Dietary and Non-Dietary Phytochemicals and Cancer

A special issue of Toxins (ISSN 2072-6651). This special issue belongs to the section "Plant Toxins".

Deadline for manuscript submissions: closed (15 March 2016) | Viewed by 82783

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Special Issue Editor

Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, Corso d’Augusto 237, 47921 Rimini, Italy
Interests: anticancer pharmacology; natural products; in vitro studies; apoptosis; cell death; non-canonical cell death; genotoxicity
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Dear Colleagues,

The role of many phytochemicals in the modulation of the carcinogenesis process has been well documented by combining in vitro and animal studies, as well as epidemiological evidence. When acting in synergy, phytochemicals exert potential anti-cancer properties and much progress has been made in defining their many biological activities at the molecular level. However, an interesting feature in the field of phytochemicals and cancer is the role of some phytochemicals in promoting cancer development. This Special Issue of Toxins aims to provide a comprehensive look at the contribution of dietary and non-dietary phytochemicals to cancer development and at the molecular mechanisms by which phytochemicals inhibit or promote cancer. These aspects are extremely useful for the definition of efficient preventive measures against cancer.

Prof. Dr. Carmela Fimognari
Guest Editor

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Keywords

  • phytochemicals
  • plant extracts
  • cell proliferation
  • cell death
  • neoangiogenesis
  • inflammation
  • genotoxicity
  • metastatization

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Published Papers (11 papers)

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Editorial

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Editorial
Introduction to the Toxins Special Issue on Dietary and Non-Dietary Phytochemicals and Cancer
by Carmela Fimognari
Toxins 2017, 9(1), 12; https://doi.org/10.3390/toxins9010012 - 28 Dec 2016
Cited by 1 | Viewed by 4436
Abstract
The role of many phytochemicals in the modulation of the carcinogenesis process has been well documented by combining in vitro and animal studies, as well as epidemiological evidence. When acting in synergy, phytochemicals exert potential anti-cancer properties, and much progress has been made [...] Read more.
The role of many phytochemicals in the modulation of the carcinogenesis process has been well documented by combining in vitro and animal studies, as well as epidemiological evidence. When acting in synergy, phytochemicals exert potential anti-cancer properties, and much progress has been made in defining their many biological activities at the molecular level. However, an interesting feature in the field of phytochemicals and cancer is the role of some phytochemicals in promoting cancer development. This Special Issue of Toxins aims to provide a comprehensive look at the contribution of dietary and non-dietary phytochemicals to cancer development and at the molecular mechanisms by which phytochemicals inhibit or promote cancer.[...] Full article
(This article belongs to the Special Issue Dietary and Non-Dietary Phytochemicals and Cancer)

