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Ligor M, Szultka-Młyńska M, Rafińska K, Cwudzińska A. Comparative Studies of Extracts Obtained from Brassica oleracea L. Plants at Different Stages of Growth by Isolation and Determination of Isothiocyanates: An Assessment of Chemopreventive Properties of Broccoli. Molecules 2024; 29:519. [PMID: 38276596 PMCID: PMC11154519 DOI: 10.3390/molecules29020519] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 01/10/2024] [Accepted: 01/17/2024] [Indexed: 01/27/2024] Open
Abstract
The main goal of this work was to develop analytical procedures for the isolation and determination of selected isothiocyanates. As an example, particularly sulforaphane from plants of the Brassicaceae Burnett or Cruciferae Juss family. The applied methodology was mainly based on classical extraction methods and high-performance liquid chromatography coupled with tandem mass spectrometry. Moreover, the effect of temperature on the release of isothiocyanates from plant cells was considered. The cytotoxic activity of the obtained plant extracts against a selected cancer cell line has also been included. The results allow evaluating the usefulness of obtained plant extracts and raw sprouts regarding their content of isothiocyanates-bioactive compounds with chemopreventive properties.
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Affiliation(s)
- Magdalena Ligor
- Chair of Environmental Chemistry and Bioanalytics, Faculty of Chemistry, Nicolaus Copernicus University, 7 Gagarina Street, 87-100 Toruń, Poland; (M.S.-M.); (K.R.); (A.C.)
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Lekhak N, Bhattarai HK. Phytochemicals in Cancer Chemoprevention: Preclinical and Clinical Studies. Cancer Control 2024; 31:10732748241302902. [PMID: 39629692 PMCID: PMC11615997 DOI: 10.1177/10732748241302902] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Revised: 10/11/2024] [Accepted: 11/11/2024] [Indexed: 12/08/2024] Open
Abstract
Phytochemicals, chemicals from plants, have garnered huge attention for their potential ability to prevent cancer. In vivo and preclinical models show that they do so often by affecting the hallmarks of cancer. Phytochemicals affect key pathways involved in the survival, genome maintenance, proliferation, senescence, and transendothelial migration of cancer cells. Some phytochemicals, namely antioxidants, can scavenge and quench reactive oxygen species (ROS) to prevent lipid peroxidation and DNA damage. They also trigger apoptosis by stopping the cell cycle at checkpoints to initiate the DNA damage response. Numerous in vitro and in vivo studies suggest that phytochemicals hinder cancer onset and progression by modifying major cell signaling pathways such as JAK/STAT, PI3K/Akt, Wnt, NF-kB, TGF-β, and MAPK. It is a well-known fact that the occurrence of cancer is in itself a very intricate process involving multiple mechanisms concurrently. Cancer prevention using phytochemicals is also an equally complex process that requires investigation and understanding of a myriad of processes going on in the cells and tissues. While many in vitro and preclinical studies have established that phytochemicals may be potential chemopreventive agents of cancer, their role in clinical randomized control trials needs to be established. This paper aims to shed light on the dynamics of chemoprevention using phytochemicals.
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Affiliation(s)
- Nitish Lekhak
- Department of Biotechnology, Kathmandu University, Dhulikhel, Nepal
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Bozic D, Živančević K, Baralić K, Miljaković EA, Djordjević AB, Ćurčić M, Bulat Z, Antonijević B, Đukić-Ćosić D. Conducting bioinformatics analysis to predict sulforaphane-triggered adverse outcome pathways in healthy human cells. Biomed Pharmacother 2023; 160:114316. [PMID: 36731342 DOI: 10.1016/j.biopha.2023.114316] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 01/17/2023] [Accepted: 01/26/2023] [Indexed: 02/04/2023] Open
Abstract
Sulforaphane (SFN) is a naturally occurring molecule present in plants from Brassica family. It becomes bioactive after hydrolytic reaction mediated by myrosinase or human gastrointestinal microbiota. Sulforaphane gained scientific popularity due to its antioxidant and anti-cancer properties. However, its toxicity profile and potential to cause adverse effects remain largely unidentified. Thus, this study aimed to generate SFN-triggered adverse outcome pathway (AOP) by looking at the relationship between SFN-chemical structure and its toxicity, as well as SFN-gene interactions. Quantitative structure-activity relationship (QSAR) analysis identified 2 toxophores (Derek Nexus software) that have the potential to cause chromosomal damage and skin sensitization in mammals or mutagenicity in bacteria. Data extracted from Comparative Toxicogenomics Database (CTD) linked SFN with previously proposed outcomes via gene interactions. The total of 11 and 146 genes connected SFN with chromosomal damage and skin diseases, respectively. However, network analysis (NetworkAnalyst tool) revealed that these genes function in wider networks containing 490 and 1986 nodes, respectively. The over-representation analysis (ExpressAnalyst tool) pointed out crucial biological pathways regulated by SFN-interfering genes. These pathways are uploaded to AOP-helpFinder tool which found the 2321 connections between 19 enriched pathways and SFN which were further considered as key events. Two major, interconnected AOPs were generated: first starting from disruption of biological pathways involved in cell cycle and cell proliferation leading to increased apoptosis, and the second one connecting activated immune system signaling pathways to inflammation and apoptosis. In both cases, chromosomal damage and/or skin diseases such as dermatitis or psoriasis appear as adverse outcomes.
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Affiliation(s)
- Dragica Bozic
- Department of Toxicology "Akademik Danilo Soldatović", Toxicological Risk Assessment Center, University of Belgrade - Faculty of Pharmacy, Vojvode Stepe 450, 11221 Belgrade, Serbia.
| | - Katarina Živančević
- Department of Toxicology "Akademik Danilo Soldatović", Toxicological Risk Assessment Center, University of Belgrade - Faculty of Pharmacy, Vojvode Stepe 450, 11221 Belgrade, Serbia; University of Belgrade - Faculty of Biology, Institute of Physiology and Biochemistry "Ivan Djaja", Center for Laser Microscopy, Studentski trg 16, 11158 Belgrade, Serbia
| | - Katarina Baralić
- Department of Toxicology "Akademik Danilo Soldatović", Toxicological Risk Assessment Center, University of Belgrade - Faculty of Pharmacy, Vojvode Stepe 450, 11221 Belgrade, Serbia
| | - Evica Antonijević Miljaković
- Department of Toxicology "Akademik Danilo Soldatović", Toxicological Risk Assessment Center, University of Belgrade - Faculty of Pharmacy, Vojvode Stepe 450, 11221 Belgrade, Serbia
| | - Aleksandra Buha Djordjević
- Department of Toxicology "Akademik Danilo Soldatović", Toxicological Risk Assessment Center, University of Belgrade - Faculty of Pharmacy, Vojvode Stepe 450, 11221 Belgrade, Serbia
| | - Marijana Ćurčić
- Department of Toxicology "Akademik Danilo Soldatović", Toxicological Risk Assessment Center, University of Belgrade - Faculty of Pharmacy, Vojvode Stepe 450, 11221 Belgrade, Serbia
| | - Zorica Bulat
- Department of Toxicology "Akademik Danilo Soldatović", Toxicological Risk Assessment Center, University of Belgrade - Faculty of Pharmacy, Vojvode Stepe 450, 11221 Belgrade, Serbia
| | - Biljana Antonijević
- Department of Toxicology "Akademik Danilo Soldatović", Toxicological Risk Assessment Center, University of Belgrade - Faculty of Pharmacy, Vojvode Stepe 450, 11221 Belgrade, Serbia
| | - Danijela Đukić-Ćosić
- Department of Toxicology "Akademik Danilo Soldatović", Toxicological Risk Assessment Center, University of Belgrade - Faculty of Pharmacy, Vojvode Stepe 450, 11221 Belgrade, Serbia
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Molecular Pathways Related to Sulforaphane as Adjuvant Treatment: A Nanomedicine Perspective in Breast Cancer. MEDICINA (KAUNAS, LITHUANIA) 2022; 58:medicina58101377. [PMID: 36295538 PMCID: PMC9610969 DOI: 10.3390/medicina58101377] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 09/23/2022] [Accepted: 09/28/2022] [Indexed: 11/06/2022]
Abstract
Because cancer is a multifactorial disease, it is difficult to identify the specific agents responsible for the disease's progression and development, but lifestyle and diet have been shown to play a significant role. Diverse natural compounds are demonstrating efficacy in the development of novel cancer therapies, including sulforaphane (1-isothiocyanate-4-(methylsulfinyl)butane), a compound found in broccoli and other cruciferous vegetables that promotes key biological processes such as apoptosis, cell cycle arrest, autophagy, and suppression of key signalling pathways such as the PI3K/AKT/mTOR pathway in breast cancer cells. However, one of the primary challenges with sulforaphane treatment is its low solubility in water and oral bioavailability. As a consequence, several investigations were conducted using this component complexed in nanoparticles, which resulted in superior outcomes when combined with chemotherapy drugs. In this study, we discuss the properties and benefits of sulforaphane in cancer therapy, as well as its ability to form complexes with nanomolecules and chemotherapeutic agents that synergize the antitumour response in breast cancer cells.
