Sample pooling can be a powerful, cost-effective, and rapid means of identifying the most common changes in a gene expression profile. We identified osteopontin as a clinically useful marker of tumor progression by use of gene expression profiling on pooled samples.
Two citrus flavonoids, hesperetin and naringenin, found in oranges and grapefruit, respectively, and four noncitrus flavonoids, baicalein, galangin, genistein, and quercetin, were tested singly and in one-to-one combinations for their effects on proliferation and growth of a human breast carcinoma cell line, MDA-MB-435. The concentration at which cell proliferation was inhibited by 50% (IC50), based on incorporation of [3H]thymidine, varied from 5.9 to 140 micrograms/ml for the single flavonoids, with the most potent being baicalein. IC50 values for the one-to-one combinations ranged from 4.7 micrograms/ml (quercetin + hesperetin, quercetin + naringenin) to 22.5 micrograms/ml (naringenin + hesperetin). All the flavonoids showed low cytotoxicity (> 500 micrograms/ml for 50% cell death). Naringenin is present in grapefruit mainly as its glycosylated form, naringin. These compounds, as well as grapefruit and orange juice concentrates, were tested for their ability to inhibit development of mammary tumors induced by 7,12-dimethylbenz[a]anthracene (DMBA) in female Sprague-Dawley rats. Two experiments were conducted in which groups of 21 rats were fed a semipurified diet containing 5% corn oil and were given a 5-mg dose of DMBA intragastrically at approximately 50 days of age while in diestrus. One week later, individual groups were given double-strength grapefruit juice or orange juice or fed naringin or naringenin at levels comparable to that provided by the grapefruit juice; in the second experiment, the rats were fed a semipurified diet containing 20% corn oil at that time. As expected, rats fed the high-fat diet developed more tumors than rats fed the low-fat diet, but in both experiments tumor development was delayed in the groups given orange juice or fed the naringin-supplemented diet compared with the other three groups. Although tumor incidence and tumor burden (grams of tumor/rat) were somewhat variable in the different groups, rats given orange juice had a smaller tumor burden than controls, although they grew better than any of the other groups. These experiments provide evidence of anticancer properties of orange juice and indicate that citrus flavonoids are effective inhibitors of human breast cancer cell proliferation in vitro, especially when paired with quercetin, which is widely distributed in other foods.
In light of the continuing need for effective anticancer agents, and the association of fruit and vegetable consumption with reduced cancer risk, edible plants are increasingly being considered as sources of anticancer drugs. Cranberry presscake (the material remaining after squeezing juice from the berries), when fed to mice bearing human breast tumor MDA-MB-435 cells, was shown previously to decrease the growth and metastasis of tumors. Therefore, further studies were undertaken to isolate the components of cranberry that contributed to this anticancer activity, and determine the mechanisms by which they inhibited proliferation. Using standard chromatographic techniques, a warm-water extract of cranberry presscake was fractionated, and an acidified methanol eluate (Fraction 6, or Fr6) containing flavonoids demonstrated antiproliferative activity. The extract inhibited proliferation of 8 human tumor cell lines of multiple origins. The androgen-dependent prostate cell line LNCaP was the most sensitive of those tested (10 mg/L Fr6 inhibited its growth by 50%), and the estrogen-independent breast line MDA-MB-435 and the androgen-independent prostate line DU145 were the least sensitive (250 mg/L Fr6 inhibited their growth by 50%). Other human tumor lines originating from breast (MCF-7), skin (SK-MEL-5), colon (HT-29), lung (DMS114), and brain (U87) had intermediate sensitivity to Fr6. Using flow cytometric analyses of DNA distribution (cell cycle) and annexin V-positivity (apoptosis), Fr6 was shown in MDA-MB-435 cells to block cell cycle progression (P < 0.05) and induce cells to undergo apoptosis (P < 0.05) in a dose-dependent manner. Fr6 is potentially a source of a novel anticancer agent.
Breast cancer remains a leading cause of morbidity and mortality in women, mainly due to the propensity of primary breast tumors to metastasize to regional and distant sites. Metastatic spread after the removal of a primary tumor can be difficult to identify, creating uncertainty in patients with regards to possible cancer recurrence. This is a particular problem in breast cancer, exemplified by the fact that recurrence can take place after decades of apparent disease-free survival. The mechanisms underlying tumor dormancy in breast cancer remain poorly understood, and this presents significant challenges to both experimental investigation and clinical management of breast cancer. This review will discuss what is currently known about the metastatic process and tumor dormancy, consider the growing evidence that cancer stem cells may contribute to tumor progression and dormancy, and speculate about the clinical importance and implications of this research.
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