We recently reported that cranberry proanthocyanidins (C-PACs) inhibit esophageal adenocarcinoma (EAC) by 83% through reversing reflux-induced bacterial, inflammatory and immune-implicated proteins and genes as well as reducing esophageal bile acids, which drive EAC progression. This study investigated whether C-PACs’ mitigation of bile reflux-induced transporter dysregulation mechanistically contributes to EAC prevention. RNA was isolated from water-, C-PAC- and reflux-exposed rat esophagi with and without C-PAC treatment. Differential gene expression was determined by means of RNA sequencing and RT-PCR, followed by protein assessments. The literature, coupled with the publicly available Gene Expression Omnibus dataset GSE26886, was used to assess transporter expression levels in normal and EAC patient biopsies for translational relevance. Significant changes in ATP-binding cassette (ABC) transporters implicated in therapeutic resistance in humans (i.e., Abcb1, Abcb4, Abcc1, Abcc3, Abcc4, Abcc6 and Abcc10) and the transport of drugs, xenobiotics, lipids, and bile were altered in the reflux model with C-PACs’ mitigating changes. Additionally, C-PACs restored reflux-induced changes in solute carrier (SLC), aquaporin, proton and cation transporters (i.e., Slc2a1, Slc7a11, Slc9a1, Slco2a1 and Atp6v0c). This research supports the suggestion that transporters merit investigation not only for their roles in metabolism and therapeutic resistance, but as targets for cancer prevention and targeting preventive agents in combination with chemotherapeutics.

The gut and local esophageal microbiome progressively shift from healthy commensal bacteria to inflammation-linked pathogenic bacteria in patients with gastroesophageal reflux disease, Barrett’s esophagus, and esophageal adenocarcinoma (EAC). However, mechanisms by which microbial communities and metabolites contribute to reflux-driven EAC remain incompletely understood and challenging to target. Herein, we utilized a rat reflux-induced EAC model to investigate targeting the gut microbiome–esophageal metabolome axis with cranberry proanthocyanidins (C-PAC) to inhibit EAC progression. Sprague-Dawley rats, with or without reflux induction, received water or C-PAC ad libitum (700 μg/rat/day) for 25 or 40 weeks. C-PAC exerted prebiotic activity abrogating reflux-induced dysbiosis and mitigating bile acid metabolism and transport, culminating in significant inhibition of EAC through TLR/NF-κB/TP53 signaling cascades. At the species level, C-PAC mitigated reflux-induced pathogenic bacteria (Streptococcus parasanguinis, Escherichia coli, and Proteus mirabilis). C-PAC specifically reversed reflux-induced bacterial, inflammatory, and immune-implicated proteins and genes, including Ccl4, Cd14, Crp, Cxcl1, Il6, Il1b, Lbp, Lcn2, Myd88, Nfkb1, Tlr2, and Tlr4, aligning with changes in human EAC progression, as confirmed through public databases. C-PAC is a safe, promising dietary constituent that may be utilized alone or potentially as an adjuvant to current therapies to prevent EAC progression through ameliorating reflux-induced dysbiosis, inflammation, and cellular damage.

Prostate cancer is the second most diagnosed form of cancer in men worldwide and accounted for roughly 1.3 million cases and 359,000 deaths globally in 2018, despite all the available treatment strategies including surgery, radiotherapy, and chemotherapy. Finding novel approaches to prevent and treat prostate and other urogenital cancers effectively is of major importance. Chemicals derived from plants, such as docetaxel and paclitaxel, have been used in cancer treatment, and in recent years, research interest has focused on finding other plant-derived chemicals that can be used in the fight against cancer. Ursolic acid, found in high concentrations in cranberries, is a pentacyclic triterpenoid compound demonstrated to have anti-inflammatory, antioxidant, and anticancer properties. In the present review, we summarize the research studies examining the effects of ursolic acid and its derivatives against prostate and other urogenital cancers. Collectively, the existing data indicate that ursolic acid inhibits human prostate, renal, bladder, and testicular cancer cell proliferation and induces apoptosis. A limited number of studies have shown significant reduction in tumor volume in animals xenografted with human prostate cancer cells and treated with ursolic acid. More animal studies and human clinical studies are required to examine the potential of ursolic acid to inhibit prostate and other urogenital cancers in vivo. 

