinogenesis. In the present study, the protective role of apigenin was examined against the oxidative stress caused by N-nitrosodiethylamine (NDEA) and phenobarbital (PB) in Wistar albino rats. Oxidative stress was measured in terms of lipid peroxidation (LPO) and protein carbonyl formation. Oxidative stress-induced DNA damage was measured by single cell gel electrophoresis (comet assay). Apigenin exhibited its antioxidant defense against NDEA-induced oxidative stress. We have observed minimal levels of LPO and DNA damage in apigenin-treated hepatoma bearing animals. Based on the results, we suggest that apigenin may be developed as a promising chemotherapeutic agent against the development of chemical carcinogenesis.
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PMID:Apigenin inhibits oxidative stress-induced macromolecular damage in N-nitrosodiethylamine (NDEA)-induced hepatocellular carcinogenesis in Wistar albino rats. 1592 50

Apigenin is a natural dietary flavonoid. It has recently been shown to have anticancer effects on prostate and ovarian cancer cells. However, the molecular basis of the effect of apigenin on cancer cells remains to be elucidated. In this study, we found that apigenin inhibited A549 lung cancer cell proliferation and vascular endothelial growth factor (VEGF) transcriptional activation in a dose-dependent manner. In an attempt to understand the mechanism of apigenin-inhibited VEGF expression, we found that apigenin inhibited VEGF transcriptional activation through the hypoxia-inducible factor 1 (HIF-1) binding site and specifically decreased HIF-1alpha but not HIF-1beta subunit expression in the cells. In our efforts to understand the signaling pathway that mediates VEGF transcriptional activation, we found that apigenin inhibited AKT and p70S6K1 activation. When testing the effect of apigenin in vivo, we found that apigenin significantly inhibited tumor growth in nude mice. Apigenin inhibited HIF-1alpha and VEGF expression in the tumor tissues, suggesting an inhibitory effect of apigenin on angiogenesis. To confirm this, we showed that apigenin inhibited angiogenesis in nude mice using the Matrigel assay. HIF-1alpha and VEGF are well known inducers of angiogenesis. Our data suggested that apigenin may inhibit human lung cancer angiogenesis by inhibiting HIF-1alpha and VEGF expression, thus providing a novel explanation for the anticancer action of apigenin.
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PMID:Apigenin inhibits expression of vascular endothelial growth factor and angiogenesis in human lung cancer cells: implication of chemoprevention of lung cancer. 1594 8

Flavonoids comprise a class of low molecular weight compounds displaying a variety of biological activities including inhibition of tumor growth and metastasis. To gain insight into the mechanisms underlying metastasis inhibition, we have employed the B16-BL6 murine melanoma metastasis model. B57BL/6N mice were injected i.v. with tumor cells and Apigenin, Quercetin, or Tamoxifen, each at 50 mg/kg given i.p., and lung tumor cell colonies counted 14-6 days thereafter. Three different injection schedules were used for each drug: (a) daily injection, starting 24 h before injection of the tumor cells; (b) single dose, 24 h preceding tumor challenge; (c) daily injection, starting 24 h after the injection of the tumor cells. All three compounds significantly reduced tumor lung deposits (Apigenin = Quercetin > Tamoxifen). However, when treatment was delayed by 24 h after tumor cells (schedule c), multiple daily doses of Apigenin or Quercetin were less effective that a single dose of the same compound given 24 h before tumor challenge (schedule b). Apigenin and Quercetin, but not Tamoxifen, were found to inhibit VCAM-1 expression in a dose-dependent manner in HUVEC and in murine pulmonary endothelial cells. In ex vivo experiments, the number of tumor cells adhering to lung vessels was significantly diminished in animals treated with a single dose of Apigenin and Quercetin. These findings indicate that the inhibition of tumor cell metastasis by Apigenin or Quercetin may significantly depend on the ability of these compounds to alter the host's microenvironment, further substantiating the role of the intravascular processes in the metastatic cascade.
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PMID:Flavonoids inhibit melanoma lung metastasis by impairing tumor cells endothelium interactions. 1622 12