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Mitra S, Emran TB, Chandran D, Zidan BMRM, Das R, Mamada SS, Masyita A, Salampe M, Nainu F, Khandaker MU, Idris AM, Simal-Gandara J. Cruciferous vegetables as a treasure of functional foods bioactive compounds: Targeting p53 family in gastrointestinal tract and associated cancers. Front Nutr 2022; 9:951935. [PMID: 35990357 PMCID: PMC9386315 DOI: 10.3389/fnut.2022.951935] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Accepted: 07/12/2022] [Indexed: 11/23/2022] Open
Abstract
In the past few years, phytochemicals from natural products have gotten the boundless praise in treating cancer. The promising role of cruciferous vegetables and active components contained in these vegetables, such as isothiocyanates, indole-3-carbinol, and isothiocyanates, has been widely researched in experimental in vitro and in vivo carcinogenesis models. The chemopreventive agents produced from the cruciferous vegetables were recurrently proven to affect carcinogenesis throughout the onset and developmental phases of cancer formation. Likewise, findings from clinical investigations and epidemiological research supported this statement. The anticancer activities of these functional foods bioactive compounds are closely related to their ability to upregulate p53 and its related target genes, e.g., p21. As the "guardian of the genome," the p53 family (p53, p63, and p73) plays a pivotal role in preventing the cancer progression associated with DNA damage. This review discusses the functional foods bioactive compounds derived from several cruciferous vegetables and their use in altering the tumor-suppressive effect of p53 proteins. The association between the mutation of p53 and the incidence of gastrointestinal malignancies (gastric, small intestine, colon, liver, and pancreatic cancers) is also discussed. This review contains crucial information about the use of cruciferous vegetables in the treatment of gastrointestinal tract malignancies.
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Affiliation(s)
- Saikat Mitra
- Department of Pharmacy, Faculty of Pharmacy, University of Dhaka, Dhaka, Bangladesh
| | - Talha Bin Emran
- Department of Pharmacy, BGC Trust University Bangladesh, Chittagong, Bangladesh
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka, Bangladesh
| | - Deepak Chandran
- Department of Veterinary Sciences and Animal Husbandry, Amrita School of Agricultural Sciences, Amrita Vishwa Vidyapeetham University, Coimbatore, Tamil Nadu, India
| | | | - Rajib Das
- Department of Pharmacy, Faculty of Pharmacy, University of Dhaka, Dhaka, Bangladesh
| | | | - Ayu Masyita
- Faculty of Pharmacy, Hasanuddin University, Makassar, Indonesia
| | | | - Firzan Nainu
- Faculty of Pharmacy, Hasanuddin University, Makassar, Indonesia
| | - Mayeen Uddin Khandaker
- Centre for Applied Physics and Radiation Technologies, School of Engineering and Technology, Sunway University, Subang Jaya, Selangor, Malaysia
| | - Abubakr M. Idris
- Department of Chemistry, College of Science, King Khalid University, Abha, Saudi Arabia
- Research Center for Advanced Materials Science (RCAMS), King Khalid University, Abha, Saudi Arabia
| | - Jesus Simal-Gandara
- Nutrition and Bromatology Group, Department of Analytical Chemistry and Food Science, Faculty of Science, Universidade de Vigo, Ourense, Spain
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Targeting Drug Chemo-Resistance in Cancer Using Natural Products. Biomedicines 2021; 9:biomedicines9101353. [PMID: 34680470 PMCID: PMC8533186 DOI: 10.3390/biomedicines9101353] [Citation(s) in RCA: 73] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2021] [Revised: 09/22/2021] [Accepted: 09/23/2021] [Indexed: 02/07/2023] Open
Abstract
Cancer is one of the leading causes of death globally. The development of drug resistance is the main contributor to cancer-related mortality. Cancer cells exploit multiple mechanisms to reduce the therapeutic effects of anticancer drugs, thereby causing chemotherapy failure. Natural products are accessible, inexpensive, and less toxic sources of chemotherapeutic agents. Additionally, they have multiple mechanisms of action to inhibit various targets involved in the development of drug resistance. In this review, we have summarized the basic research and clinical applications of natural products as possible inhibitors for drug resistance in cancer. The molecular targets and the mechanisms of action of each natural product are also explained. Diverse drug resistance biomarkers were sensitive to natural products. P-glycoprotein and breast cancer resistance protein can be targeted by a large number of natural products. On the other hand, protein kinase C and topoisomerases were less sensitive to most of the studied natural products. The studies discussed in this review will provide a solid ground for scientists to explore the possible use of natural products in combination anticancer therapies to overcome drug resistance by targeting multiple drug resistance mechanisms.
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Sulforaphane: A Broccoli Bioactive Phytocompound with Cancer Preventive Potential. Cancers (Basel) 2021; 13:cancers13194796. [PMID: 34638282 PMCID: PMC8508555 DOI: 10.3390/cancers13194796] [Citation(s) in RCA: 80] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Revised: 09/18/2021] [Accepted: 09/22/2021] [Indexed: 12/15/2022] Open
Abstract
Simple Summary As of the past decade, phytochemicals have become a major target of interest in cancer chemopreventive and chemotherapeutic research. Sulforaphane (SFN) is a metabolite of the phytochemical glucoraphanin, which is found in high abundance in cruciferous vegetables, such as broccoli, watercress, Brussels sprouts, and cabbage. In both distant and recent research, SFN has been shown to have a multitude of anticancer effects, increasing the need for a comprehensive review of the literature. In this review, we critically evaluate SFN as an anticancer agent and its mechanisms of action based on an impressive number of in vitro, in vivo, and clinical studies. Abstract There is substantial and promising evidence on the health benefits of consuming broccoli and other cruciferous vegetables. The most important compound in broccoli, glucoraphanin, is metabolized to SFN by the thioglucosidase enzyme myrosinase. SFN is the major mediator of the health benefits that have been recognized for broccoli consumption. SFN represents a phytochemical of high interest as it may be useful in preventing the occurrence and/or mitigating the progression of cancer. Although several prior publications provide an excellent overview of the effect of SFN in cancer, these reports represent narrative reviews that focused mainly on SFN’s source, biosynthesis, and mechanisms of action in modulating specific pathways involved in cancer without a comprehensive review of SFN’s role or value for prevention of various human malignancies. This review evaluates the most recent state of knowledge concerning SFN’s efficacy in preventing or reversing a variety of neoplasms. In this work, we have analyzed published reports based on in vitro, in vivo, and clinical studies to determine SFN’s potential as a chemopreventive agent. Furthermore, we have discussed the current limitations and challenges associated with SFN research and suggested future research directions before broccoli-derived products, especially SFN, can be used for human cancer prevention and intervention.
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Improvement of glucosinolates by metabolic engineering in Brassica crops. ABIOTECH 2021; 2:314-329. [PMID: 36303883 PMCID: PMC9590530 DOI: 10.1007/s42994-021-00057-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Accepted: 07/07/2021] [Indexed: 02/08/2023]
Abstract
Glucosinolates (GSLs) are a class of sulfur- and nitrogen-containing, and amino acid-derived important secondary metabolites, which mainly present in plants of Brassicaceae family, including Brassica crops, such as broccoli, cabbage, and oilseed rape. The bioactive GSL metabolites confer benefits to plant defense, human health, and the unique flavor of some Brassica crops. However, certain GSL profiles have adverse effects and are known as anti-nutritional factors. This has attracted mounting attempts to increase beneficial GSLs and reduce detrimental ones in the most commonly consumed Brassica crops. We provide a comprehensive overview of metabolic engineering applied in Brassica crops to achieve this purpose, including modulation of GSL biosynthesis, ablation of GSL hydrolysis, inhibition of GSL transport processes, and redirection of metabolic flux to GSL. Moreover, advances in omics approaches, i.e., genomics, transcriptome, and metabolome, applied in the elucidation of GSL metabolism in Brassica crops, as well as promising and potential genome-editing technologies are also discussed.
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Kumar R, Harilal S, Carradori S, Mathew B. A Comprehensive Overview of Colon Cancer- A Grim Reaper of the 21st Century. Curr Med Chem 2021; 28:2657-2696. [PMID: 33106132 DOI: 10.2174/0929867327666201026143757] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Revised: 09/18/2020] [Accepted: 09/18/2020] [Indexed: 12/09/2022]
Abstract
A few decades ago, the incidence of colorectal cancer (CRC) was low and is now the fourth in the list of deadly cancers producing nearly a million deaths annually. A population that is aging along with risk factors such as smoking, obesity, sedentary lifestyle with little or no physical activity, and non-healthy food habits of developed countries can increase the risk of colorectal cancer. The balance in gut microbiota and the metabolites produced during bacterial fermentation within the host plays a significant role in regulating intestinal diseases as well as colorectal cancer development. Recent progress in the understanding of illness resulted in multiple treatment options such as surgery, radiation, and chemotherapy, including targeted therapy and multitherapies. The treatment plan for CRC depends on the location, stage and grade of cancer as well as genomic biomarker tests. Despite all the advancements made in the genetic and molecular aspects of the disease, the knowledge seems inadequate as the drug action as well as the wide variation in drug response did not appear strongly correlated with the individual molecular and genetic characteristics, which suggests the requirement of comprehensive molecular understanding of this complex heterogeneous disease. Furthermore, multitherapies or a broad spectrum approach, which is an amalgamation of the various promising as well as effective therapeutic strategies that can tackle heterogeneity and act on several targets of the disease, need to be validated in clinical studies. The latest treatment options have significantly increased the survival of up to three years in the case of advanced disease. The fact that colorectal cancer is developed from a polypoid precursor, as well as the symptoms of the disease that occur at an advanced stage, underlines how screening programs can help early detection and decrease mortality as well as morbidity from CRC.