Background/Aim: Glioblastoma, also known as glioblastoma multiforme (GBM), is the most aggressive type of primary brain tumor and a cornerstone in its treatment is radiotherapy (RT). However, RT for GBM is largely ineffective at clinically safe doses, thus, the study of radiosensitizers is of great significance.Materials and Methods: With accumulating evidence for the anticancer effect of compounds from cranberry, this study was designed to investigate if cranberry extract (CE) sensitizes GBM to RT in the widely used human glioblastoma cell line U87. We utilized clonogenic survival assays, cell proliferation assays, and caspase-3 activity kits. Potential proliferative and apoptotic molecular mechanisms were evaluated by reverse transcription-polymerase chain reaction.Results: We found that CE alone had little effect on the survival of U87 cells. However, RT supplemented by CE significantly inhibited proliferation and promoted apoptosis of U87 cells when compared with RT alone. The proliferation-inhibitory effect of RT/CE might be attributable to the up-regulation of p21, along with the down-regulation of cyclin B and cyclin-dependent kinase 4. This pro-apoptotic effect might additionally be attributable to the down-regulation of surviving.Conclusion: These results warrant further study of the potential radiosensitizing capacity of CE in glioblastoma and other cancer types.

Natural compounds are extensively used in the treatment of various diseases. Regular consumption of polyphenols plays an important role in the protection of health by reducing the risk of degenerative diseases, including cancer. The evaluation of the cytotoxic effect of the newly obtained multifruit polyphenolic preparation (composed of seven fruit) on T47D and MCF-7 breast cancer cells and MCF-12A normal cells. The PP was produced on the basis of combined ultrafiltrates obtained from chokeberry, raspberry, wild strawberry, apricot, peach, bilberry, and cranberry. The experiments were performed using human mammary gland cancer cell lines T47D (ductal cancer) and MCF-7 (adenocarcinoma) and normal breast cell line MCF-12A. Chromatographic techniques confirmed the highest contribution of cyanidin 3-O-glucoside, p-coumaroyl glucoside and chlorogenic acid in the PP. The PP exhibited dose-dependent cytotoxic effects towards MCF-7 and T47D cancer cell lines (IC50=1.2 g.cm-3) and MCF-12A cells (IC50=0.6 g.cm-3). The MTT cytotoxicity assay and microscopic observations confirmed the cytopathic effect of the PP on cell lines. It is supposed that berry polyphenols interfered with estrogen receptors leading to changes in the production of paracrine growth factors and therefore, PP was less cytotoxic towards the MCF-7 and T47D cell lines than against the MCF-12A cell line.

Esophageal adenocarcinoma (EAC) is a cancer characterized by rapidly rising incidence and poor survival, resulting in the need for new prevention and treatment options. We utilized two cranberry polyphenol extracts, one proanthocyanidin enriched (C-PAC) and a combination of anthocyanins, flavonoids, and glycosides (AFG) to assess inhibitory mechanisms utilizing premalignant Barrett's esophagus (BE) and EAC derived cell lines. We employed reverse phase protein arrays (RPPA) and Western blots to examine cancer-associated pathways and specific signaling cascades modulated by C-PAC or AFG. Viability results show that C-PAC is more potent than AFG at inducing cell death in BE and EAC cell lines. Based on the RPPA results, C-PAC significantly modulated 37 and 69 proteins in JH-EsoAd1 (JHAD1) and OE19 EAC cells, respectively. AFG treatment significantly altered 49 proteins in both JHAD1 and OE19 cells. Bioinformatic analysis of RPPA results revealed many previously unidentified pathways as modulated by cranberry polyphenols including NOTCH signaling, immune response, and epithelial to mesenchymal transition. Collectively, these results provide new insight regarding mechanisms by which cranberry polyphenols exert cancer inhibitory effects targeting EAC, with implications for potential use of cranberry constituents as cancer preventive agents.

