Soy processing influences growth of estrogen-dependent breast cancer tumors

Soy-based products consumed in Asian countries are minimally processed whereas in the USA many of the soy foods and soy ingredients are highly processed. Soy foods contain complex mixtures of bioactive compounds, which may interact with one another. The objective of this study was to evaluate the ability of various soy products containing genistin, the glycoside form of genistein, to affect growth of MCF-7 cells transplanted into ovariectomized athymic mice. Products investigated included soy flour, two crude extracts of soy (soy molasses and Novasoy(R)), a mixture of isoflavones and genistin in pure form. Each of the soy flour-processed products was added to the diet to provide equivalent amounts of genistein aglycone equivalents (750 p.p.m.). Tumors in the negative control animals regressed throughout the study while the tumors in the soy flour-fed animals remained basically the same size (neither grew nor regressed). In animals consuming soy molasses, Novasoy(R), mixed isoflavones or genistin alone, tumor growth was stimulated when compared with animals consuming a control diet devoid of soy. These same dietary treatments resulted in increased cellular proliferation. Changes in mRNA expression of gene targets (estrogen responsiveness, cell cycle progression, apoptosis and aromatase activity) in tumors induced by the different diets were evaluated. The relative expression of pS2, progesterone receptor and cyclin D1 was increased in animals consuming the Novasoy(R), mixed isoflavones and genistin. Bcl2 mRNA expression was low in most of the dietary treatment groups compared with positive (estradiol implant) controls. Aromatase expression was not affected in any of the treatment groups. The degree of soy flour processing affects the estrogenicity of products containing a constant amount of genistein. Collectively, these findings suggest that for postmenopausal women with estrogen-dependent breast cancer, the consumption of foods containing soy flour is more advisable than consuming isoflavones in more purified forms.     

Reconstituted basement membrane (Matrigel) promotes the survival and influences the growth of murine tumors.

The effects of reconstituted basement membrane (Matrigel) on in vivo survival and growth of several murine tumors were studied. Survival of tumor cells was enhanced in all experiments which resulted in increased incidence and/or in increased tumor mass. While basement membrane enhanced the in vivo growth of B16F6 melanoma cells, survival of these mice was prolonged. Basement membrane increased the incidence but reduced the growth of Ehrlich ascites tumor. Walker-256 hypercalcemic breast carcinosarcoma growth was enhanced and glandular-like structures were observed when grown on Matrigel. The results indicate that the enhanced survival of tumor cells in the presence of basement membrane is not unequivocally linked with increased malignancy.     

Treatment of hematologic malignancies and solid tumors by inhibiting IGF receptor signaling

Insulin-like growth factors (IGF) and their receptors (IGF-1R) constitute a complex biologic system implicated in diverse regulatory levels of cell proliferation, viability, differentiation and metabolism. Extensive epidemiologic data have implicated the IGF/IGF-1R pathway in the establishment of human malignancies, consistent with experimental data on the role of this signaling cascade in promoting cell transformation, resistance to apoptosis, metastases and other aspects of the biology of human cancers. However, historically, the IGF/IGF-1R pathway has not been viewed as an attractive target for therapeutic intervention. The widespread IGF-1R expression in normal tissues and its close homology to the insulin receptor had led to the assumption that IGF-1R inhibition would cause unacceptable toxicities in vivo. Even though neutralizing antibodies against human IGF-1R have been efficacious against xenograft tumors, a lack of reactivity against the host rodent receptor has confounded the assessment of its therapeutic index. Furthermore, the lack of a clear understanding of the relevant significance for neoplastic cells in the function of IGF-1R versus other growth factor receptors provided an additional disincentive for the study of this pathway. However, recent reports from the authors' group and others have shown that small molecule inhibitors of tyrosine kinase activity of IGF-1R can be safely and efficaciously administered in vivo in clinically relevant orthotopic models of human neoplasias, such as multiple myeloma. This article reviews the data that validated IGF-1R as a therapeutic target for a broad spectrum of malignancies and provides in vivo proof-of-concept for the use of selective IGF-1R kinase inhibitors as primary antitumor therapy or in synergistic combination as chemosensitizers. These results have not only provided the rationale for clinical trials of small molecule IGF-1R inhibitors, but have also rekindled interest in other therapeutic modalities (e.g., monoclonal antibodies) aimed at suppressing the function of this critical pathway for tumor cell pathophysiology.     

Loxoprofen sodium suppresses mouse tumor growth by inhibiting vascular endothelial growth factor

There is increasing evidence to suggest the anti-tumor effects of non-steroidal anti-inflammatory drugs (NSAIDs). In this study it was shown that the most popular NSAID in Japan, loxoprofen sodium (LOX), inhibited in vivo growth of implanted Lewis lung carcinoma (LLC), whereas LOX did not affect the proliferation and viability of LLC cells in vitro. Intratumoral vessel density in LOX-treated mice was significantly lower than that of mice without treatment. Intratumoral expressions of vascular endothelial growth factor (VEGF) mRNA were attenuated by the LOX treatment. LOX suppressed both intratumoral and systemic VEGF protein in LLC-implanted mice. LOX also inhibited tubular formation of primary cultured human umbilical vein endothelial cells, presumably due to the inhibition of VEGF. In patients with advanced non-small cell lung cancer, LOX medication (120 mg/day) for a week significantly decreased the plasma VEGF level. These results suggest that LOX may have potent anti-cancer effects in patients with advanced NSCLC.     