Research

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3656 KiB  
Article
Tenuifolide B from Cinnamomum tenuifolium Stem Selectively Inhibits Proliferation of Oral Cancer Cells via Apoptosis, ROS Generation, Mitochondrial Depolarization, and DNA Damage
by Chung-Yi Chen, Ching-Yu Yen, Hui-Ru Wang, Hui-Ping Yang, Jen-Yang Tang, Hurng-Wern Huang, Shih-Hsien Hsu and Hsueh-Wei Chang
Toxins 2016, 8(11), 319; https://doi.org/10.3390/toxins8110319 - 05 Nov 2016
Cited by 44 | Viewed by 6315
Abstract
The development of drugs that selectively kill oral cancer cells but are less harmful to normal cells still provide several challenges. In this study, the antioral cancer effects of tenuifolide B (TFB), extracted from the stem of the plant Cinnamomum tenuifolium are evaluated [...] Read more.
The development of drugs that selectively kill oral cancer cells but are less harmful to normal cells still provide several challenges. In this study, the antioral cancer effects of tenuifolide B (TFB), extracted from the stem of the plant Cinnamomum tenuifolium are evaluated in terms of their effects on cancer cell viability, cell cycle analysis, apoptosis, oxidative stress, and DNA damage. Cell viability of oral cancer cells (Ca9-22 and CAL 27) was found to be significantly inhibited by TFB in a dose-responsive manner in terms of ATP assay, yielding IC50 = 4.67 and 7.05 μM (24 h), but are less lethal to normal oral cells (HGF-1). Dose-responsive increases in subG1 populations as well as the intensities of flow cytometry-based annexin V/propidium iodide (PI) analysis and pancaspase activity suggested that apoptosis was inducible by TFB in these two types of oral cancer cells. Pretreatment with the apoptosis inhibitor (Z-VAD-FMK) reduced the annexin V intensity of these two TFB-treated oral cancer cells, suggesting that TFB induced apoptosis-mediated cell death to oral cancer cells. Cleaved-poly (ADP-ribose) polymerase (PARP) and cleaved-caspases 3, 8, and 9 were upregulated in these two TFB-treated oral cancer cells over time but less harmful for normal oral HGF-1 cells. Dose-responsive and time-dependent increases in reactive oxygen species (ROS) and decreases in mitochondrial membrane potential (MitoMP) in these two TFB-treated oral cancer cells suggest that TFB may generate oxidative stress as measured by flow cytometry. N-acetylcysteine (NAC) pretreatment reduced the TFB-induced ROS generation and further validated that ROS was relevant to TFB-induced cell death. Both flow cytometry and Western blotting demonstrated that the DNA double strand marker γH2AX dose-responsively increased in TFB-treated Ca9-22 cells and time-dependently increased in two TFB-treated oral cancer cells. Taken together, we infer that TFB can selectively inhibit cell proliferation of oral cancer cells through apoptosis, ROS generation, mitochondrial membrane depolarization, and DNA damage. Full article
(This article belongs to the Special Issue Dietary and Non-Dietary Phytochemicals and Cancer)
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Article
Pueraria mirifica Exerts Estrogenic Effects in the Mammary Gland and Uterus and Promotes Mammary Carcinogenesis in Donryu Rats
by Anna Kakehashi, Midori Yoshida, Yoshiyuki Tago, Naomi Ishii, Takahiro Okuno, Min Gi and Hideki Wanibuchi
Toxins 2016, 8(11), 275; https://doi.org/10.3390/toxins8110275 - 04 Nov 2016
Cited by 12 | Viewed by 8403
Abstract
Pueraria mirifica (PM), a plant whose dried and powdered tuberous roots are now widely used in rejuvenating preparations to promote youthfulness in both men and women, may have major estrogenic influence. In this study, we investigated modifying effects of PM at various doses [...] Read more.
