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Natural Products for Cancer Chemoprevention

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Natural Products Chemistry".

Deadline for manuscript submissions: closed (30 September 2019) | Viewed by 79315

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Prof. Dr. Gary D. Stoner

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Guest Editor

Montana State University, MT, USA
Interests: cancer chemoprevention; chemical carcinogenesis; berries; isothiocyanates
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This issue focuses on the identification and use of selected naturally-occurring foodstuffs, and of compounds in these foods, for use in the prevention of cancer. The relative merits of using whole foods versus individual compounds within these foods for cancer prevention are discussed. Where available, the results are presented from both preclinical studies and clinical trials of these foodstuffs and their compounds. These results include toxicity assessments, pharmacokinetic studies of compound bioavailability, and mechanisms of inhibition of both the initiation and promotion/progression stages of cancer development. Future directions for the use of both whole foods and individual compounds for the more effective chemoprevention of specific cancer types are discussed.

Prof. Gary D. Stoner
Guest Editor

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Keywords

Cancer chemoprevention
Whole foods
Bioactive compounds
Toxicity
Pharmacokinetics
Cancer initiation and promotion/progression
Preclinical and clinical studies

Published Papers (11 papers)

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Research

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23 pages, 3808 KiB

Open AccessArticle

Activation of JNK and p38 in MCF-7 Cells and the In Vitro Anticancer Activity of Alnus hirsuta Extract

by Mina Ryu, Chung Ki Sung, Young Jun Im and ChangJu Chun

Molecules 2020, 25(5), 1073; https://doi.org/10.3390/molecules25051073 - 27 Feb 2020

Cited by 15 | Viewed by 3548

Abstract

JNK and p38 are important mitogen-activated protein kinases (MAPKs) that respond to stress stimuli. The stress-activated MAPKs associated with apoptotic cell death play vital roles in mammalian cells. Alnus hirsuta, which contains abundant diarylheptanoids derivatives, is a valuable medicinal plant. The CHCl₃ extract (AHC) containing platyphyllenone (1) and platyphyllone (3) as main compounds showed in vitro anticancer effects. We report the biological activities of A. hirsuta extract associated with the regulation of apoptosis and JNK and p38 in MCF-7 breast cancer cells. Levels of phospho-JNK and phospho-p38 by AHC treatment were evaluated by enzyme-linked immunosorbent assay (ELISA). ROS production, apoptotic effect, and DNA contents of the cells were measured by flow cytometry. The two diarylheptanoids 1 and 3 and the AHC extract exhibited cytotoxic effects on MCF-7 cells in MTT assay, with IC₅₀ values of 18.1, 46.9, 260.0 μg/mL, respectively. AHC induced ROS generation and elevated the endogenous levels of phospho-JNK and phospho-p38. AHC resulted in apoptosis and cell cycle arrest. We suggest that the antitumor effect of A. hirsuta extract is achieved by apoptosis promotion and cell cycle arrest mediated by the activation of JNK and p38 signaling pathway via ROS generation. Full article

(This article belongs to the Special Issue Natural Products for Cancer Chemoprevention)

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15 pages, 3286 KiB

Open AccessArticle

Quercetin Synergistically Inhibit EBV-Associated Gastric Carcinoma with Ganoderma lucidum Extracts

by Sora Huh, Seulki Lee, Su Jin Choi, Zhexue Wu, Jae-Han Cho, Lina Kim, Yu Su Shin, Byung Woog Kang, Jong Gwang Kim, Kwanghyeon Liu, Hyosun Cho and Hyojeung Kang

Molecules 2019, 24(21), 3834; https://doi.org/10.3390/molecules24213834 - 24 Oct 2019