Bortezomib enhances radiation-induced apoptosis in solid tumors by inhibiting CIP2A

Previously, we demonstrated that cancerous inhibitor of protein phosphatase 2A (CIP2A) mediates bortezomib-induced apoptosis in hepatocellular carcinoma cells. Herein, we report that bortezomib sensitizes solid tumor cells to radiation-induced apoptosis. Treatment with a combination of bortezomib and radiation downregulated CIP2A in a dose-dependent manner in solid tumor cells. Knockdown of CIP2A enhanced radiation-induced apoptosis in cancer cells, and ectopic expression of CIP2A in cancer cells abolished radiation-induced apoptosis. Finally, our in vivo data showed that bortezomib and radiation combination treatment decreased tumor growth significantly. Thus, bortezomib sensitized solid tumor cells to radiation through the inhibition of CIP2A.     

p53 function influences the effect of fractionated radiotherapy on glioblastoma tumors

PURPOSE: Glioblastoma multiforme brain tumors (GM) are treated with a spectrum of fractionation regimens based on the clinical and anatomical characteristics of the tumor but rarely based on the molecular characteristics of the individual neoplasm. This study tests the hypothesis that the response of cell lines derived from GM to fractionated radiotherapy depends on the function of wild-type p53 (wt p53), a tumor suppressor gene frequently mutated in GM tumors. METHODS & MATERIALS: Isogenic derivatives of glioblastoma cells differing only in p53 function were prepared using a retroviral vector expressing a dominant negative mutant of p53 (mt p53). Radiation survival in vitro was quantitated using linear quadratic and repair-saturation mathematical models. Apoptosis was assayed by a terminal deoxynucleotide transferase-labeling technique and chromatin morphology. RESULTS: We have previously reported the generation of isogenic GM cell lines differing only in p53 function. U87-175.4, lacking wt p53 function, had a significantly lower alpha/beta value than U87-LUX.8, expressing functional wt p53, leading us to hypothesize that fractionated irradiation would preferentially spare GM cells harboring mt p53 compared with those expressing functional, wt p53. Survival curves following either 2.0 Gy or 3.5 Gy/fraction demonstrated that lack of functional wt p53 was associated with resistance to fractionated irradiation. Radiation-induced apoptosis could not account for the observed differences in clonogenic survival. Rather, our data suggested that a deficit in the G1-checkpoint contributed to increased resistance to fractionated irradiation of cells expressing mutant p53. CONCLUSIONS: The effect of fractionated radiotherapy in GM may depend on the function of the tumor suppressor gene p53. A potential clinical consequence of these findings is that hyperfractionation regimens may provide a therapeutic advantage specifically for tumors expressing wt p53 whereas a radiotherapy course of fewer, larger fractions may be appropriate for the treatment of tumors carrying p53 mutations. Further studies are needed to confirm our proposal that the p53 status of GM tumors can be used to guide our choice of fractionation schemes.     

大蒜素抑制肿瘤生长机制的实验研究

目的:研究大蒜素对肿瘤中血管内皮生长因子(VEGF)及其上游调节基因HIF-1α表达的影响,并探讨其抑制肿瘤生长的机制.方法:皮下荷瘤小鼠体内注射不同刺量的大蒜素,监测肿瘤生长情况;处死小鼠后以ELISA法检测小鼠血清VEGF的表达;realtime-PCR法检测肿瘤中VEGF和HIF-1α mRNA的表达;免疫组化法检测肿瘤中CD34的表达并量化微血管教;蛋白质印迹法检测HIF-1α蛋白的表达.结果:不同剂量大蒜素均对小鼠皮下肿瘤生长有抑制作用,且呈剂量依赖关系.低、高剂量大蒜素对肿瘤的抑制作用与对照组相比分别为71.4%和40.8%;小鼠体内以及肿瘤处的VEGF表达都显著降低,与对照组相比分别为64.5%和62.9%(血清)、34.6%和32.3%(瘤内);同时HIF-1α蛋白表达亦降低,分别是对照组的26.7%和25.1%;肿瘤组织中的CD34表达也明显减少,与对照组相比分别为16.8%和14.4%,P<0.01.结论:大蒜素可以通过抑制肿瘤VEGF的生成,进而抑制肿瘤血管的形成,可能是通过先阻断VEGF的上游调控基因HIF-1的表达来实现的,这为肿瘤临床药理学研究提供一定的理论基础.