Pueraria mirifica (PM), a plant whose dried and powdered tuberous roots are now widely used in rejuvenating preparations to promote youthfulness in both men and women, may have major estrogenic influence. In this study, we investigated modifying effects of PM at various doses on mammary and endometrial carcinogenesis in female Donryu rats. Firstly, PM administered to ovariectomized animals at doses of 0.03%, 0.3%, and 3% in a phytoestrogen-low diet for 2 weeks caused significant increase in uterus weight. Secondly, a 4 week PM application to non-operated rats at a dose of 3% after 7,12-dimethylbenz[a]anthracene (DMBA) initiation resulted in significant elevation of cell proliferation in the mammary glands. In a third experiment, postpubertal administration of 0.3% (200 mg/kg body weight (b.w.)/day) PM to 5-week-old non-operated animals for 36 weeks following initiation of mammary and endometrial carcinogenesis with DMBA and N-ethyl-N′-nitro-N-nitrosoguanidine (ENNG), respectively, resulted in significant increase of mammary adenocarcinoma incidence. A significant increase of endometrial atypical hyperplasia multiplicity was also observed. Furthermore, PM at doses of 0.3%, and more pronouncedly, at 1% induced dilatation, hemorrhage and inflammation of the uterine wall. In conclusion, postpubertal long-term PM administration to Donryu rats exerts estrogenic effects in the mammary gland and uterus, and at a dose of 200 mg/kg b.w./day was found to promote mammary carcinogenesis initiated by DMBA. Full article
(This article belongs to the Special Issue Dietary and Non-Dietary Phytochemicals and Cancer)
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Communication
Cells Deficient in the Fanconi Anemia Protein FANCD2 are Hypersensitive to the Cytotoxicity and DNA Damage Induced by Coffee and Caffeic Acid
by Estefanía Burgos-Morón, José Manuel Calderón-Montaño, Manuel Luis Orta, Emilio Guillén-Mancina, Santiago Mateos and Miguel López-Lázaro
Toxins 2016, 8(7), 211; https://doi.org/10.3390/toxins8070211 - 08 Jul 2016
Cited by 5 | Viewed by 5055
Abstract
Epidemiological studies have found a positive association between coffee consumption and a lower risk of cardiovascular disorders, some cancers, diabetes, Parkinson and Alzheimer disease. Coffee consumption, however, has also been linked to an increased risk of developing some types of cancer, including bladder [...] Read more.
Epidemiological studies have found a positive association between coffee consumption and a lower risk of cardiovascular disorders, some cancers, diabetes, Parkinson and Alzheimer disease. Coffee consumption, however, has also been linked to an increased risk of developing some types of cancer, including bladder cancer in adults and leukemia in children of mothers who drink coffee during pregnancy. Since cancer is driven by the accumulation of DNA alterations, the ability of the coffee constituent caffeic acid to induce DNA damage in cells may play a role in the carcinogenic potential of this beverage. This carcinogenic potential may be exacerbated in cells with DNA repair defects. People with the genetic disease Fanconi Anemia have DNA repair deficiencies and are predisposed to several cancers, particularly acute myeloid leukemia. Defects in the DNA repair protein Fanconi Anemia D2 (FANCD2) also play an important role in the development of a variety of cancers (e.g., bladder cancer) in people without this genetic disease. This communication shows that cells deficient in FANCD2 are hypersensitive to the cytotoxicity (clonogenic assay) and DNA damage (γ-H2AX and 53BP1 focus assay) induced by caffeic acid and by a commercial lyophilized coffee extract. These data suggest that people with Fanconi Anemia, or healthy people who develop sporadic mutations in FANCD2, may be hypersensitive to the carcinogenic activity of coffee. Full article
(This article belongs to the Special Issue Dietary and Non-Dietary Phytochemicals and Cancer)
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Article
Withania somnifera Induces Cytotoxic and Cytostatic Effects on Human T Leukemia Cells
by Eleonora Turrini, Cinzia Calcabrini, Piero Sestili, Elena Catanzaro, Elena De Gianni, Anna Rita Diaz, Patrizia Hrelia, Massimo Tacchini, Alessandra Guerrini, Barbara Canonico, Stefano Papa, Giovanni Valdrè and Carmela Fimognari
Toxins 2016, 8(5), 147; https://doi.org/10.3390/toxins8050147 - 12 May 2016
Cited by 30 | Viewed by 7593
Abstract
Cancer chemotherapy is characterized by an elevated intrinsic toxicity and the development of drug resistance. Thus, there is a compelling need for new intervention strategies with an improved therapeutic profile. Immunogenic cell death (ICD) represents an innovative anticancer strategy where dying cancer cells [...] Read more.
