Dr. Weeks’ Comment: Cranberries are powerful medicine as any woman who has use it for treatment of a urinary tract infection knows all too well. But the SEED of the cranberry is the most powerful part of the plant so eating the whole seed (as we do in the powerful herbal seed based detoxifying drink CORE) is the most optimal way to benefit from the cranberry. Got cancer? eat raw organic non-GMO cranberries
“…Cranberry proanthocyanidins are also known to mitigate inflammatory responses of oral epithelial cells and to inhibit oral biofilm formation [12,78]; thus, cranberry derived constituents may be particularly efficacious inhibitors targeting oral pre-malignancy…”
and note the benefits of black raspberries (featured in the anti-inflammatory seed drink SOUL) below:
“…It should be noted that the efficacy of natural products in head and neck, esophageal and colon cancers has been demonstrated by black raspberries…”
Cranberries and Cancer: An Update of Preclinical Studies Evaluating the Cancer Inhibitory Potential of Cranberry and Cranberry Derived Constituents
1. Introduction
Incorporation of fruit and vegetables, including cranberries, into a healthy-balanced diet is suggested for prevention of human disease. The positive health benefits of cranberries and cranberry derived constituents include improvements of cardiovascular function as measured by decreases in lipid peroxidation, oxidative stress, total and low-density lipoprotein (LDL} cholesterol and high-density lipoprotein (HDL) cholesterol level increases [1,2]. Cranberry derived products can also increase immune function by increasing γδ-T cells, NK cells and B-cells [3], as well as exhibit antimicrobial and anti-adhesion activities against Gram-positive bacteria [4], Gram-negative bacteria [5,6,7,8,9,10,11] and yeast [12,13]. Utilization of cranberry and cranberry derived constituents in the prevention of cancer is an underexplored area, but one with mounting preclinical in vitro and in vivo research as will be reviewed herein. To date, there have been no clinical trials conducted which utilize cranberries to prevent or delay cancer progression.
The beneficial effects of cranberries are attributable to the berries’ rich phytonutrient composition which has been extensively and expertly reviewed by Pappas et al. [14]. Compositional analysis of the cranberry has resulted in identification and characterization of over 150 different bioactive constituents and human metabolomic studies have revealed differential pharmacokinetic profiles for these molecules [14,15,16,17]. Included in the family of polyphenols are three flavonoid classes: anthocyanins, flavonols and proanthocyanidins. Specifically, flavonoids and phenolic acids are detected in the urine and plasma of healthy older adults following a single dose of 54% cranberry juice [15]. Cranberries and cranberry derived constituents are capable of exerting antioxidant and anti-inflammatory functions as supported by several clinical trials investigating cardiovascular health improvements measured via increases in flow mediated dilation, total antioxidant performance of plasma, blood glutathione peroxidase levels and superoxide dismutase activity following consumption of a cranberry juice cocktail [15,18,19,20,21].
The cancer inhibitory potential of cranberries and cranberry derived products is being elucidated based on multiple in vitro investigations and a small number of in vivo studies. This review will encompass a total of 34 preclinical studies utilizing 45 cancer cell lines isolated from 16 target organs and studies targeting seven cancers utilizing in vivo carcinogenesis and xenograft models to investigate mechanisms by which cranberries and cranberry derived constituents modulate or inhibit cancer-related processes. Mechanisms of cranberry-linked cancer inhibition are summarized in Figure 1. Preclinical studies support that cranberries modulate cell viability, cell proliferation, cell death, adhesion, inflammation, oxidative stress and signal transduction pathways. Many of the in vitro studies initially focus on the effectiveness of cranberry derived constituents in cell density and viability assays, as logical starting points for determining whether further mechanistic analysis is warranted. Collectively, these in vitro studies provide the fundamental basis for additional in vivo studies and may inform the design and implementation of cancer-based clinical trials evaluating cranberries as cancer preventive agents.
