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Special Issue "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)

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editor

Guest Editor
Prof. Dr. Carmela Fimognari

Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, Corso d’Augusto 237, 47921 Rimini, Italy
Website | E-Mail
Fax: +39 051 2095624
Interests: 1) antitumour pharmacology: identification of natural agents as potential antitumor drugs and definition of their cellular (analysis of apoptosis/necrosis; cell proliferation; cell-cycle progression; cytodifferentiation) and molecular (level of proteins involved in apoptosis and cell-cycle regulation) mechanism; 2) cellular and genetic toxicology: study of the cellular response after treatment with xenobiotics (cytotoxicity; analysis of DNA and RNA damage; fluorescence in situ hybridization)

Special Issue Information

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

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a double-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Toxins is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

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

Related Special Issue

Published Papers (11 papers)

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Editorial

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Open AccessEditorial
Introduction to the Toxins Special Issue on Dietary and Non-Dietary Phytochemicals and Cancer
Received: 15 December 2016 / Revised: 21 December 2016 / Accepted: 21 December 2016 / Published: 28 December 2016
Cited by 1 | PDF Full-text (193 KB) | HTML Full-text | XML Full-text
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

Research

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Open AccessArticle
Tenuifolide B from Cinnamomum tenuifolium Stem Selectively Inhibits Proliferation of Oral Cancer Cells via Apoptosis, ROS Generation, Mitochondrial Depolarization, and DNA Damage
Toxins 2016, 8(11), 319; https://doi.org/10.3390/toxins8110319
Received: 15 January 2016 / Revised: 11 October 2016 / Accepted: 19 October 2016 / Published: 5 November 2016
Cited by 10 | PDF Full-text (3656 KB) | HTML Full-text | XML Full-text
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
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Open AccessArticle
Pueraria mirifica Exerts Estrogenic Effects in the Mammary Gland and Uterus and Promotes Mammary Carcinogenesis in Donryu Rats
Toxins 2016, 8(11), 275; https://doi.org/10.3390/toxins8110275
Received: 3 June 2016 / Accepted: 13 September 2016 / Published: 4 November 2016
Cited by 1 | PDF Full-text (1071 KB) | HTML Full-text | XML Full-text | Supplementary Files
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
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Open AccessCommunication
Cells Deficient in the Fanconi Anemia Protein FANCD2 are Hypersensitive to the Cytotoxicity and DNA Damage Induced by Coffee and Caffeic Acid
Received: 15 March 2016 / Revised: 11 June 2016 / Accepted: 1 July 2016 / Published: 8 July 2016
Cited by 2 | PDF Full-text (1720 KB) | HTML Full-text | XML Full-text
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
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Open AccessArticle
Withania somnifera Induces Cytotoxic and Cytostatic Effects on Human T Leukemia Cells
Received: 30 December 2015 / Revised: 29 April 2016 / Accepted: 9 May 2016 / Published: 12 May 2016
Cited by 3 | PDF Full-text (2452 KB) | HTML Full-text | XML Full-text
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
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Open AccessArticle
Ovatodiolide Inhibits Breast Cancer Stem/Progenitor Cells through SMURF2-Mediated Downregulation of Hsp27
Received: 8 March 2016 / Revised: 12 April 2016 / Accepted: 20 April 2016 / Published: 28 April 2016
Cited by 6 | PDF Full-text (2553 KB) | HTML Full-text | XML Full-text | Supplementary Files
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
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Open AccessFeature PaperArticle
Cancer Therapy by Catechins Involves Redox Cycling of Copper Ions and Generation of Reactive Oxygen Species
Received: 2 January 2016 / Revised: 23 January 2016 / Accepted: 26 January 2016 / Published: 4 February 2016
Cited by 21 | PDF Full-text (4095 KB) | HTML Full-text | XML Full-text
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
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Open AccessArticle
Chemical Characterization and in Vitro Cytotoxicity on Squamous Cell Carcinoma Cells of Carica Papaya Leaf Extracts
Received: 26 October 2015 / Revised: 14 December 2015 / Accepted: 18 December 2015 / Published: 24 December 2015
Cited by 8 | PDF Full-text (2342 KB) | HTML Full-text | XML Full-text
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
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Review

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Open AccessReview
Therapeutic Effectiveness of Anticancer Phytochemicals on Cancer Stem Cells
Received: 29 March 2016 / Revised: 17 June 2016 / Accepted: 23 June 2016 / Published: 30 June 2016
Cited by 16 | PDF Full-text (532 KB) | HTML Full-text | XML Full-text
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
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Open AccessReview
Roles of Dietary Phytoestrogens on the Regulation of Epithelial-Mesenchymal Transition in Diverse Cancer Metastasis
Received: 6 March 2016 / Revised: 18 May 2016 / Accepted: 19 May 2016 / Published: 24 May 2016
Cited by 22 | PDF Full-text (793 KB) | HTML Full-text | XML Full-text
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
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Open AccessFeature PaperReview
Ellagitannins in Cancer Chemoprevention and Therapy
Received: 31 March 2016 / Revised: 28 April 2016 / Accepted: 9 May 2016 / Published: 13 May 2016
Cited by 20 | PDF Full-text (1232 KB) | HTML Full-text | XML Full-text
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
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