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Affiliation(s)
- Rajesh Kumar
- Department of Pharmacy, Kerala University of Health Sciences, Thrissur, Kerala, India
| | - Seetha Harilal
- Department of Pharmacy, Kerala University of Health Sciences, Thrissur, Kerala, India
| | - Simone Carradori
- Department of Pharmacy, "G. d'Annunzio" University of Chieti-Pescara, via dei Vestini 31, 66100 Chieti, Italy
| | - Bijo Mathew
- Department of Pharmaceutical Chemistry, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Sciences Campus, Kochi-682 041, India
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Elkashty OA, Tran SD. Sulforaphane as a Promising Natural Molecule for Cancer Prevention and Treatment. Curr Med Sci 2021; 41:250-269. [PMID: 33877541 DOI: 10.1007/s11596-021-2341-2] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2019] [Accepted: 04/24/2020] [Indexed: 12/13/2022]
Abstract
Tumorigenicity-inhibiting compounds have been identified in our daily diet. For example, isothiocyanates (ITCs) found in cruciferous vegetables were reported to have potent cancer-prevention activities. The best characterized ITC is sulforaphane (SF). SF can simultaneously modulate multiple cellular targets involved in carcinogenesis, including (1) modulating carcinogen-metabolizing enzymes and blocking the action of mutagens; (2) inhibition of cell proliferation and induction of apoptosis; and (3) inhibition of neo-angiogenesis and metastasis. SF targets cancer stem cells through modulation of nuclear factor kappa B (NF-κB), Sonic hedgehog (SHH), epithelial-mesenchymal transition, and Wnt/β-catenin pathways. Conventional chemotherapy/SF combination was tested in several studies and resulted in favorable outcomes. With its favorable toxicological profile, SF is a promising agent in cancer prevention and/or therapy. In this article, we discuss the human metabolism of SF and its effects on cancer prevention, treatment, and targeting cancer stem cells, as well as providing a brief review of recent human clinical trials on SF.
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Affiliation(s)
- Osama A Elkashty
- McGill Craniofacial Tissue Engineering and Stem Cells Laboratory, Faculty of Dentistry, McGill University, Montreal, H3A 0G4, Canada.,Department of Oral Pathology, Faculty of Dentistry, Mansoura University, Mansoura, 35516, Egypt
| | - Simon D Tran
- McGill Craniofacial Tissue Engineering and Stem Cells Laboratory, Faculty of Dentistry, McGill University, Montreal, H3A 0G4, Canada.
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Mancilla VJ, Peeri NC, Silzer T, Basha R, Felini M, Jones HP, Phillips N, Tao MH, Thyagarajan S, Vishwanatha JK. Understanding the Interplay Between Health Disparities and Epigenomics. Front Genet 2020; 11:903. [PMID: 32973872 PMCID: PMC7468461 DOI: 10.3389/fgene.2020.00903] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Accepted: 07/21/2020] [Indexed: 12/13/2022] Open
Abstract
Social epigenomics has emerged as an integrative field of research focused on identification of socio-environmental factors, their influence on human biology through epigenomic modifications, and how they contribute to current health disparities. Several health disparities studies have been published using genetic-based approaches; however, increasing accessibility and affordability of molecular technologies have allowed for an in-depth investigation of the influence of external factors on epigenetic modifications (e.g., DNA methylation, micro-RNA expression). Currently, research is focused on epigenetic changes in response to environment, as well as targeted epigenetic therapies and environmental/social strategies for potentially minimizing certain health disparities. Here, we will review recent findings in this field pertaining to conditions and diseases over life span encompassing prenatal to adult stages.
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Affiliation(s)
- Viviana J. Mancilla
- Department of Microbiology, Immunology and Genetics, Graduate School of Biomedical Sciences, University of North Texas Health Science Center, Fort Worth, TX, United States
| | - Noah C. Peeri
- Department of Biostatistics and Epidemiology, School of Public Health, University of North Texas Health Science Center, Fort Worth, TX, United States
| | - Talisa Silzer
- Department of Microbiology, Immunology and Genetics, Graduate School of Biomedical Sciences, University of North Texas Health Science Center, Fort Worth, TX, United States
| | - Riyaz Basha
- Department of Pediatrics, Texas College of Osteopathic Medicine, University of North Texas Health Science Center, Fort Worth, TX, United States
- Texas Center for Health Disparities, University of North Texas Health Science Center, Fort Worth, TX, United States
| | - Martha Felini
- Department of Pediatrics, Texas College of Osteopathic Medicine, University of North Texas Health Science Center, Fort Worth, TX, United States
- Texas Center for Health Disparities, University of North Texas Health Science Center, Fort Worth, TX, United States
| | - Harlan P. Jones
- Department of Microbiology, Immunology and Genetics, Graduate School of Biomedical Sciences, University of North Texas Health Science Center, Fort Worth, TX, United States
- Texas Center for Health Disparities, University of North Texas Health Science Center, Fort Worth, TX, United States
| | - Nicole Phillips
- Department of Microbiology, Immunology and Genetics, Graduate School of Biomedical Sciences, University of North Texas Health Science Center, Fort Worth, TX, United States
- Texas Center for Health Disparities, University of North Texas Health Science Center, Fort Worth, TX, United States
| | - Meng-Hua Tao
- Department of Biostatistics and Epidemiology, School of Public Health, University of North Texas Health Science Center, Fort Worth, TX, United States
- Texas Center for Health Disparities, University of North Texas Health Science Center, Fort Worth, TX, United States
| | - Srikantha Thyagarajan
- Department of Microbiology, Immunology and Genetics, Graduate School of Biomedical Sciences, University of North Texas Health Science Center, Fort Worth, TX, United States
- Texas Center for Health Disparities, University of North Texas Health Science Center, Fort Worth, TX, United States
| | - Jamboor K. Vishwanatha
- Department of Microbiology, Immunology and Genetics, Graduate School of Biomedical Sciences, University of North Texas Health Science Center, Fort Worth, TX, United States
- Texas Center for Health Disparities, University of North Texas Health Science Center, Fort Worth, TX, United States
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Sulforaphane-enriched extracts from glucoraphanin-rich broccoli exert antimicrobial activity against gut pathogens in vitro and innovative cooking methods increase in vivo intestinal delivery of sulforaphane. Eur J Nutr 2020; 60:1263-1276. [PMID: 32651764 PMCID: PMC7987625 DOI: 10.1007/s00394-020-02322-0] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Accepted: 07/01/2020] [Indexed: 12/19/2022]
Abstract
Purpose Studies on broccoli (Brassica oleracea var. italica) indicate beneficial effects against a range of chronic diseases, commonly attributed to their bioactive phytochemicals. Sulforaphane, the bioactive form of glucoraphanin, is formed by the action of the indigenous enzyme myrosinase. This study explored the role that digestion and cooking practices play in bioactivity and bioavailability, especially the rarely considered dose delivered to the colon. Methods The antimicrobial activity of sulforaphane extracts from raw, cooked broccoli and cooked broccoli plus mustard seeds (as a source myrosinase) was assessed. The persistence of broccoli phytochemicals in the upper gastrointestinal tract was analysed in the ileal fluid of 11 ileostomates fed, in a cross-over design, broccoli soup prepared with and without mustard seeds. Results The raw broccoli had no antimicrobial activity, except against Bacillus cereus, but cooked broccoli (with and without mustard seeds) showed considerable antimicrobial activity against various tested pathogens. The recovery of sulforaphane in ileal fluids post soup consumption was < 1% but the addition of mustard seeds increased colon-available sulforaphane sixfold. However, when sulforaphane was extracted from the ileal fluid with the highest sulforaphane content and tested against Escherichia coli K12, no inhibitory effects were observed. Analysis of glucosinolates composition in ileal fluids revealed noticeable inter-individual differences, with six “responding” participants showing increases in glucosinolates after broccoli soup consumption. Conclusions Sulforaphane-rich broccoli extracts caused potent antimicrobial effects in vitro, and the consumption of sulforaphane-enriched broccoli soup may inhibit bacterial growth in the stomach and upper small intestine, but not in the terminal ileum or the colon. Electronic supplementary material The online version of this article (10.1007/s00394-020-02322-0) contains supplementary material, which is available to authorized users.
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Rai R, Gong Essel K, Mangiaracina Benbrook D, Garland J, Daniel Zhao Y, Chandra V. Preclinical Efficacy and Involvement of AKT, mTOR, and ERK Kinases in the Mechanism of Sulforaphane against Endometrial Cancer. Cancers (Basel) 2020; 12:E1273. [PMID: 32443471 PMCID: PMC7281543 DOI: 10.3390/cancers12051273] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 05/14/2020] [Accepted: 05/14/2020] [Indexed: 12/12/2022] Open
Abstract
Sulforaphane exerts anti-cancer activity against multiple cancer types. Our objective was to evaluate utility of sulforaphane for endometrial cancer therapy. Sulforaphane reduced viability of endometrial cancer cell lines in association with the G2/M cell cycle arrest and cell division cycle protein 2 (Cdc2) phosphorylation, and intrinsic apoptosis. Inhibition of anchorage-independent growth, invasion, and migration of the cell lines was associated with sulforaphane-induced alterations in epithelial-to-mesenchymal transition (EMT) markers of increased E-cadherin and decreased N-cadherin and vimentin expression. Proteomic analysis identified alterations in AKT, mTOR, and ERK kinases in the networks of sulforaphane effects in the Ishikawa endometrial cancer cell line. Western blots confirmed sulforaphane inhibition of AKT, mTOR, and induction of ERK with alterations in downstream signaling. AKT and mTOR inhibitors reduced endometrial cancer cell line viability and prevented further reduction by sulforaphane. Accumulation of nuclear phosphorylated ERK was associated with reduced sensitivity to the ERK inhibitor and its interference with sulforaphane activity. Sulforaphane induced apoptosis-associated growth inhibition of Ishikawa xenograft tumors to a greater extent than paclitaxel, with no evidence of toxicity. These results verify sulforaphane's potential as a non-toxic treatment candidate for endometrial cancer and identify AKT, mTOR, and ERK kinases in the mechanism of action with interference in the mechanism by nuclear phosphorylated ERK.