Epidemiological studies suggest that increased intake of fruits and vegetables may be associated with a reduced risk of prostate cancer. Apigenin (4', 5, 7,-trihydroxyflavone), a common dietary flavonoid abundantly present in fruits and vegetables, has shown remarkable anti-proliferative effects against various malignant cell lines. However, the mechanisms underlying these effects remain to be elucidated. We investigated the in vivo growth inhibitory effects of apigenin on androgen-sensitive human prostate carcinoma 22Rv1 tumor xenograft subcutaneously implanted in athymic male nude mice. Apigenin was administered to mice by gavage at doses of 20 and 50 mug/mouse/day in 0.2 ml of a vehicle containing 0.5% methyl cellulose and 0.025% Tween 20 in two different protocols. In the first protocol, apigenin was administered for 2 wk before inoculation of tumor and was continued for 8 wk, resulting in significant inhibition of tumor volume by 44 and 59% (P<0.002 and 0.0001), and wet weight of tumor by 41 and 53% (P<0.05), respectively. In the second protocol, administration of apigenin began 2 wk after tumor inoculation and continued for 8 wk; tumor volume and wet weights of tumor were reduced by 39 and 53% (P<0.01 and 0.002) and 31 and 42% (P<0.05), respectively. The tumor inhibitory effect of apigenin was more pronounced in the first protocol of extended treatment, which was associated with increased accumulation of human IGFBP-3 in mouse serum along with significant increase in IGFBP-3 mRNA and protein expression in tumor xenograft. Apigenin intake by these mice also resulted in simultaneous decrease in serum IGF-I levels and induction of apoptosis in tumor xenograft. Importantly, tumor growth inhibition, induction of apoptosis, and accumulation of IGFBP-3 correlated with increasing serum and tumor apigenin levels. In both studies, animals did not exhibit any signs of toxicity or reduced food consumption. In cell culture studies, apigenin treatment resulted in cell growth inhibition and induction of apoptosis, which correlated with increased accumulation of IGFBP-3 in culture medium and cell lysate. These effects were associated with significant reduction in IGF-I secretion; inhibition of IGF-I-induced cell cycle progression and insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation, along with an increase in sub-G1 peak by apigenin. Further, treatment of cells with IGFBP-3 antisense oligonucleotide reversed these effects and attenuated apigenin-mediated inhibition of IRS-1 phosphorylation conferring inhibitory effects of apigenin on IGF-signaling. This study presents the first evidence that the in vitro and in vivo growth inhibitory effects of apigenin involve modulation of IGF-axis signaling in prostate cancer.
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PMID:Up-regulation of insulin-like growth factor binding protein-3 by apigenin leads to growth inhibition and apoptosis of 22Rv1 xenograft in athymic nude mice. 1623 Mar 33

Apigenin is a non-toxic dietary flavonoid with anti-tumor properties. We recently showed that apigenin-inhibited hypoxia-inducible factor-1 (HIF-1) and vascular endothelial growth factor (VEGF) expression in human ovarian cancer cells under normoxic condition. However, the effect of apigenin in angiogenesis remains to be elucidated. Angiogenesis is the formation of new blood vessels and is required for tumor growth and metastasis. In this study, we showed that apigenin-inhibited expression of HIF-1 and VEGF in different cancer cells under both normoxic and hypoxic conditions. We demonstrated that apigenin significantly inhibited tumor angiogenesis in vivo, by using both the chicken chorioallantoic membrane and Matrigel plug assays. The inhibition of tumor angiogenesis was associated with the decrease of HIF-1 and VEGF in tumor tissues. Taken together, our results show that apigenin suppresses tumor angiogenesis through HIF-1 and VEGF expression.
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PMID:Apigenin inhibits tumor angiogenesis through decreasing HIF-1alpha and VEGF expression. 1707 32

