Abstract
BackgroundNaturally occurring polyphenolic compounds from fruits, particularly from blueberries, have been reported to be significantly involved in cancer chemoprevention and chemotherapy. Biotransformation of blueberry juice by Serratia vaccinii increases its polyphenolic content and endows it with anti-inflammatory properties.MethodsThis study evaluated the effect of a polyphenol-enriched blueberry preparation (PEBP) and its non-fermented counterpart (NBJ), on mammary cancer stem cell (CSC) development in in vitro, in vivo and ex vivo settings. Effects of PEBP on cell proliferation, mobility, invasion, and mammosphere formation were measured in vitro in three cell lines: murine 4T1 and human MCF7 and MDA-MB-231. Ex vivo mammosphere formation, tumor growth and metastasis observations were carried out in a BALB/c mouse model.ResultsOur research revealed that PEBP influence cellular signaling cascades of breast CSCs, regulating the activity of transcription factors and, consequently, inhibiting tumor growth in vivo by decreasing metastasis and controlling PI3K/AKT, MAPK/ERK, and STAT3 pathways, central nodes in CSC inflammatory signaling. PEBP significantly inhibited cell proliferation of 4T1, MCF-7 and MDA-MB-231. In all cell lines, PEBP reduced mammosphere formation, cell mobility and cell migration. In vivo, PEBP significantly reduced tumor development, inhibited the formation of ex vivo mammospheres, and significantly reduced lung metastasis.ConclusionsThis study showed that polyphenol enrichment of a blueberry preparation by fermentation increases its chemopreventive potential by protecting mice against tumor development, inhibiting the formation of cancer stem cells and reducing lung metastasis. Thus, PEBP may represent a novel complementary alternative medicine therapy and a source for novel therapeutic agents against breast cancer.
Highlights
Occurring polyphenolic compounds from fruits, from blueberries, have been reported to be significantly involved in cancer chemoprevention and chemotherapy
Inhibition of breast cancer cell proliferation At a concentration of 200 μM Gallic Acid Equivalent (GAE), polyphenol-enriched blueberry preparation (PEBP) significantly inhibited the proliferation of 4T1, MDA-MB-231 and MCF-7 cancer cells by 34, 24 and 33 % respectively (Fig. 1), whereas the same concentration of normal blueberry juice (NBJ) only showed an inhibition of 32 % in 4T1 cell proliferation (Fig. 1a)
Both PEBP and NBJ did not show any toxicity on the three cell lines at tested concentrations, as determined by an Lactate Dehydrogenase (LDH) assay
Summary
Occurring polyphenolic compounds from fruits, from blueberries, have been reported to be significantly involved in cancer chemoprevention and chemotherapy. Biotransformation of blueberry juice by Serratia vaccinii increases its polyphenolic content and endows it with anti-inflammatory properties. CSCs by fermented blueberry preparation, named Polyphenols-Enriched Blueberry Preparation (referred hereafter as PEBP), supports diet-mediated targeting of CSCs. The chemopreventive effects of blueberry polyphenolics on breast cancer are well-known [5, 6]. Phenolic extracts from European blueberry were shown to inhibit proliferation and induce apoptosis in breast cancer cells [7]. Increasing the phenolic content of blueberry might enhance its anticancer properties and reduce its metastatic potential. Biotransformation of blueberry juice with a novel strain of bacteria isolated from the blueberry flora increases its phenolic content and antioxidant activity [8]
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