Cited by 15 | Viewed by 4618

Abstract

Mycotherapy has been shown to improve the overall response rate during cancer treatment and reduce some chemotherapy-related adverse events. Ganoderma lucidum is a traditional mushroom used for pharmaceutical purposes. G. lucidum extracts (GLE) showed potential antitumor activities against several cancers. These tumor inhibitory effects of GLE were attributed to the suppression of the proliferation and metastasis of cancer cells. Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVaGC) is defined as the monoclonal proliferation of carcinoma cells with latent EBV infection. The inhibitory effects of GLE against EBVaGC are questionable. The aim of this study was to investigate GLE as potential antitumor agents and a counterpart of quercetin (QCT) for the cotreatment in suppressing EBVaGC development. Therefore, this study conducted antitumor assays using a EBVaGC xenograft mice model and found that GLE could suppress tumor development. These inhibitory effects were significantly augmented by the low concentration of the quercetin (QCT) cotreatment in the xenograft mice. The addition of GLE in low concentrations synergistically reinforced QCT-induced apoptosis and EBV lytic reactivation. GLE contains various polysaccharides and triterpenes, such as ganoderic acid. Interestingly, the addition of ganoderic acid A (GAA) could produce similar bioactive effects like GLE in QCT-mediated antitumor activity. The GAA addition in low concentrations synergistically reinforced QCT-induced apoptosis and EBV lytic reactivation. GAA was sufficiently effective as much as GLE. Therefore, our results suggested that QCT-supplemented GLE could be a potential food adjunct for the prevention of EBVaGC development. Full article

(This article belongs to the Special Issue Natural Products for Cancer Chemoprevention)

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13 pages, 13320 KiB

Open AccessArticle

In Vivo Anti-Tumor Effects of Citral on 4T1 Breast Cancer Cells via Induction of Apoptosis and Downregulation of Aldehyde Dehydrogenase Activity

by Siyamak Ebrahimi Nigjeh, Swee Keong Yeap, Norshariza Nordin, Heshu Rahman and Rozita Rosli

Molecules 2019, 24(18), 3241; https://doi.org/10.3390/molecules24183241 - 5 Sep 2019

Cited by 28 | Viewed by 5063

Abstract

Breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death among females globally. The tumorigenic activities of cancer cells such as aldehyde dehydrogenase (ALDH) activity and differentiation have contributed to relapse and eventual mortality in breast cancer. Thus, current drug discovery research is focused on targeting breast cancer cells with ALDH activity and their capacity to form secondary tumors. Citral (3,7-dimethyl-2,6-octadienal), from lemon grass (Cymbopogon citrates), has been previously reported to have a cytotoxic effect on breast cancer cells. Hence, this study was conducted to evaluate the in vivo effect of citral in targeting ALDH activity of breast cancer cells. BALB/c mice were challenged with 4T1 breast cancer cells followed by daily oral feeding of 50 mg/kg citral or distilled water for two weeks. The population of ALDH⁺ tumor cells and their capacity to form secondary tumors in both untreated and citral treated 4T1 challenged mice were assessed by Aldefluor assay and tumor growth upon cell reimplantation in normal mice, respectively. Citral treatment reduced the size and number of cells with ALDH⁺ activity of the tumors in 4T1-challenged BALB/c mice. Moreover, citral-treated mice were also observed with smaller tumor size and delayed tumorigenicity after reimplantation of the primary tumor cells into normal mice. These findings support the antitumor effect of citral in targeting ALDH⁺ cells and tumor recurrence in breast cancer cells. Full article

(This article belongs to the Special Issue Natural Products for Cancer Chemoprevention)

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14 pages, 3488 KiB

Open AccessArticle

Dendrobium officinale Polysaccharides Inhibit 1-Methyl-2-Nitro-1-Nitrosoguanidine Induced Precancerous Lesions of Gastric Cancer in Rats through Regulating Wnt/β-Catenin Pathway and Altering Serum Endogenous Metabolites

by Yi Zhao, Bingtao Li, Gaoyu Wang, Shuchao Ge, Ximing Lan, Guoliang Xu and Hongning Liu

Molecules 2019, 24(14), 2660; https://doi.org/10.3390/molecules24142660 - 23 Jul 2019