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Affiliation(s)
- Rajani Rai
- Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (R.R.); (D.M.B.); (J.G.)
| | - Kathleen Gong Essel
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA;
| | - Doris Mangiaracina Benbrook
- Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (R.R.); (D.M.B.); (J.G.)
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA;
| | - Justin Garland
- Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (R.R.); (D.M.B.); (J.G.)
| | - Yan Daniel Zhao
- Biostatistics & Epidemiology, College of Public Health University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA;
| | - Vishal Chandra
- Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (R.R.); (D.M.B.); (J.G.)
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA;
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14
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Santana-Gálvez J, Villela-Castrejón J, Serna-Saldívar SO, Cisneros-Zevallos L, Jacobo-Velázquez DA. Synergistic Combinations of Curcumin, Sulforaphane, and Dihydrocaffeic Acid against Human Colon Cancer Cells. Int J Mol Sci 2020; 21:ijms21093108. [PMID: 32354075 PMCID: PMC7246525 DOI: 10.3390/ijms21093108] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2020] [Revised: 04/26/2020] [Accepted: 04/26/2020] [Indexed: 01/13/2023] Open
Abstract
Nutraceutical combinations that act synergistically could be a powerful solution against colon cancer, which is the second deadliest malignancy worldwide. In this study, curcumin (C), sulforaphane (S), and dihydrocaffeic acid (D, a chlorogenic acid metabolite) were evaluated, individually and in different combinations, over the viability of HT-29 and Caco-2 colon cancer cells, and compared against healthy fetal human colon (FHC) cells. The cytotoxic concentrations to kill 50%, 75%, and 90% of the cells (CC50, CC75, and CC90) were obtained, using the MTS assay. Synergistic, additive, and antagonistic effects were determined by using the combination index (CI) method. The 1:1 combination of S and D exerted synergistic effects against HT-29 at 90% cytotoxicity level (doses 90:90 µM), whereas CD(1:4) was synergistic at all cytotoxicity levels (9:36–34:136 µM) and CD(9:2) at 90% (108:24 µM) against Caco-2 cells. SD(1:1) was significantly more cytotoxic for cancer cells than healthy cells, while CD(1:4) and CD(9:2) were similarly or more cytotoxic for healthy cells. Therefore, the SD(1:1) combination was chosen as the best. A model explaining SD(1:1) synergy is proposed. SD(1:1) can be used as a basis to develop advanced food products for the prevention/co-treatment of colon cancer.
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Affiliation(s)
- Jesús Santana-Gálvez
- Tecnologico de Monterrey, Escuela de Ingeniería y Ciencias, Ave. Eugenio Garza Sada 2501, Monterrey, NL C.P. 64849, Mexico
| | - Javier Villela-Castrejón
- Tecnologico de Monterrey, Escuela de Ingeniería y Ciencias, Ave. Eugenio Garza Sada 2501, Monterrey, NL C.P. 64849, Mexico
| | - Sergio O. Serna-Saldívar
- Tecnologico de Monterrey, Escuela de Ingeniería y Ciencias, Ave. Eugenio Garza Sada 2501, Monterrey, NL C.P. 64849, Mexico
| | - Luis Cisneros-Zevallos
- Department of Horticultural Sciences, Texas A&M University, College Station, TX 77843-2133, USA
| | - Daniel A. Jacobo-Velázquez
- Tecnologico de Monterrey, Escuela de Ingeniería y Ciencias, Ave. Eugenio Garza Sada 2501, Monterrey, NL C.P. 64849, Mexico
- Correspondence: ; Tel.: +52-33-3669-3000
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15
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Wilcox A, Murphy M, Tucker D, Laprade D, Roussel B, Chin C, Hallisey V, Kozub N, Brass A, Austriaco N. Sulforaphane alters the acidification of the yeast vacuole. MICROBIAL CELL 2020; 7:129-138. [PMID: 32391394 PMCID: PMC7199281 DOI: 10.15698/mic2020.05.716] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Sulforaphane (SFN) is a compound [1-isothiocyanato-4-(methylsulfinyl)-butane] found in broccoli and other cruciferous vegetables that is currently of interest because of its potential as a chemopreventive and a chemotherapeutic drug. Recent studies in a diverse range of cellular and animal models have shown that SFN is involved in multiple intracellular pathways that regulate xenobiotic metabolism, inflammation, cell death, cell cycle progression, and epigenetic regulation. In order to better understand the mechanisms of action behind SFN-induced cell death, we undertook an unbiased genome wide screen with the yeast knockout (YKO) library to identify SFN sensitive (SFNS) mutants. The mutants were enriched with knockouts in genes linked to vacuolar function suggesting a link between this organelle and SFN's mechanism of action in yeast. Our subsequent work revealed that SFN increases the vacuolar pH of yeast cells and that varying the vacuolar pH can alter the sensitivity of yeast cells to the drug. In fact, several mutations that lower the vacuolar pH in yeast actually made the cells resistant to SFN (SFNR). Finally, we show that human lung cancer cells with more acidic compartments are also SFNR suggesting that SFN's mechanism of action identified in yeast may carry over to higher eukaryotic cells.
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Affiliation(s)
- Alexander Wilcox
- Department of Biology, Providence College, 1 Cunningham Square, Providence, RI 02918, USA.,These authors contributed equally to the manuscript
| | - Michael Murphy
- Department of Biology, Providence College, 1 Cunningham Square, Providence, RI 02918, USA.,These authors contributed equally to the manuscript
| | - Douglass Tucker
- Department of Biology, Providence College, 1 Cunningham Square, Providence, RI 02918, USA.,These authors contributed equally to the manuscript
| | - David Laprade
- Department of Biology, Providence College, 1 Cunningham Square, Providence, RI 02918, USA
| | - Breton Roussel
- Department of Biology, Providence College, 1 Cunningham Square, Providence, RI 02918, USA
| | - Christopher Chin
- Department of Microbiology and Physiological Systems, University of Massachusetts School of Medicine, 368 Plantation St., ASC 1001, Worcester, MA 01605, USA
| | - Victoria Hallisey
- Department of Biology, Providence College, 1 Cunningham Square, Providence, RI 02918, USA
| | - Noah Kozub
- Department of Biology, Providence College, 1 Cunningham Square, Providence, RI 02918, USA
| | - Abraham Brass
- Department of Microbiology and Physiological Systems, University of Massachusetts School of Medicine, 368 Plantation St., ASC 1001, Worcester, MA 01605, USA
| | - Nicanor Austriaco
- Department of Biology, Providence College, 1 Cunningham Square, Providence, RI 02918, USA
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16
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Chiang TC, Koss B, Su LJ, Washam CL, Byrum SD, Storey A, Tackett AJ. Effect of Sulforaphane and 5-Aza-2'-Deoxycytidine on Melanoma Cell Growth. MEDICINES 2019; 6:medicines6030071. [PMID: 31252639 PMCID: PMC6789461 DOI: 10.3390/medicines6030071] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Revised: 06/21/2019] [Accepted: 06/24/2019] [Indexed: 12/12/2022]
Abstract
Background: UV exposure-induced oxidative stress is implicated as a driving mechanism for melanoma. Increased oxidative stress results in DNA damage and epigenetic dysregulation. Accordingly, we explored whether a low dose of the antioxidant sulforaphane (SFN) in combination with the epigenetic drug 5-aza-2’-deoxycytidine (DAC) could slow melanoma cell growth. SFN is a natural bioactivated product of the cruciferous family, while DAC is a DNA methyltransferase inhibitor. Methods: Melanoma cell growth characteristics, gene transcription profiles, and histone epigenetic modifications were measured after single and combination treatments with SFN and DAC. Results: We detected melanoma cell growth inhibition and specific changes in gene expression profiles upon combinational treatments with SFN and DAC, while no significant alterations in histone epigenetic modifications were observed. Dysregulated gene transcription of a key immunoregulator cytokine—C-C motif ligand 5 (CCL-5)—was validated. Conclusions: These results indicate a potential combinatorial effect of a dietary antioxidant and an FDA-approved epigenetic drug in controlling melanoma cell growth.
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Affiliation(s)
- Tung-Chin Chiang
- Department of Environmental and Occupational Health, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
| | - Brian Koss
- Department of Biochemistry & Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
| | - L Joseph Su
- Winthrop P. Rockefeller Cancer Institute, Cancer Prevention and Population Sciences Program & Department of Epidemiology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
| | - Charity L Washam
- Department of Biochemistry & Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
- Arkansas Children's Research Institute, Little Rock, AR 72202, USA
| | - Stephanie D Byrum
- Department of Biochemistry & Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
- Arkansas Children's Research Institute, Little Rock, AR 72202, USA
| | - Aaron Storey
- Department of Biochemistry & Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
| | - Alan J Tackett
- Department of Biochemistry & Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
- Arkansas Children's Research Institute, Little Rock, AR 72202, USA.
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17
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Mitsiogianni M, Koutsidis G, Mavroudis N, Trafalis DT, Botaitis S, Franco R, Zoumpourlis V, Amery T, Galanis A, Pappa A, Panayiotidis MI. The Role of Isothiocyanates as Cancer Chemo-Preventive, Chemo-Therapeutic and Anti-Melanoma Agents. Antioxidants (Basel) 2019; 8:E106. [PMID: 31003534 PMCID: PMC6523696 DOI: 10.3390/antiox8040106] [Citation(s) in RCA: 86] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2019] [Revised: 04/03/2019] [Accepted: 04/12/2019] [Indexed: 12/11/2022] Open
Abstract
Many studies have shown evidence in support of the beneficial effects of phytochemicals in preventing chronic diseases, including cancer. Among such phytochemicals, sulphur-containing compounds (e.g., isothiocyanates (ITCs)) have raised scientific interest by exerting unique chemo-preventive properties against cancer pathogenesis. ITCs are the major biologically active compounds capable of mediating the anticancer effect of cruciferous vegetables. Recently, many studies have shown that a higher intake of cruciferous vegetables is associated with reduced risk of developing various forms of cancers primarily due to a plurality of effects, including (i) metabolic activation and detoxification, (ii) inflammation, (iii) angiogenesis, (iv) metastasis and (v) regulation of the epigenetic machinery. In the context of human malignant melanoma, a number of studies suggest that ITCs can cause cell cycle growth arrest and also induce apoptosis in human malignant melanoma cells. On such basis, ITCs could serve as promising chemo-therapeutic agents that could be used in the clinical setting to potentiate the efficacy of existing therapies.