Cancer chemotherapy is characterized by an elevated intrinsic toxicity and the development of drug resistance. Thus, there is a compelling need for new intervention strategies with an improved therapeutic profile. Immunogenic cell death (ICD) represents an innovative anticancer strategy where dying cancer cells release damage-associated molecular patterns promoting tumor-specific immune responses. The roots of Withania somnifera (W. somnifera) are used in the Indian traditional medicine for their anti-inflammatory, immunomodulating, neuroprotective, and anticancer activities. The present study is designed to explore the antileukemic activity of the dimethyl sulfoxide extract obtained from the roots of W. somnifera (WE). We studied its cytostatic and cytotoxic activity, its ability to induce ICD, and its genotoxic potential on a human T-lymphoblastoid cell line by using different flow cytometric assays. Our results show that WE has a significant cytotoxic and cytostatic potential, and induces ICD. Its proapoptotic mechanism involves intracellular Ca2+ accumulation and the generation of reactive oxygen species. In our experimental conditions, the extract possesses a genotoxic potential. Since the use of Withania is suggested in different contexts including anti-infertility and osteoarthritis care, its genotoxicity should be carefully considered for an accurate assessment of its risk–benefit profile. Full article
(This article belongs to the Special Issue Dietary and Non-Dietary Phytochemicals and Cancer)
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Article
Ovatodiolide Inhibits Breast Cancer Stem/Progenitor Cells through SMURF2-Mediated Downregulation of Hsp27
by Kuan-Ta Lu, Bing-Yen Wang, Wan-Yu Chi, Ju Chang-Chien, Jiann-Jou Yang, Hsueh-Te Lee, Yew-Min Tzeng and Wen-Wei Chang
Toxins 2016, 8(5), 127; https://doi.org/10.3390/toxins8050127 - 28 Apr 2016
Cited by 20 | Viewed by 5851
Abstract
Cancer stem/progenitor cells (CSCs) are a subpopulation of cancer cells involved in tumor initiation, resistance to therapy and metastasis. Targeting CSCs has been considered as the key for successful cancer therapy. Ovatodiolide (Ova) is a macrocyclic diterpenoid compound isolated from Anisomeles indica (L.) [...] Read more.
Cancer stem/progenitor cells (CSCs) are a subpopulation of cancer cells involved in tumor initiation, resistance to therapy and metastasis. Targeting CSCs has been considered as the key for successful cancer therapy. Ovatodiolide (Ova) is a macrocyclic diterpenoid compound isolated from Anisomeles indica (L.) Kuntze with anti-cancer activity. Here we used two human breast cancer cell lines (AS-B145 and BT-474) to examine the effect of Ova on breast CSCs. We first discovered that Ova displayed an anti-proliferation activity in these two breast cancer cells. Ova also inhibited the self-renewal capability of breast CSCs (BCSCs) which was determined by mammosphere assay. Ova dose-dependently downregulated the expression of stemness genes, octamer-binding transcription factor 4 (Oct4) and Nanog, as well as heat shock protein 27 (Hsp27), but upregulated SMAD ubiquitin regulatory factor 2 (SMURF2) in mammosphere cells derived from AS-B145 or BT-474. Overexpression of Hsp27 or knockdown of SMURF2 in AS-B145 cells diminished the therapeutic effect of ovatodiolide in the suppression of mammosphere formation. In summary, our data reveal that Ova displays an anti-CSC activity through SMURF2-mediated downregulation of Hsp27. Ova could be further developed as an anti-CSC agent in the treatment of breast cancer. Full article
(This article belongs to the Special Issue Dietary and Non-Dietary Phytochemicals and Cancer)
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Article
Cancer Therapy by Catechins Involves Redox Cycling of Copper Ions and Generation of Reactive Oxygen Species
by Mohd Farhan, Husain Yar Khan, Mohammad Oves, Ahmed Al-Harrasi, Nida Rehmani, Hussain Arif, Sheikh Mumtaz Hadi and Aamir Ahmad
Toxins 2016, 8(2), 37; https://doi.org/10.3390/toxins8020037 - 04 Feb 2016
Cited by 65 | Viewed by 8996
Abstract