Cited by 37 | Viewed by 4147

Abstract

Dendrobium officinale is a herb in traditional Chinese medicine where D. officinale polysaccharides (DOP) are the main active ingredient. This study aimed at evaluating DOP efficiency at inhibiting 1-Methyl-2-nitro-1-nitrosoguanidine (MNNG) induced precancerous lesions of gastric cancer (PLGC) in rats through the Wnt/b-catenin pathway and analyzing the variations of serum endogenous metabolites. PLGC was established in male Sprague-Dawley (SD) rats by administering 150 μg/mL MNNG in drinking water for 7 months and giving 0.1 mL of 10% NaCl once weekly during the initial 20 weeks. Treatment with DOP inhibited the progress of PLGC through decreasing the expression of β-catenin by immunohistochemical analysis. The futher study indicated DOP downregulated gene expression of Wnt2β, Gsk3β, PCNA, CyclinD1, and β-catenin, as well as protein expression of Wnt2β, PCNA, and β-catenin. On the other hand, there were nine endogenous metabolites identified after the DOP treatment. Among these, the most significant one is betaine because of its strong antioxidant activity, leading to an anti-tumor effect. DOP can inhibit MNNG-induced PLGC models via regulating Wnt/β-catenin pathway and by changing endogenous metabolites. Full article

(This article belongs to the Special Issue Natural Products for Cancer Chemoprevention)

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12 pages, 1732 KiB

Open AccessArticle

Protective Effects of Defatted Sticky Rice Bran Extracts on the Early Stages of Hepatocarcinogenesis in Rats

by Aphisit Dokkaew, Charatda Punvittayagul, Orapin Insuan, Pornngarm Limtrakul (Dejkriengkraikul) and Rawiwan Wongpoomchai

Molecules 2019, 24(11), 2142; https://doi.org/10.3390/molecules24112142 - 6 Jun 2019

Cited by 22 | Viewed by 3145

Abstract

Use of natural products is one strategy to lessen cancer incidence. Rice bran, especially from colored rice, contains high antioxidant activity. Cancer chemopreventive effects of hydrophilic purple rice bran extract (PRBE) and white rice bran extract (WRBE) on carcinogen-induced preneoplastic lesion formation in livers of rats were investigated. A 15-week administration of PRBE and WRBE did not induce hepatic glutathione S-transferase placental form (GST-P) positive foci formation as the biomarker of rat hepatocarcinogenesis. PRBE and WRBE at 500 mg/kg body weight significantly decreased number and size of GST-P positive foci in diethylnitrosamine (DEN)-initiated rats. The number of proliferating nuclear antigen positive hepatocytes were also reduced in preneoplastic lesions in both PRBE and WRBE fed DEN-treated rats. Notably, the inhibitory effect on GST-P positive foci formation induced by DEN during the initiation stage was found only in rats treated by PRBE for five weeks. Furthermore, PRBE attenuated the expression of proinflammatory cytokines involving genes including TNF-α, iNOS, and NF-κB. PBRE contained a higher number of anthocyanins and other phenolic compounds and vitamin E. PRBE might protect DEN-induced hepatocarcinogenesis in rats via attenuation of cellular inflammation and cell proliferation. Anthocyanins and other phenolic compounds, as well as vitamin E, might play a role in cancer chemopreventive activity in rice bran extract. Full article

(This article belongs to the Special Issue Natural Products for Cancer Chemoprevention)

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16 pages, 5040 KiB

Open AccessArticle

Imaging Flow Cytometric Analysis of Stilbene-Dependent Apoptosis in Drug Resistant Human Leukemic Cell Lines

by Marcin Czop, Anna Bogucka-Kocka, Tomasz Kubrak, Karolina Knap-Czop, Anna Makuch-Kocka, Dariusz Galkowski, Joanna Wawer, Tomasz Kocki and Janusz Kocki

Molecules 2019, 24(10), 1896; https://doi.org/10.3390/molecules24101896 - 17 May 2019