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Affiliation(s)
- Melina Mitsiogianni
- Department of Applied Sciences, Northumbria University, Newcastle Upon Tyne NE1 8ST, UK.
| | - Georgios Koutsidis
- Department of Applied Sciences, Northumbria University, Newcastle Upon Tyne NE1 8ST, UK.
| | - Nikos Mavroudis
- Department of Food and Nutritional Sciences, University of Reading, Reading RG6 6AP, UK.
| | - Dimitrios T Trafalis
- Laboratory of Pharmacology, Unit of Clinical Pharmacology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece.
| | - Sotiris Botaitis
- Second Department of Surgery, Democritus University of Thrace, 68100 Alexandroupolis, Greece.
| | - Rodrigo Franco
- Redox Biology Centre, University of Nebraska-Lincoln, Lincoln, NE 68588, USA.
- School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE 68583, USA.
| | - Vasilis Zoumpourlis
- Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, 11635 Athens, Greece.
| | - Tom Amery
- The Watrercress Company / The Wasabi Company, Waddock, Dorchester, Dorset DT2 8QY, UK.
| | - Alex Galanis
- Department of Molecular Biology and Genetics, Democritus University of Thrace, 68100 Alexandroupolis, Greece.
| | - Aglaia Pappa
- Department of Molecular Biology and Genetics, Democritus University of Thrace, 68100 Alexandroupolis, Greece.
| | - Mihalis I Panayiotidis
- Department of Applied Sciences, Northumbria University, Newcastle Upon Tyne NE1 8ST, UK.
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18
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Soundararajan P, Kim JS. Anti-Carcinogenic Glucosinolates in Cruciferous Vegetables and Their Antagonistic Effects on Prevention of Cancers. Molecules 2018; 23:E2983. [PMID: 30445746 PMCID: PMC6278308 DOI: 10.3390/molecules23112983] [Citation(s) in RCA: 141] [Impact Index Per Article: 20.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Revised: 11/09/2018] [Accepted: 11/13/2018] [Indexed: 12/16/2022] Open
Abstract
Glucosinolates (GSL) are naturally occurring β-d-thioglucosides found across the cruciferous vegetables. Core structure formation and side-chain modifications lead to the synthesis of more than 200 types of GSLs in Brassicaceae. Isothiocyanates (ITCs) are chemoprotectives produced as the hydrolyzed product of GSLs by enzyme myrosinase. Benzyl isothiocyanate (BITC), phenethyl isothiocyanate (PEITC) and sulforaphane ([1-isothioyanato-4-(methyl-sulfinyl) butane], SFN) are potential ITCs with efficient therapeutic properties. Beneficial role of BITC, PEITC and SFN was widely studied against various cancers such as breast, brain, blood, bone, colon, gastric, liver, lung, oral, pancreatic, prostate and so forth. Nuclear factor-erythroid 2-related factor-2 (Nrf2) is a key transcription factor limits the tumor progression. Induction of ARE (antioxidant responsive element) and ROS (reactive oxygen species) mediated pathway by Nrf2 controls the activity of nuclear factor-kappaB (NF-κB). NF-κB has a double edged role in the immune system. NF-κB induced during inflammatory is essential for an acute immune process. Meanwhile, hyper activation of NF-κB transcription factors was witnessed in the tumor cells. Antagonistic activity of BITC, PEITC and SFN against cancer was related with the direct/indirect interaction with Nrf2 and NF-κB protein. All three ITCs able to disrupts Nrf2-Keap1 complex and translocate Nrf2 into the nucleus. BITC have the affinity to inhibit the NF-κB than SFN due to the presence of additional benzyl structure. This review will give the overview on chemo preventive of ITCs against several types of cancer cell lines. We have also discussed the molecular interaction(s) of the antagonistic effect of BITC, PEITC and SFN with Nrf2 and NF-κB to prevent cancer.
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Affiliation(s)
- Prabhakaran Soundararajan
- Genomics Division, Department of Agricultural Bio-Resources, National Institute of Agricultural Sciences, Rural Development Administration, Wansan-gu, Jeonju 54874, Korea.
| | - Jung Sun Kim
- Genomics Division, Department of Agricultural Bio-Resources, National Institute of Agricultural Sciences, Rural Development Administration, Wansan-gu, Jeonju 54874, Korea.
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19
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Chen HE, Lin JF, Tsai TF, Lin YC, Chou KY, Hwang TIS. Allyl Isothiocyanate Induces Autophagy through the Up-Regulation of Beclin-1 in Human Prostate Cancer Cells. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2018; 46:1-19. [PMID: 30284468 DOI: 10.1142/s0192415x18500830] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Allyl isothiocyanate (AITC), one of the most widely studied phytochemicals, inhibits the survival of human prostate cancer cells while minimally affecting normal prostate epithelial cells. Our study demonstrates the mechanism of AITC-induced cell death in prostate cancer cells. AITC induces autophagy in RV1 and PC3 cells, judging from the increased level of LC3-II protein in a dose- and time-dependent manner, but not in the normal prostate epithelial cell (PrEC). Inhibition of autophagy in AITC-treated cells decreased cell viability and enhanced apoptosis, suggesting that the autophagy played a protective role. There are several pathways activated in ATIC-treated cells. We detected the phosphorylation forms of mTOR, ERK, AMPK, JNK and p38, and ERK AMPK and JNK activation were also detected. However, inhibition of AITC-activated ERK, AMPK and JNK by pre-treatment of specific inhibitors did not alter autophagy induction. Finally, increased beclin-1 expression was detected in AITC-treated cells, and inhibition of AITC-induced beclin-1 attanuated autophagy induction, indicating that AITC-induced autophagy occurs through upregulating beclin-1. Overall, our data show for the first time that AITC induces protective autophagy in Rv1 and PC3 cells through upregulation of beclin-1. Our results could potentially contribute to a therapeutic application of AITC in prostate cancer patients.
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Affiliation(s)
- Hung-En Chen
- * Division of Urology, Department of Surgery, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei 111, Taiwan
| | - Ji-Fan Lin
- † Central Laboratory, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei 111, Taiwan
| | - Te-Fu Tsai
- * Division of Urology, Department of Surgery, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei 111, Taiwan
- ‡ Division of Urology, School of Medicine, Fu-Jen Catholic University, New Taipei 242, Taiwan
| | - Yi-Chia Lin
- * Division of Urology, Department of Surgery, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei 111, Taiwan
- ‡ Division of Urology, School of Medicine, Fu-Jen Catholic University, New Taipei 242, Taiwan
| | - Kuang-Yu Chou
- * Division of Urology, Department of Surgery, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei 111, Taiwan
- ‡ Division of Urology, School of Medicine, Fu-Jen Catholic University, New Taipei 242, Taiwan
| | - Thomas I-Sheng Hwang
- * Division of Urology, Department of Surgery, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei 111, Taiwan
- ‡ Division of Urology, School of Medicine, Fu-Jen Catholic University, New Taipei 242, Taiwan
- § Department of Urology, Taipei Medical University, Taipei 111, Taiwan
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20
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Mitsiogianni M, Amery T, Franco R, Zoumpourlis V, Pappa A, Panayiotidis MI. From chemo-prevention to epigenetic regulation: The role of isothiocyanates in skin cancer prevention. Pharmacol Ther 2018; 190:187-201. [DOI: 10.1016/j.pharmthera.2018.06.001] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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21
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Jiang X, Liu Y, Ma L, Ji R, Qu Y, Xin Y, Lv G. Chemopreventive activity of sulforaphane. DRUG DESIGN DEVELOPMENT AND THERAPY 2018; 12:2905-2913. [PMID: 30254420 PMCID: PMC6141106 DOI: 10.2147/dddt.s100534] [Citation(s) in RCA: 71] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Cancer is one of the major causes of morbidity and mortality in the world. Carcinogenesis is a multistep process induced by genetic and epigenetic changes that disrupt pathways controlling cell proliferation, apoptosis, differentiation, and senescence. In this context, many bioactive dietary compounds from vegetables and fruits have been demonstrated to be effective in cancer prevention and intervention. Over the years, sulforaphane (SFN), found in cruciferous vegetables, has been shown to have chemopreventive activity in vitro and in vivo. SFN protects cells from environmental carcinogens and also induces growth arrest and/or apoptosis in various cancer cells. In this review, we will discuss several potential mechanisms of the chemopreventive activity of SFN, including regulation of Phase I and Phase II drug-metabolizing enzymes, cell cycle arrest, and induction of apoptosis, especially via regulation of signaling pathways such as Nrf2-Keap1 and NF-κB. Recent studies suggest that SFN can also affect the epigenetic control of key genes and greatly influence the initiation and progression of cancer. This research may provide a basis for the clinical use of SFN for cancer chemoprevention and enable us to design preventive strategies for cancer management, reduce cancer development and recurrence, and thus improve patient survival.
