Soybean Phytochemicals Inhibit the Growth of Transplantable Human Prostate Carcinoma and Tumor Angiogenesis in Mice

Abstract

The objectives of our studies are to characterize the ability of dietary soybean components to inhibit the growth of prostate cancer in mice and alter tumor biomarkers associated with angiogenesis. Soy isoflavones (genistein or daidzein) or soy phytochemical concentrate inhibit the growth of prostate cancer cells LNCaP, DU 145 and PC-3 in vitro, but only at supraphysiologic concentrations, i.e., 50% inhibitory concentration (IC(50)) > 50 micromol/L. G2-M arrest and DNA fragmentation consistent with apoptosis of prostate cancer cells are also observed at concentrations causing growth inhibition. In contrast, the in vitro proliferation of vascular endothelial cells was inhibited by soy phytochemcials at much lower concentrations. We evaluated the ability of dietary soy phytochemical concentrate and soy protein isolate to inhibit the growth of the LNCaP human prostate cancer in severe combined immune-deficient mice. Mice inoculated subcutaneously with LNCaP cells (2 x 10(6)) were randomly assigned to one of the six dietary groups based on the AIN-76A formulation for 3 wk. A 2 x 3 factorial design was employed with two protein sources (20%, casein vs. soy protein) and three levels of soy phytochemical concentrate (0, 0.2 and 1.0% of the diet). Soy components did not alter body weight gain or food intake. Compared with casein-fed controls, the tumor volumes after 3 wk were reduced by 11% (P = 0.45) by soy protein, 19% (P = 0.17) by 0.2% soy phytochemical concentrate, 28% by soy protein with 0.2% soy phytochemical concentrate (P < 0.05), 30% by 1.0% soy phytochemical concentrate (P < 0.05) and 40% by soy protein with 1.0% soy phytochemical concentrate (P < 0.005). Histologic examination of tumor tissue showed that consumption of soy products significantly reduced tumor cell proliferation, increased apoptosis and reduced microvessel density. The angiogenic protein insulin-like growth factor-I was reduced in the circulation of mice fed soy protein and phytochemical concentrate. Our data suggest that dietary soy products may inhibit experimental prostate tumor growth through a combination of direct effects on tumor cells and indirect effects on tumor neovasculature.

Dietary Determinants of Circulating Insulin-like Growth Factor (IGF)-I and IGF Binding Proteins 1, -2 and -3 in Women in the Netherlands

“…tamoxifen, raloxifene) have been shown to decrease circulating IGF-I levels in previous human studies [27][28][29], and may also increase some IGFBP levels [27,28]. Additionally, studies in mouse models showed a reduction of serum IGF-I or IGF-I mRNA expression in breast or prostate tissue by phytoestrogens [52][53][54]. Residual + total energy intake in linear regression model.…”

Soy isoflavones enhance radiotherapy in a metastatic prostate cancer model

“…However, despite similar alterations induced by pure genistein versus soy isoflavones, we consistently found that pure genistein, but not a mixture of soy isoflavones, promotes metastatic spread to lymph nodes. Genistein was found to cause antiangiogenic effects 15 and thus could cause poor oxygenation and hypoxia. Hypoxic microenvironments in solid tumors will promote alterations in gene expression and selection of tumor variants that could contribute to metastatic progression of tumor cells.…”

“…15,[21][22][23][24] Feeding mice with soy phytochemical concentrate (SPC, containing genistein, daidzein and glycitein) or an aglycone isoflavone preparation reduced tumor growth of s.c. implanted human LNCaP cells in immunocompromised mice. 15,22 In a prevention study of Zhou et al, 23 using an orthotopic model of LNCaP cells in SCID mice similar to our model, SPC was more effective than genistein or soy protein. This prevention study is in agreement with the efficacy demonstrated by soy isoflavones in our therapeutic study of established prostate tumors.…”

“…8,9 Interestingly, soy isoflavones did not cause increased lymph node metastasis. Genistein was found to cause antiangiogenic effects 15 and thus could cause poor oxygenation and hypoxia. To determine whether genistein induces hypoxia and expression of the transcription factor hypoxia-inducible factor 1 (HIF-1), sections of PC-3 prostate tumors treated with genistein or soy isoflavones alone or combined with radiation were immunostained for HIF1-a expression.…”

Soy isoflavonoids and cancer — metabolism at the target site

“…In each case, a protective effect of isoflavones has been observed. One study examined the role of soy and soy extracts on the growth of a transplantable prostate tumor in rats [16]. In a similar animal model, dietary genistein was also shown to inhibit prostate tumor growth [17].…”