Cited by 16 | Viewed by 3575

Abstract

Background: The natural compounds have been researched extensively as an alternative to the conventional chemotherapy and radiation. Stilbene derivatives appear as a group of therapeutics which deserves special attention. The present study was designed to analyze the effects of stilbene derivatives on drug resistant human leukemic cells. The aim of this work was to evaluate the apoptotic effect of stilbene derivatives in various concentrations on leukemic cells (LC) with and without resistant phenotype. Methods: Human acute promyelocytic leukemia (APL) cell lines (HL60, HL60/MX1, HL60/MX2) and acute lymphoblastic leukemia (ALL) cell lines (CEM/C1, CCRF-CEM) were studied. T-resveratrol, piceatannol, rhaponticin, deoxyrhaponticin, pterostilbene were used to stimulate apoptosis. Mitoxantrone (MIT) was applied to induce drug resistance. Results: t-Resveratrol (RES), deoxyrhaponticin (D-RHAP), rhaponticin (RHAP), pterostilbene (PTER), and piceatannol (PIC) influenced viability and induced apoptosis in all investigated cell lines. Conclusions: Our results confirmed that RES, PIC, RHAP, D-RHAP, and PTER are essential therapeutic compounds with anticancer activity exhibited by induction of apoptosis in leukemic cells with and without resistant phenotype. Stilbene-induced apoptosis in HL60/MX1, HL60/MX2, CEM/C1, and CCRF-CEM leukemia cell lines have been presented in very few studies so far and our research is an important contribution to the investigation of these substances. Full article

(This article belongs to the Special Issue Natural Products for Cancer Chemoprevention)

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17 pages, 2447 KiB

Open AccessArticle

Adlay (Coix lachryma-jobi L. var. ma-yuen Stapf.) Hull Extract and Active Compounds Inhibit Proliferation of Primary Human Leiomyoma Cells and Protect against Sexual Hormone-Induced Mice Smooth Muscle Hyperproliferation

by Po-Han Lin, Chun-Kuang Shih, Yu-Ting Yen, Wenchang Chiang and Shih-Min Hsia

Molecules 2019, 24(8), 1556; https://doi.org/10.3390/molecules24081556 - 19 Apr 2019

Cited by 18 | Viewed by 4443

Abstract

Uterine leiomyomas, also known as fibroids, are benign neoplasms of the uterus and have a high incidence rate in women of reproductive age. Hysterectomy or myomectomy is the initial treatment, but fibroids will recur if the patient is still exposed to similar risk factors. Therefore, developing new therapeutic strategies are urgently necessary. In this study, the anti-proliferation effects of each fraction of adlay seeds were evaluated in uterine leiomyomas, and we identified the potential phytochemical compounds. We found that the ethyl acetate fraction of adlay hull (AHE-ea) appeared to be highly efficient in the anti-proliferation of rat uterine leiomyoma ELT3 cells and primary human uterine leiomyoma (hUL) cells. The proliferation of primary human normal uterine smooth muscle (UtSMC) and normal uterine myometrial (hUM) cells were also suppressed by AHE-ea. Two phytosterols, stigmasterol and β-sitosterol, were identified from AHE-ea fraction. Mice treated with AHE-ea and stigmasterol alone demonstrated reduced diethylstilbestrol/medroxyprogesterone 17-acetate (DES/MPA)-induced uterine myometrial hyperplasia, which is the critical step for the development of leiomyoma. Taken together, our results suggest that the AHE-ea fraction could be considered as a natural plant-based medicine in the prevention or treatment of uterine leiomyoma growth. Full article

(This article belongs to the Special Issue Natural Products for Cancer Chemoprevention)

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Review

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38 pages, 3091 KiB

Open AccessReview

Broccoli or Sulforaphane: Is It the Source or Dose That Matters?

by Yoko Yagishita, Jed W. Fahey, Albena T. Dinkova-Kostova and Thomas W. Kensler

Molecules 2019, 24(19), 3593; https://doi.org/10.3390/molecules24193593 - 6 Oct 2019

Cited by 195 | Viewed by 31260

Abstract

There is robust epidemiological evidence for the beneficial effects of broccoli consumption on health, many of them clearly mediated by the isothiocyanate sulforaphane. Present in the plant as its precursor, glucoraphanin, sulforaphane is formed through the actions of myrosinase, a β-thioglucosidase present in either the plant tissue or the mammalian microbiome. Since first isolated from broccoli and demonstrated to have cancer chemoprotective properties in rats in the early 1990s, over 3000 publications have described its efficacy in rodent disease models, underlying mechanisms of action or, to date, over 50 clinical trials examining pharmacokinetics, pharmacodynamics and disease mitigation. This review evaluates the current state of knowledge regarding the relationships between formulation (e.g., plants, sprouts, beverages, supplements), bioavailability and efficacy, and the doses of glucoraphanin and/or sulforaphane that have been used in pre-clinical and clinical studies. We pay special attention to the challenges for better integration of animal model and clinical studies, particularly with regard to selection of dose and route of administration. More effort is required to elucidate underlying mechanisms of action and to develop and validate biomarkers of pharmacodynamic action in humans. A sobering lesson is that changes in approach will be required to implement a public health paradigm for dispensing benefit across all spectrums of the global population. Full article