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Affiliation(s)
- Xin Jiang
- Department of Radiation Oncology, The First Hospital of Jilin University, Changchun 130021, China
| | - Ye Liu
- Department of Pathobiology, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai 519000, China
| | - Lixin Ma
- Department of Radiation Oncology, The First Hospital of Jilin University, Changchun 130021, China
| | - Rui Ji
- Department of Internal Medicine, Florida Hospital, Orlando, FL, USA
| | - Yaqin Qu
- Department of Radiation Oncology, The First Hospital of Jilin University, Changchun 130021, China
| | - Ying Xin
- Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun 130021, China,
| | - Guoyue Lv
- Department of General Surgery, The First Hospital of Jilin University, Changchun 130021, China,
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22
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Li HY, Li M, Luo CC, Wang JQ, Zheng N. Lactoferrin Exerts Antitumor Effects by Inhibiting Angiogenesis in a HT29 Human Colon Tumor Model. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2017; 65:10464-10472. [PMID: 29112400 DOI: 10.1021/acs.jafc.7b03390] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
To investigate the effect and potential mechanisms of lactoferrin on colon cancer cells and tumors, HT29 and HCT8 cells were exposed to varying concentrations of lactoferrin, and the impacts on cell proliferation, migration, and invasion were observed. Cell proliferation test showed that high dosage of lactoferrin (5-100 mg/mL) inhibited cell viability in a dose-dependent manner, with the 50% concentration of inhibition at 81.3 ± 16.7 mg/mL and 101 ± 23.8 mg/mL for HT29 and HCT8 cells, respectively. Interestingly, migration and invasion of the cells were inhibited dramatically by 20 mg/mL lactoferrin, consistent with the significant down regulation of VEGFR2, VEGFA, pPI3K, pAkt, and pErk1/2 proteins. HT29 was chosen as the sensitive cell line to construct a tumor-bearing nude mice model. Notably, HT29 tumor weight was greatly reduced in both the lactoferrin group (26.5 ± 6.7 mg) and the lactoferrin/5-Fu group (14.5 ± 5.1 mg), compared with the control one (39.3 ± 6.5 mg), indicating that lactoferrin functioned as a tumor growth inhibitor. Considering lactoferrin also reduced the growth of blood vessels and the degree of malignancy, we concluded that HT29 tumors were effectively suppressed by lactoferrin, which might be achieved by regulation of phosphorylation from various kinases and activation of the VEGFR2-PI3K/Akt-Erk1/2 pathway.
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Affiliation(s)
- Hui-Ying Li
- Institute of Animal Sciences of Chinese Academy of Agricultural Sciences , Beijing 100193, People's Republic of China
| | - Ming Li
- Institute of Animal Sciences of Chinese Academy of Agricultural Sciences , Beijing 100193, People's Republic of China
| | - Chao-Chao Luo
- Institute of Animal Sciences of Chinese Academy of Agricultural Sciences , Beijing 100193, People's Republic of China
| | - Jia-Qi Wang
- Institute of Animal Sciences of Chinese Academy of Agricultural Sciences , Beijing 100193, People's Republic of China
| | - Nan Zheng
- Institute of Animal Sciences of Chinese Academy of Agricultural Sciences , Beijing 100193, People's Republic of China
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23
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Soni K, Rizwanullah M, Kohli K. Development and optimization of sulforaphane-loaded nanostructured lipid carriers by the Box-Behnken design for improved oral efficacy against cancer: in vitro, ex vivo and in vivo assessments. ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2017; 46:15-31. [DOI: 10.1080/21691401.2017.1408124] [Citation(s) in RCA: 76] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Affiliation(s)
- Kriti Soni
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India
| | - Md. Rizwanullah
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India
| | - Kanchan Kohli
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India
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24
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Russo M, Spagnuolo C, Russo GL, Skalicka-Woźniak K, Daglia M, Sobarzo-Sánchez E, Nabavi SF, Nabavi SM. Nrf2 targeting by sulforaphane: A potential therapy for cancer treatment. Crit Rev Food Sci Nutr 2017; 58:1391-1405. [PMID: 28001083 DOI: 10.1080/10408398.2016.1259983] [Citation(s) in RCA: 146] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
In the past decades, extensive studies have reported the potential chemopreventive activity of sulforaphane, an isothiocyanate derived from glucoraphanin, occurring in large amounts in Brassica genus plants. Sulforaphane was found to be active against several forms of cancer. A growing body of data shows that sulforaphane acts against cancer at different levels, from development to progression, through pleiotropic effects. In this review, we discuss the available experimental and clinical data on the potential therapeutic role of sulforaphane against cancer. Its effects range from the protection of cells from DNA damage to the modulation of the cell cycle via pro-apoptotic, anti-angiogenesis and anti-metastasis activities. At molecular level, sulforaphane modulates cellular homeostasis via the activation of the transcription factor Nrf2. Although data from clinical studies are limited, sulforaphane remains a good candidate in the adjuvant therapy based on natural molecules against several types of cancer.
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Affiliation(s)
- Maria Russo
- a Institute of Food Sciences, National Research Council , Avellino , Italy
| | - Carmela Spagnuolo
- a Institute of Food Sciences, National Research Council , Avellino , Italy
| | - Gian Luigi Russo
- a Institute of Food Sciences, National Research Council , Avellino , Italy
| | - Krystyna Skalicka-Woźniak
- b Department of Pharmacognosy with Medicinal Plants Unit , Medical University of Lublin , Lublin , Poland
| | - Maria Daglia
- c Department of Drug Sciences , Medicinal Chemistry and Pharmaceutical Technology Section, University of Pavia , Italy
| | - Eduardo Sobarzo-Sánchez
- d Laboratory of Pharmaceutical Chemistry, Department of Organic Chemistry , Faculty of Pharmacy, University of Santiago de Compostela , Spain
| | - Seyed Fazel Nabavi
- e Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences , Tehran , Iran
| | - Seyed Mohammad Nabavi
- e Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences , Tehran , Iran
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Pan JH, Abernathy B, Kim YJ, Lee JH, Kim JH, Shin EC, Kim JK. Cruciferous vegetables and colorectal cancer prevention through microRNA regulation: A review. Crit Rev Food Sci Nutr 2017; 58:2026-2038. [DOI: 10.1080/10408398.2017.1300134] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Affiliation(s)
- Jeong Hoon Pan
- School of Human Environmental Sciences, University of Arkansas, Fayetteville, Arkansas, USA
| | - Breann Abernathy
- Department of Food Science and Nutrition, University of Minnesota, St. Paul, Minnesota, USA
| | - Young Jun Kim
- Department of Food and Biotechnology, Korea University, Sejong, Republic of Korea
| | - Jin Hyup Lee
- Department of Food and Biotechnology, Korea University, Sejong, Republic of Korea
| | - Jun Ho Kim
- Department of Food and Biotechnology, Korea University, Sejong, Republic of Korea
| | - Eui Cheol Shin
- Department of Food Science, Gyeongnam National University of Science and Technology, Jinju, Republic of Korea
| | - Jae Kyeom Kim
- School of Human Environmental Sciences, University of Arkansas, Fayetteville, Arkansas, USA
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Pereira LP, Silva P, Duarte M, Rodrigues L, Duarte CMM, Albuquerque C, Serra AT. Targeting Colorectal Cancer Proliferation, Stemness and Metastatic Potential Using Brassicaceae Extracts Enriched in Isothiocyanates: A 3D Cell Model-Based Study. Nutrients 2017; 9:nu9040368. [PMID: 28394276 PMCID: PMC5409707 DOI: 10.3390/nu9040368] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2017] [Revised: 03/23/2017] [Accepted: 04/01/2017] [Indexed: 01/28/2023] Open
Abstract
Colorectal cancer (CRC) recurrence is often attributable to circulating tumor cells and/or cancer stem cells (CSCs) that resist to conventional therapies and foster tumor progression. Isothiocyanates (ITCs) derived from Brassicaceae vegetables have demonstrated anticancer effects in CRC, however little is known about their effect in CSCs and tumor initiation properties. Here we examined the effect of ITCs-enriched Brassicaceae extracts derived from watercress and broccoli in cell proliferation, CSC phenotype and metastasis using a previously developed three-dimensional HT29 cell model with CSC-like traits. Both extracts were phytochemically characterized and their antiproliferative effect in HT29 monolayers was explored. Next, we performed cell proliferation assays and flow cytometry analysis in HT29 spheroids treated with watercress and broccoli extracts and respective main ITCs, phenethyl isothiocyanate (PEITC) and sulforaphane (SFN). Soft agar assays and relative quantitative expression analysis of stemness markers and Wnt/β-catenin signaling players were performed to evaluate the effect of these phytochemicals in stemness and metastasis. Our results showed that both Brassicaceae extracts and ITCs exert antiproliferative effects in HT29 spheroids, arresting cell cycle at G₂/M, possibly due to ITC-induced DNA damage. Colony formation and expression of LGR5 and CD133 cancer stemness markers were significantly reduced. Only watercress extract and PEITC decreased ALDH1 activity in a dose-dependent manner, as well as β-catenin expression. Our research provides new insights on CRC therapy using ITC-enriched Brassicaceae extracts, specially watercress extract, to target CSCs and circulating tumor cells by impairing cell proliferation, ALDH1-mediated chemo-resistance, anoikis evasion, self-renewal and metastatic potential.
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Affiliation(s)
- Lucília P Pereira
- iBET, Instituto de Biologia Experimental e Tecnológica, Apartado 12, 2780-901 Oeiras, Portugal.
- Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa (ITQB NOVA), 2780-157 Oeiras, Portugal.
| | - Patrícia Silva
- Unidade de Investigação em Patobiologia Molecular (UIPM), Instituto Português de Oncologia de Lisboa Francisco Gentil, E.P.E (IPOLFG, EPE), 1099-023 Lisboa, Portugal.
| | - Marlene Duarte
- Unidade de Investigação em Patobiologia Molecular (UIPM), Instituto Português de Oncologia de Lisboa Francisco Gentil, E.P.E (IPOLFG, EPE), 1099-023 Lisboa, Portugal.
| | - Liliana Rodrigues
- iBET, Instituto de Biologia Experimental e Tecnológica, Apartado 12, 2780-901 Oeiras, Portugal.
- Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa (ITQB NOVA), 2780-157 Oeiras, Portugal.
| | - Catarina M M Duarte
- iBET, Instituto de Biologia Experimental e Tecnológica, Apartado 12, 2780-901 Oeiras, Portugal.
- Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa (ITQB NOVA), 2780-157 Oeiras, Portugal.
| | - Cristina Albuquerque
- Unidade de Investigação em Patobiologia Molecular (UIPM), Instituto Português de Oncologia de Lisboa Francisco Gentil, E.P.E (IPOLFG, EPE), 1099-023 Lisboa, Portugal.
| | - Ana Teresa Serra
- iBET, Instituto de Biologia Experimental e Tecnológica, Apartado 12, 2780-901 Oeiras, Portugal.
- Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa (ITQB NOVA), 2780-157 Oeiras, Portugal.
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Kawarazaki A, Horinaka M, Yasuda S, Numajiri T, Nishino K, Sakai T. Sulforaphane suppresses cell growth and collagen expression of keloid fibroblasts. Wound Repair Regen 2017; 25:224-233. [PMID: 28120534 DOI: 10.1111/wrr.12512] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2016] [Accepted: 01/19/2017] [Indexed: 02/06/2023]
Abstract
Keloids are fibroproliferative diseases characterized by the accumulation of an extracellular matrix including collagen. Various growth factors, or cytokines, and their receptors are overexpressed in keloids, and they are expected to be therapy targets. Sulforaphane, a dietary isothiocyanate, has recently shown anti-tumor, anti-inflammatory, and anti-fibrotic properties. In this study, we found that sulforaphane inhibited cell growth and reduced collagen at the mRNA and protein levels in keloid fibroblasts. Moreover, sulforaphane markedly suppressed the expression of IL-6 and α-SMA and inhibited Stat3 and Smad3 signaling pathways in keloid fibroblast KF112 cells. Sulforaphane induced G2/M cell-cycle arrest with the induction of p21 in KF112 cells. In addition, sulforaphane inhibited cell growth and suppressed the expression of collagen in keloid fibroblasts under a coculture with peripheral blood mononuclear cells. Furthermore, sulforaphane suppressed IL-6, Stat3, and Smad3 signaling in the coculture system. This study suggests that sulforaphane may be a novel keloid treatment.
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Affiliation(s)
- Ayako Kawarazaki
- Department of Molecular-Targeting Cancer Prevention.,Department of Surgery, Division of Plastic and Reconstructive Surgery, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | | | | | - Toshiaki Numajiri
- Department of Surgery, Division of Plastic and Reconstructive Surgery, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Kenichi Nishino
- Department of Surgery, Division of Plastic and Reconstructive Surgery, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
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Bailon-Moscoso N, Cevallos-Solorzano G, Romero-Benavides JC, Orellana MIR. Natural Compounds as Modulators of Cell Cycle Arrest: Application for Anticancer Chemotherapies. Curr Genomics 2017; 18:106-131. [PMID: 28367072 PMCID: PMC5345333 DOI: 10.2174/1389202917666160808125645] [Citation(s) in RCA: 110] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2015] [Revised: 11/13/2015] [Accepted: 11/20/2015] [Indexed: 12/22/2022] Open
Abstract
Natural compounds from various plants, microorganisms and marine species play an important role in the discovery novel components that can be successfully used in numerous biomedical applications, including anticancer therapeutics. Since uncontrolled and rapid cell division is a hallmark of cancer, unraveling the molecular mechanisms underlying mitosis is key to understanding how various natural compounds might function as inhibitors of cell cycle progression. A number of natural compounds that inhibit the cell cycle arrest have proven effective for killing cancer cells in vitro, in vivo and in clinical settings. Significant advances that have been recently made in the understanding of molecular mechanisms underlying the cell cycle regulation using the chemotherapeutic agents is of great importance for improving the efficacy of targeted therapeutics and overcoming resistance to anticancer drugs, especially of natural origin, which inhibit the activities of cyclins and cyclin-dependent kinases, as well as other proteins and enzymes involved in proper regulation of cell cycle leading to controlled cell proliferation.
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Guamán-Ortiz LM, Orellana MIR, Ratovitski EA. Natural Compounds As Modulators of Non-apoptotic Cell Death in Cancer Cells. Curr Genomics 2017; 18:132-155. [PMID: 28367073 PMCID: PMC5345338 DOI: 10.2174/1389202917666160803150639] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2015] [Revised: 11/24/2015] [Accepted: 11/28/2015] [Indexed: 02/07/2023] Open
Abstract
Cell death is an innate capability of cells to be removed from microenvironment, if and when they are damaged by multiple stresses. Cell death is often regulated by multiple molecular pathways and mechanism, including apoptosis, autophagy, and necroptosis. The molecular network underlying these processes is often intertwined and one pathway can dynamically shift to another one acquiring certain protein components, in particular upon treatment with various drugs. The strategy to treat human cancer ultimately relies on the ability of anticancer therapeutics to induce tumor-specific cell death, while leaving normal adjacent cells undamaged. However, tumor cells often develop the resistance to the drug-induced cell death, thus representing a great challenge for the anticancer approaches. Numerous compounds originated from the natural sources and biopharmaceutical industries are applied today in clinics showing advantageous results. However, some exhibit serious toxic side effects. Thus, novel effective therapeutic approaches in treating cancers are continued to be developed. Natural compounds with anticancer activity have gained a great interest among researchers and clinicians alike since they have shown more favorable safety and efficacy then the synthetic marketed drugs. Numerous studies in vitro and in vivo have found that several natural compounds display promising anticancer potentials. This review underlines certain information regarding the role of natural compounds from plants, microorganisms and sea life forms, which are able to induce non-apoptotic cell death in tumor cells, namely autophagy and necroptosis.
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Affiliation(s)
- Luis Miguel Guamán-Ortiz
- 1 Departamento de Ciencias de la Salud, Universidad Técnica Particular de Loja, Loja, Ecuador ; 2 Head and Neck Cancer Research Division, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Maria Isabel Ramirez Orellana
- 1 Departamento de Ciencias de la Salud, Universidad Técnica Particular de Loja, Loja, Ecuador ; 2 Head and Neck Cancer Research Division, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Edward A Ratovitski
- 1 Departamento de Ciencias de la Salud, Universidad Técnica Particular de Loja, Loja, Ecuador ; 2 Head and Neck Cancer Research Division, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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Wang N, Wang W, Liu C, Jin J, Shao B, Shen L. Inhibition of growth and induction of apoptosis in A549 cells by compounds from oxheart cabbage extract. JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE 2016; 96:3813-3820. [PMID: 26679410 DOI: 10.1002/jsfa.7575] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/19/2015] [Revised: 11/11/2015] [Accepted: 12/18/2015] [Indexed: 06/05/2023]
Abstract
BACKGROUND Oxheart cabbage (Brassica oleracea var. capitata) is a member of the Brassica genus. Although some studies on the anticancer effects of extracts from oxheart cabbage have been reported, comprehensive information on the bioactive fractions and components from oxheart cabbage extracts is still lacking. The aim of this study was to isolate and identify the bioactive fractions and components from oxheart cabbage seeds using activity-guided isolation methods. RESULTS The cytotoxicity and apoptotic effects of fraction II, fraction III, iberverin, sulforaphane and iberin from oxheart cabbage seed extract were investigated. The results showed that all five components had inhibitory effects on the in vitro growth of A549 cells which were dose-dependent. These compounds also changed the morphology of A549 cells, and their inhibitory activity on A549 cells was as follows: sulforaphane > iberin > iberverin > fraction III > fraction II. The IC50 values were 3.53 ± 0.63, 4.93 ± 1.02, 7.07 ± 0.51, 15.56 ± 0.24 and 27.32 ± 0.63 µg mL(-1) respectively. Fraction II, fraction III, iberverin, sulforaphane and iberin induced cell apoptosis by increasing early apoptosis and late apoptosis/necrosis, and activation of caspase-3, -8 and -9. CONCLUSION These results indicated that the decrease in A549 cell viability by active compounds from oxheart cabbage seed extract was due to the induction of apoptosis. © 2015 Society of Chemical Industry.