Aim/Background: Osteosarcoma is one of the prevalent cancers occurring mostly in adolescents and has a high risk of malignancy. With complications involved in the current treatment strategies, alternates including the use of phytochemicals have gained fame. Cranberries are known for their exceptional health benefits and have been explored for their effective activities in various cancers. The current study aimed at evaluating the anti-cancer properties of cranberry juice concentrate (CJC) on MG-63 cell line for human osteosarcoma, by investigating its apoptotic activity through changes in cell viability and mitochondrial membrane potential. Materials and Methods: Cranberry juice concentrate was obtained by pulverization and lyophilization. The MG-63 cells were treated with 12.5-800 mu g/mL of the CJC and incubated for 24, 48, and 72 hr. The percentage cell viability and IC50 values were obtained. The mitochondrial membrane potential and nuclear changes were examined. The induction of apoptosis was studied by flow cytometer using BD cell Quest 7.5.3 software. GraphPad Prism was used for statistical analysis with significant p-value at <0.05. Results: The IC50 values obtained for CJC were 847.9, 637.4, and 440.6 mu g/mL for 24, 48, and 72 hr respectively. Change in the mitochondrial membrane potential and nuclear morphology was observed following incubation with CJC. Flow cytometric analysis shows cells detected at early and late apoptoic stages after treatment with CJC. Conclusion: Our result suggests that CJC has significant effects on MG-63 osteosarcoma cells and can be considered to supplement conventional therapeutic strategies.

Cranberries contain various constituents relevant to human health. Our previous study demonstrated the chemopreventive effects of whole cranberry against colon cancer in mice. In order to determine the role of different cranberry secondary metabolites in inhibiting colon cancer, cranberry ethyl acetate extract (EAE) and polyphenol extract (PPE) were obtained. The free-radical scavenging activities and chemical composition of the cranberry extracts were determined. EAE consisted of triterpenes and sterols and a trace amount of proanthocyanidins. PPE mainly contained polyphenol with a trace amount of triterpenes. The chemopreventive effects of orally administered EAE and PPE on colitis-associated colon carcinogenesis were determined in mice. Dietary EAE and PPE significantly suppressed tumor metrics without noticeable adverse effects. Gene expression levels of key proinflammatory cytokines were also attenuated by EAE and PPE in the mouse colon. In conclusion, the novel cranberry extracts may offer an efficacious and safe means to prevent colonic tumorigenesis in humans.

Consumption of cranberry fruits or juice rich in polyphenols is associated with a wide range of potential health benefits. We and others have previously showed that cranberry juice concentrate and its phytochemicals, flavonols, anthocyanins and A-type proanthocyandins, may have potential to be chemopreventive agents. Although a number of cranberry constituents have been implicated in cancer prevention, our understanding about which metabolites are bio-available to reach target sites and thereby elicit cancer chemopreventive properties is still lacking. However, poor plasma bioavailability of cranberry constituents may be overcome by their potential interactions with gut microbiota by providing cancer prevention through induction of compositional and functional modifications of gut microbiota. Well-designed clinical trials evaluating metabolic and gut microbiome changes associated with cranberry consumption would provide useful information about the cancer patient's response to dietary intervention with cranberry constituents

BACKGROUND: Cranberry has been studied as a potential anticancer agent as it is capable of inducing apoptosis within cancer cells. The aim of this study was to better define the mechanism by which cranberry triggers apoptosis in HL-60 cells. METHODS: The study was carried on cranberry extracts (CB). Anti-apoptotic B-cell lymphoma-2 (BCL-2) and pro-apoptotic BCL-2-associated death promoter death (BAD) proteins in cell lysates were detected through Western blotting techniques. Equivalent protein loading was confirmed through anti-alpha-tubulin antibody. RESULTS: The results showed that treatment of HL-60 cells with CB causes a significant increase in the levels of caspase-9 and caspases-3/7 and increased mitochondrial outer membrane permeability, leading to the release of cytochrome C and Smac. These apoptotic events were associated with a significant decrease in protein kinase B (AKT) phosphorylation, which caused significant increase in BAD de-phosphorylation and promoted a sequence of events that led to intrinsic apoptosis. CONCLUSION: The study findings have described a molecular framework for CB-initiated apoptosis in HL-60 cells and suggested a direction for future in vivo studies investigating the anticancer effect of cranberry