(This article belongs to the Special Issue Natural Products for Cancer Chemoprevention)

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27 pages, 729 KiB

Open AccessReview

Gingers and Their Purified Components as Cancer Chemopreventative Agents

by John F. Lechner and Gary D. Stoner

Molecules 2019, 24(16), 2859; https://doi.org/10.3390/molecules24162859 - 7 Aug 2019

Cited by 31 | Viewed by 6375

Abstract

Chemoprevention by ingested substituents is the process through which nutraceuticals and/or their bioactive components antagonize carcinogenesis. Carcinogenesis is the course of action whereby a normal cell is transformed into a neoplastic cell. This latter action involves several steps, starting with initiation and followed by promotion and progression. Driving these stages is continued oxidative stress and inflammation, which in turn, causes a myriad of aberrant gene expressions and mutations within the transforming cell population and abnormal gene expressions by the cells within the surrounding lesion. Chemoprevention of cancer with bioreactive foods or their extracted/purified components occurs primarily via normalizing these inappropriate gene activities. Various foods/agents have been shown to affect different gene expressions. In this review, we discuss how the chemoprevention activities of gingers antagonize cancer development. Full article

(This article belongs to the Special Issue Natural Products for Cancer Chemoprevention)

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12 pages, 477 KiB

Open AccessFeature PaperReview

Red Beetroot and Betalains as Cancer Chemopreventative Agents

by John F. Lechner and Gary D. Stoner

Molecules 2019, 24(8), 1602; https://doi.org/10.3390/molecules24081602 - 23 Apr 2019

Cited by 70 | Viewed by 8353

Abstract

Carcinogenesis is the process whereby a normal cell is transformed into a neoplastic cell. This action involves several steps starting with initiation and followed by promotion and progression. Driving these stages are oxidative stress and inflammation, which in turn encompasses a myriad of aberrant gene expressions, both within the transforming cell population and the cells within the surrounding lesion. Chemoprevention of cancer with bioreactive foods or their extracted/purified components occurs via normalizing these inappropriate gene activities. Various foods/agents have been shown to affect different gene expressions. In this review, we discuss whereby the chemoprevention activities of the red beetroot itself may disrupt carcinogenesis and the activities of the water-soluble betalains extracted from the plant. Full article

(This article belongs to the Special Issue Natural Products for Cancer Chemoprevention)

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17 pages, 583 KiB

Open AccessReview

Free Accessible Databases as a Source of Information about Food Components and Other Compounds with Anticancer Activity–Brief Review

by Piotr Minkiewicz, Marta Turło, Anna Iwaniak and Małgorzata Darewicz

Molecules 2019, 24(4), 789; https://doi.org/10.3390/molecules24040789 - 22 Feb 2019

Cited by 6 | Viewed by 4016

Abstract

Diet is considered to be a significant factor in cancer prevention and therapy. Many food components reveal anticancer activity. The increasing number of experiments concerning the anticancer potential of chemical compounds, including food components, is a challenge for data searching. Specialized databases provide an opportunity to overcome this problem. Data concerning the anticancer activity of chemical compounds may be found in general databases of chemical compounds and databases of drugs, including specialized resources concerning anticancer compounds, databases of food components, and databases of individual groups of compounds, such as polyphenols or peptides. This brief review summarizes the state of knowledge of chemical databases containing information concerning natural anticancer compounds (e.g., from food). Additionally, the information about text- and structure-based search options and links between particular internet resources is provided in this paper. Examples of the application of databases in food and nutrition sciences are also presented with special attention to compounds that are interesting from the point of view of dietary cancer prevention. Simple examples of potential database search possibilities are also discussed. Full article

(This article belongs to the Special Issue Natural Products for Cancer Chemoprevention)

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