Apigenin is a dietary flavonoid possessing therapeutic potential against cancers. This study was designed to investigate whether combination therapy with gemcitabine and apigenin enhanced anti-tumor efficacy in pancreatic cancer. In vitro, the combination treatment resulted in more growth inhibition and apoptosis through the down-regulation of NF-kappa B activity with suppression of Akt activation in pancreatic cancer cell lines (MiaPaca-2, AsPC-1). In vivo, the combination therapy augmented tumor growth inhibition through the down-regulation of NF-kappa B activity with the suppression of Akt in tumor tissue. The combination of gemcitabine and apigenin enhanced anti-tumor efficacy through Akt and NF-kappa B activity suppression and apoptosis induction.
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PMID:Enhanced anti-tumor effect of combination therapy with gemcitabine and apigenin in pancreatic cancer. 1796 5

Deregulation of insulin-like growth factor (IGF)-I/IGF-IR signaling has been implicated in the development and progression of prostate cancer. Agents that can suppress the mitogenic activity of the IGF/IGF-IR growth axis may be of preventive or therapeutic value. We have previously demonstrated that apigenin, a plant flavone, modulates IGF signaling through upregulation of IGFBP-3. In this study, we investigated the mechanism(s) of apigenin action on the IGF/IGF-IR signaling pathway. Exposure of human prostate cancer DU145 cells to apigenin markedly reduced IGF-I-stimulated cell proliferation and induced apoptosis. Apigenin inhibited IGF-I-induced activation of IGF-IR and Akt in DU145 cells. Similar growth inhibitory and apoptotic responses were observed in PC-3 cells, which constitutively overexpress this pathway. This effect of apigenin appears to be due partially to reduced autophosphorylation of IGF-IR. Inhibition of p-Akt by apigenin resulted in decreased phosphorylation of GSK-3beta along with decreased expression of cyclin D1 and increased expression of p27/kip1. In vivo administration of apigenin to PC-3 tumor xenografts inhibited tumor growth, resulted in IGF-IR inactivation and dephosphorylation of Akt and its downstream signaling. These results suggest that inhibition of cell proliferation and induction of apoptosis by apigenin are mediated, at least in part, by its ability to inhibit IGF/IGF-IR signaling and the PI3K/Akt pathway.
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PMID:Apigenin suppresses insulin-like growth factor I receptor signaling in human prostate cancer: an in vitro and in vivo study. 1872 72

The use of progestins as a component of hormone replacement therapy has been linked to an increase in breast cancer risk in postmenopausal women. We have previously shown that medroxyprogesterone acetate (MPA), a commonly administered synthetic progestin, increases production of the potent angiogenic factor vascular endothelial growth factor (VEGF) by tumor cells, leading to the development of new blood vessels and tumor growth. We sought to identify nontoxic chemicals that would inhibit progestin-induced tumorigenesis. We used a recently developed progestin-dependent mammary cancer model in which tumors are induced in Sprague-Dawley rats by 7,12-dimethylbenz(a)anthracene (DMBA) treatment. The flavonoid apigenin, which we previously found to inhibit progestin-dependent VEGF synthesis in human breast cancer cells in vitro, significantly delayed the development of, and decreased the incidence and multiplicity of, MPA-accelerated DMBA-induced mammary tumors in this animal model. Whereas apigenin decreased the occurrence of such tumors, it did not block MPA-induced intraductal and lobular epithelial cell hyperplasia in the mammary tissue. Apigenin blocked MPA-dependent increases in VEGF, and suppressed VEGF receptor-2 (VEGFR-2) but not VEGFR-1 in regions of hyperplasia. No differences were observed in estrogen or progesterone receptor (ER/PR) levels, or the number of estrogen receptor-positive cells, within the mammary gland of MPA-treated animals administered apigenin, MPA-treated animals, and placebo treated animals. However, the number of progesterone receptor-positive cells was reduced in animals treated with MPA or MPA and apigenin compared with those treated with placebo. These findings suggest that apigenin has important chemopreventive properties for those breast cancers that develop in response to progestins.
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PMID:Apigenin prevents development of medroxyprogesterone acetate-accelerated 7,12-dimethylbenz(a)anthracene-induced mammary tumors in Sprague-Dawley rats. 2150 81


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