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

Department of Cell Biology and Physiology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
The FASEB Journal (Impact Factor: 5.48). 01/2006; 19(14):2042-4. DOI: 10.1096/fj.05-3740fje
Source: PubMed

ABSTRACT 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.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The insulin-like growth factor (IGF) axis is manipulated throughout prostate epithelium neo-plastic transformation to promote tumor growth, survival, and invasive metastasis. Natural and synthetic compounds that can target the IGF axis to prevent or reverse the aberrations associated with prostate cancer development and progression may be extremely useful in the chemoprevention and/or chemotherapy of prostate cancer. Apigenin, a naturally-occurring plant flavone found in many fruits and vegetables, is one such compound that can correc-tively modulate the IGF axis to induce growth arrest and apoptosis in many pre-clinical in vi-tro and in vivo models of prostate cancer. Because of its known mechanism of action and low toxicity and high effectiveness at physiologically relevant doses in animal models of prostate cancer, apigenin is an excellent candidate for a clinical pilot study to determine the effect of oral apigenin supplementation on prostate cancer development and progression in humans.
  • Source
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Polyphenols are a large family of natural compounds widely distributed in plants and are the most studied chemopreventive agents. The biological activities and mechanism(s) of chemopreventive effects of polyphenols have been extensively studied. Therefore, this review focuses mainly on the evidence related to chemopreventive efficacy of polyphenols and describing their mechanism(s) of anti-initiating, anti-promoting and anti-progressor action(s) in different in vivo experimental systems. Studies employing in vivo experimental rodent models have demonstrated several polyphenols to modulate incidence, multiplicity, latency period of carcinogen-induced tumors at various organ sites and tumor angiogenesis, metastasis and behavior of transplanted tumors/xenografts. The observed in vivo anti-initiating, anti-promoting and anti-progressor activity of polyphenols in chemical and genetic models involve modulation of signaling kinases ultimately leading to effects on genes and cell signaling pathways at multiple levels. Overall, the mechanism(s) implicated in the polyphenol(s)-mediated inhibition are diverse and involve effects on multiple molecular pathways and genes.
    Polyphenols in Human Health and Disease, 2 edited by Ronald R. Watson, Victor R. Preedy, Sherma Zibadi, 01/2014: chapter Polyphenol(s)-mediated in vivo cellular responses during carcinogenesis: pages 1141-1179; Elsevier., ISBN: 978-0-12-398472-2

Full-text (2 Sources)

Available from
May 26, 2014