Catechins, the dietary phytochemicals present in green tea and other beverages, are considered to be potent inducers of apoptosis and cytotoxicity to cancer cells. While it is believed that the antioxidant properties of catechins and related dietary agents may contribute to lowering the [...] Read more.
Catechins, the dietary phytochemicals present in green tea and other beverages, are considered to be potent inducers of apoptosis and cytotoxicity to cancer cells. While it is believed that the antioxidant properties of catechins and related dietary agents may contribute to lowering the risk of cancer induction by impeding oxidative injury to DNA, these properties cannot account for apoptosis induction and chemotherapeutic observations. Catechin (C), epicatechin (EC), epigallocatechin (EGC) and epigallocatechin-3-gallate (EGCG) are the four major constituents of green tea. In this article, using human peripheral lymphocytes and comet assay, we show that C, EC, EGC and EGCG cause cellular DNA breakage and can alternatively switch to a prooxidant action in the presence of transition metals such as copper. The cellular DNA breakage was found to be significantly enhanced in the presence of copper ions. Catechins were found to be effective in providing protection against oxidative stress induced by tertbutylhydroperoxide, as measured by oxidative DNA breakage in lymphocytes. The prooxidant action of catechins involved production of hydroxyl radicals through redox recycling of copper ions. We also determined that catechins, particularly EGCG, inhibit proliferation of breast cancer cell line MDA-MB-231 leading to a prooxidant cell death. Since it is well established that tissue, cellular and serum copper levels are considerably elevated in various malignancies, cancer cells would be more subject to redox cycling between copper ions and catechins to generate reactive oxygen species (ROS) responsible for DNA breakage. Such a copper dependent prooxidant cytotoxic mechanism better explains the anticancer activity and preferential cytotoxicity of dietary phytochemicals against cancer cells. Full article
(This article belongs to the Special Issue Dietary and Non-Dietary Phytochemicals and Cancer)
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Article
Chemical Characterization and in Vitro Cytotoxicity on Squamous Cell Carcinoma Cells of Carica Papaya Leaf Extracts
by Thao T. Nguyen, Marie-Odile Parat, Mark P. Hodson, Jenny Pan, Paul N. Shaw and Amitha K. Hewavitharana
Toxins 2016, 8(1), 7; https://doi.org/10.3390/toxins8010007 - 24 Dec 2015
Cited by 30 | Viewed by 9090
Abstract
In traditional medicine, Carica papaya leaf has been used for a wide range of therapeutic applications including skin diseases and cancer. In this study, we investigated the in vitro cytotoxicity of aqueous and ethanolic extracts of Carica papaya leaves on the human oral [...] Read more.
In traditional medicine, Carica papaya leaf has been used for a wide range of therapeutic applications including skin diseases and cancer. In this study, we investigated the in vitro cytotoxicity of aqueous and ethanolic extracts of Carica papaya leaves on the human oral squamous cell carcinoma SCC25 cell line in parallel with non-cancerous human keratinocyte HaCaT cells. Two out of four extracts showed a significantly selective effect towards the cancer cells and were found to contain high levels of phenolic and flavonoid compounds. The chromatographic and mass spectrometric profiles of the extracts obtained with Ultra High Performance Liquid Chromatography-Quadrupole Time of Flight-Mass Spectrometry were used to tentatively identify the bioactive compounds using comparative analysis. The principal compounds identified were flavonoids or flavonoid glycosides, particularly compounds from the kaempferol and quercetin families, of which several have previously been reported to possess anticancer activities. These results confirm that papaya leaf is a potential source of anticancer compounds and warrant further scientific investigation to validate the traditional use of papaya leaf to treat cancer. Full article
(This article belongs to the Special Issue Dietary and Non-Dietary Phytochemicals and Cancer)
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Review