2. Materials and Methods
A thorough bibliographic search was conducted in Pubmed through 4 June 2016 to identify all cancer focused research utilizing cranberries or cranberry derivatives. Keyword searches were performed by searching cranberry and each individual cancer target: breast, cervical, colon, esophageal, glioblastoma, leukemia, liver cancer, lung, lymphoma, melanoma, neuroblastoma, oral cavity, ovarian, prostate, renal/kidney, stomach and bladder. A secondary search was conducted using the same keywords in Scopus, an abstract and citation database for peer-reviewed literature, which yielded additional manuscripts not available in Pubmed. Finally, a bibliographic search was completed in the Health Research Library provided by the Cranberry Institute using the following keywords: cancer, reactive oxygen species, anti-oxidant and oxidative stress.
3. In Vitro Inhibition of Cancer Processes by Cranberries
Utilization of cancer cell lines to test cranberries, cranberry derived constituents and extracts has been the initial basis for defining cancer inhibitory capacity of these natural components in vitro. The majority of studies have been performed following treatment of immortalized cancer cell lines with cranberry extracts or juices, while one study has determined the benefit of pretreating the cells first to measure protective capacity against oxidative stress [22]. As summarized in Table 1, there are 31 in vitro based published reports describing cranberry linked cancer inhibition in 45 cancer cell lines derived from 16 targets. Eight mechanisms will be discussed with respect to cranberry derived extracts and constituents including cell density and viability, cell proliferation, cell cycle kinetics, cell death, signaling pathways, adhesion and migration, oxidative status and inflammation.
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5. Conclusions
Evaluation of cranberries and cranberry derived constituents in preclinical in vitro and in vivo studies evaluating cancer inhibition is key for the future development of cranberry-based interventions in high-risk human cohorts. The data presented in this review strongly support the anti-proliferative and pro-death capacities of cranberries in a multitude of cancer cell lines and select in vivo models including xenograft and chemically induced cancer models. The precise cancer inhibitory mechanisms associated with cranberries in specific targets are still be elucidated, but preclinical studies utilizing cranberry proanthocyanidins show inactivation of the PI3K/AKT/mTOR pathways and modulation of MAPK signaling in esophageal, neuroblastoma, ovarian and prostate cancer cells and in esophageal xenografts [39,44,49,52]. Moreover, cranberry proanthocyanidins have recently been shown to induce autophagic markers in vitro and in vivo [39], suggesting an alternative mode of cell death induction and tumor inhibition that requires further evaluation in additional cancer targets. A recent study published by The Cancer Genome Atlas Network showed that a large number of genetic alterations were shared across 279 patients with head and neck squamous cell carcinomas including activating mutations in PIK3CA, the gene encoding the catalytic subunit of phosphatidylinositol 3-kinase (PI3K) [77]. Cranberry proanthocyanidins are also known to mitigate inflammatory responses of oral epithelial cells and to inhibit oral biofilm formation [12,78]; thus, cranberry derived constituents may be particularly efficacious inhibitors targeting oral premalignancy. Researchers should continue to define the mechanisms of cancer inhibition in vitro and in vivo with the goal of informing mechanistically driven human clinical trials. It should be noted that the efficacy of natural products in head and neck, esophageal and colon cancers has been demonstrated by black raspberries [79]. The use of cranberries and cranberry derived constituents in cancer prevention is at an early stage. Still, results are highly promising considering positive preclinical results following treatment at relatively low, behaviorally achievable, concentrations when administered in a drink formulation, consumed as food or as a supplement. A recent study by Marette et al. reported cranberry polyphenols protect from diet-induced obesity, insulin resistance and intestinal inflammation [80]. The latter research findings were associated with a shift in fecal microbiome profiles and although cancer was not an outcome under evaluation, further assessments of cranberries targeting obesity-linked cancers seems logical. In conclusion, additional research focused on issues of metabolism, bioavailability, pharmacokinetics, pharmacodynamics, active fractionation, optimum dose, formulation, routes of delivery and duration are required to inform the cancer preventive utility of cranberries in high risk human cohorts.
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