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Review
Therapeutic Effectiveness of Anticancer Phytochemicals on Cancer Stem Cells
by Jisun Oh, Lynn Hlatky, Yong-Seob Jeong and Dohoon Kim
Toxins 2016, 8(7), 199; https://doi.org/10.3390/toxins8070199 - 30 Jun 2016
Cited by 49 | Viewed by 6919
Abstract
Understanding how to target cancer stem cells (CSCs) may provide helpful insights for the development of therapeutic or preventive strategies against cancers. Dietary phytochemicals with anticancer properties are promising candidates and have selective impact on CSCs. This review summarizes the influence of phytochemicals [...] Read more.
Understanding how to target cancer stem cells (CSCs) may provide helpful insights for the development of therapeutic or preventive strategies against cancers. Dietary phytochemicals with anticancer properties are promising candidates and have selective impact on CSCs. This review summarizes the influence of phytochemicals on heterogeneous cancer cell populations as well as on specific targeting of CSCs. Full article
(This article belongs to the Special Issue Dietary and Non-Dietary Phytochemicals and Cancer)
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Review
Roles of Dietary Phytoestrogens on the Regulation of Epithelial-Mesenchymal Transition in Diverse Cancer Metastasis
by Geum-A. Lee, Kyung-A. Hwang and Kyung-Chul Choi
Toxins 2016, 8(6), 162; https://doi.org/10.3390/toxins8060162 - 24 May 2016
Cited by 48 | Viewed by 8626
Abstract
Epithelial-mesenchymal transition (EMT) plays a key role in tumor progression. The cells undergoing EMT upregulate the expression of cell motility-related proteins and show enhanced migration and invasion. The hallmarks of EMT in cancer cells include changed cell morphology and increased metastatic capabilities in [...] Read more.
Epithelial-mesenchymal transition (EMT) plays a key role in tumor progression. The cells undergoing EMT upregulate the expression of cell motility-related proteins and show enhanced migration and invasion. The hallmarks of EMT in cancer cells include changed cell morphology and increased metastatic capabilities in cell migration and invasion. Therefore, prevention of EMT is an important tool for the inhibition of tumor metastasis. A novel preventive therapy is needed, such as treatment of natural dietary substances that are nontoxic to normal human cells, but effective in inhibiting cancer cells. Phytoestrogens, such as genistein, resveratrol, kaempferol and 3,3′-diindolylmethane (DIM), can be raised as possible candidates. They are plant-derived dietary estrogens, which are found in tea, vegetables and fruits, and are known to have various biological efficacies, including chemopreventive activity against cancers. Specifically, these phytoestrogens may induce not only anti-proliferation, apoptosis and cell cycle arrest, but also anti-metastasis by inhibiting the EMT process in various cancer cells. There have been several signaling pathways found to be associated with the induction of the EMT process in cancer cells. Phytoestrogens were demonstrated to have chemopreventive effects on cancer metastasis by inhibiting EMT-associated pathways, such as Notch-1 and TGF-beta signaling. As a result, phytoestrogens can inhibit or reverse the EMT process by upregulating the expression of epithelial phenotypes, including E-cadherin, and downregulating the expression of mesenchymal phenotypes, including N-cadherin, Snail, Slug, and vimentin. In this review, we focused on the important roles of phytoestrogens in inhibiting EMT in many types of cancer and suggested phytoestrogens as prominent alternative compounds to chemotherapy. Full article
(This article belongs to the Special Issue Dietary and Non-Dietary Phytochemicals and Cancer)
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Review
Ellagitannins in Cancer Chemoprevention and Therapy
by Tariq Ismail, Cinzia Calcabrini, Anna Rita Diaz, Carmela Fimognari, Eleonora Turrini, Elena Catanzaro, Saeed Akhtar and Piero Sestili
Toxins 2016, 8(5), 151; https://doi.org/10.3390/toxins8050151 - 13 May 2016
Cited by 83 | Viewed by 10812
Abstract
It is universally accepted that diets rich in fruit and vegetables lead to reduction in the risk of common forms of cancer and are useful in cancer prevention. Indeed edible vegetables and fruits contain a wide variety of phytochemicals with proven antioxidant, anti-carcinogenic, [...] Read more.
It is universally accepted that diets rich in fruit and vegetables lead to reduction in the risk of common forms of cancer and are useful in cancer prevention. Indeed edible vegetables and fruits contain a wide variety of phytochemicals with proven antioxidant, anti-carcinogenic, and chemopreventive activity; moreover, some of these phytochemicals also display direct antiproliferative activity towards tumor cells, with the additional advantage of high tolerability and low toxicity. The most important dietary phytochemicals are isothiocyanates, ellagitannins (ET), polyphenols, indoles, flavonoids, retinoids, tocopherols. Among this very wide panel of compounds, ET represent an important class of phytochemicals which are being increasingly investigated for their chemopreventive and anticancer activities. This article reviews the chemistry, the dietary sources, the pharmacokinetics, the evidence on chemopreventive efficacy and the anticancer activity of ET with regard to the most sensitive tumors, as well as the mechanisms underlying their clinically-valuable properties. Full article
(This article belongs to the Special Issue Dietary and Non-Dietary Phytochemicals and Cancer)
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