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Affiliation(s)
- Nan Wang
- College of Biology and Environmental Engineering, Zhejiang Shuren University, Hangzhou 310021, China
| | - Wei Wang
- Institute of Quality and Standard for Agriculture Products, Zhejiang Academy of Agriculture Sciences, Hangzhou 310021, China
| | - Caiqin Liu
- College of Biology and Environmental Engineering, Zhejiang Shuren University, Hangzhou 310021, China
| | - Jianchang Jin
- College of Biology and Environmental Engineering, Zhejiang Shuren University, Hangzhou 310021, China
| | - Bo Shao
- College of Biology and Environmental Engineering, Zhejiang Shuren University, Hangzhou 310021, China
| | - Lianqing Shen
- College of Food Science and Biotechnology Engineering, Zhejiang Gongshang University, Hangzhou 310018, China
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Kheiri Manjili H, Ma’mani L, Tavaddod S, Mashhadikhan M, Shafiee A, Naderi-Manesh H. D, L-Sulforaphane Loaded Fe3O4@ Gold Core Shell Nanoparticles: A Potential Sulforaphane Delivery System. PLoS One 2016; 11:e0151344. [PMID: 26982588 PMCID: PMC4794166 DOI: 10.1371/journal.pone.0151344] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2015] [Accepted: 02/08/2016] [Indexed: 11/19/2022] Open
Abstract
A novel design of gold-coated iron oxide nanoparticles was fabricated as a potential delivery system to improve the efficiency and stability of d, l-sulforaphane as an anticancer drug. To this purpose, the surface of gold-coated iron oxide nanoparticles was modified for sulforaphane delivery via furnishing its surface with thiolated polyethylene glycol-folic acid and thiolated polyethylene glycol-FITC. The synthesized nanoparticles were characterized by different techniques such as FTIR, energy dispersive X-ray spectroscopy, UV-visible spectroscopy, scanning and transmission electron microscopy. The average diameters of the synthesized nanoparticles before and after sulforaphane loading were obtained ∼ 33 nm and ∼ 38 nm, respectively, when ∼ 2.8 mmol/g of sulforaphane was loaded. The result of cell viability assay which was confirmed by apoptosis assay on the human breast cancer cells (MCF-7 line) as a model of in vitro-cancerous cells, proved that the bare nanoparticles showed little inherent cytotoxicity, whereas the sulforaphane-loaded nanoparticles were cytotoxic. The expression rate of the anti-apoptotic genes (bcl-2 and bcl-xL), and the pro-apoptotic genes (bax and bak) were quantified, and it was found that the expression rate of bcl-2 and bcl-xL genes significantly were decreased when MCF-7 cells were incubated by sulforaphane-loaded nanoparticles. The sulforaphane-loaded into the designed gold-coated iron oxide nanoparticles, acceptably induced apoptosis in MCF-7 cells.
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Affiliation(s)
- Hamidreza Kheiri Manjili
- Department of Nanobiotechnology, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Leila Ma’mani
- Department of Nanotechnology, Agricultural Biotechnology Research Institute of Iran (ABRII), Agricultural Research, Education and Extension Organization (AREEO), Karaj, Iran
| | - Sharareh Tavaddod
- Department of Nanobiotechnology, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Maedeh Mashhadikhan
- Department of Biology, Faculty of Science, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Abbas Shafiee
- Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran 14176, Iran
| | - Hossein Naderi-Manesh
- Department of Nanobiotechnology, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
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Synthesis and Structure–Activity Relations in Allylsulfide and Isothiocyanate Compounds From Garlic and Broccoli Against In Vitro Cancer Cell Growth. ACTA ACUST UNITED AC 2016. [DOI: 10.1016/b978-0-444-63749-9.00001-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/08/2023]
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Kim DH, Sung B, Kang YJ, Hwang SY, Kim MJ, Yoon JH, Im E, Kim ND. Sulforaphane inhibits hypoxia-induced HIF-1α and VEGF expression and migration of human colon cancer cells. Int J Oncol 2015; 47:2226-32. [PMID: 26498863 DOI: 10.3892/ijo.2015.3200] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2015] [Accepted: 09/22/2015] [Indexed: 12/13/2022] Open
Abstract
The effects of sulforaphane (a natural product commonly found in broccoli) was investigated on hypoxia inducible factor-1α (HIF-1α) expression in HCT116 human colon cancer cells and AGS human gastric cancer cells. We found that hypoxia-induced HIF-1α protein expression in HCT116 and AGS cells, while treatment with sulforaphane markedly and concentration-dependently inhibited HIF-1α expression in both cell lines. Treatment with sulforaphane inhibited hypoxia-induced vascular endothelial growth factor (VEGF) expression in HCT116 cells. Treatment with sulforaphane modulated the effect of hypoxia on HIF-1α stability. However, degradation of HIF-1α by sulforaphane was not mediated through the 26S proteasome pathway. We also found that the inhibition of HIF-1α by sulforaphane was not mediated through AKT and extracellular signal-regulated kinase phosphorylation under hypoxic conditions. Finally, hypoxia-induced HCT116 cell migration was inhibited by sulforaphane. These data suggest that sulforaphane may inhibit human colon cancer progression and cancer cell angiogenesis by inhibiting HIF-1α and VEGF expression. Taken together, these results indicate that sulforaphane is a new and potent chemopreventive drug candidate for treating patients with human colon cancer.
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Affiliation(s)
- Dong Hwan Kim
- Department of Pharmacy, Molecular Inflammation Research Center for Aging Intervention, Pusan National University, Busan 46241, Republic of Korea
| | - Bokyung Sung
- Department of Pharmacy, Molecular Inflammation Research Center for Aging Intervention, Pusan National University, Busan 46241, Republic of Korea
| | - Yong Jung Kang
- Department of Pharmacy, Molecular Inflammation Research Center for Aging Intervention, Pusan National University, Busan 46241, Republic of Korea
| | - Seong Yeon Hwang
- Department of Pharmacy, Molecular Inflammation Research Center for Aging Intervention, Pusan National University, Busan 46241, Republic of Korea
| | - Min Jeong Kim
- Department of Pharmacy, Molecular Inflammation Research Center for Aging Intervention, Pusan National University, Busan 46241, Republic of Korea
| | - Jeong-Hyun Yoon
- Department of Pharmacy, Molecular Inflammation Research Center for Aging Intervention, Pusan National University, Busan 46241, Republic of Korea
| | - Eunok Im
- Department of Pharmacy, Molecular Inflammation Research Center for Aging Intervention, Pusan National University, Busan 46241, Republic of Korea
| | - Nam Deuk Kim
- Department of Pharmacy, Molecular Inflammation Research Center for Aging Intervention, Pusan National University, Busan 46241, Republic of Korea
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Tortorella SM, Royce SG, Licciardi PV, Karagiannis TC. Dietary Sulforaphane in Cancer Chemoprevention: The Role of Epigenetic Regulation and HDAC Inhibition. Antioxid Redox Signal 2015; 22:1382-424. [PMID: 25364882 PMCID: PMC4432495 DOI: 10.1089/ars.2014.6097] [Citation(s) in RCA: 143] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
SIGNIFICANCE Sulforaphane, produced by the hydrolytic conversion of glucoraphanin after ingestion of cruciferous vegetables, particularly broccoli and broccoli sprouts, has been extensively studied due to its apparent health-promoting properties in disease and limited toxicity in normal tissue. Recent Studies: Recent identification of a sub-population of tumor cells with stem cell-like self-renewal capacity that may be responsible for relapse, metastasis, and resistance, as a potential target of the dietary compound, may be an important aspect of sulforaphane chemoprevention. Evidence also suggests that sulforaphane may target the epigenetic alterations observed in specific cancers, reversing aberrant changes in gene transcription through mechanisms of histone deacetylase inhibition, global demethylation, and microRNA modulation. CRITICAL ISSUES In this review, we discuss the biochemical and biological properties of sulforaphane with a particular emphasis on the anticancer properties of the dietary compound. Sulforaphane possesses the capacity to intervene in multistage carcinogenesis through the modulation and/or regulation of important cellular mechanisms. The inhibition of phase I enzymes that are responsible for the activation of pro-carcinogens, and the induction of phase II enzymes that are critical in mutagen elimination are well-characterized chemopreventive properties. Furthermore, sulforaphane mediates a number of anticancer pathways, including the activation of apoptosis, induction of cell cycle arrest, and inhibition of NFκB. FUTURE DIRECTIONS Further characterization of the chemopreventive properties of sulforaphane and its capacity to be selectively toxic to malignant cells are warranted to potentially establish the clinical utility of the dietary compound as an anti-cancer compound alone, and in combination with clinically relevant therapeutic and management strategies.
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Affiliation(s)
- Stephanie M Tortorella
- 1 Epigenomic Medicine, Baker IDI Heart and Diabetes Institute, The Alfred Medical Research and Education Precinct , Melbourne, Australia
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Bao C, Ko J, Park HC, Kim MC, Kim J, Auh JH, Lee HJ. Sulforaphane inhibited tumor necrosis factor-α induced migration and invasion in estrogen receptor negative human breast cancer cells. Food Sci Biotechnol 2015. [DOI: 10.1007/s10068-015-0046-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
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Chung YK, Chi-Hung Or R, Lu CH, Ouyang WT, Yang SY, Chang CC. Sulforaphane down-regulates SKP2 to stabilize p27KIP1 for inducing antiproliferation in human colon adenocarcinoma cells. J Biosci Bioeng 2015; 119:35-42. [DOI: 10.1016/j.jbiosc.2014.06.009] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2014] [Revised: 06/12/2014] [Accepted: 06/17/2014] [Indexed: 12/18/2022]
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Fimognari C, Turrini E, Sestili P, Calcabrini C, Carulli G, Fontanelli G, Rousseau M, Cantelli-Forti G, Hrelia P. Antileukemic activity of sulforaphane in primary blasts from patients affected by myelo- and lympho-proliferative disorders and in hypoxic conditions. PLoS One 2014; 9:e101991. [PMID: 25019218 PMCID: PMC4096754 DOI: 10.1371/journal.pone.0101991] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2014] [Accepted: 06/13/2014] [Indexed: 11/18/2022] Open
Abstract
Sulforaphane is a dietary isothiocyanate found in cruciferous vegetables showing antileukemic activity. With the purpose of extending the potential clinical impact of sulforaphane in the oncological field, we investigated the antileukemic effect of sulforaphane on blasts from patients affected by different types of leukemia and, taking into account the intrinsically hypoxic nature of bone marrow, on a leukemia cell line (REH) maintained in hypoxic conditions. In particular, we tested sulforaphane on patients with chronic lymphocytic leukemia, acute myeloid leukemia, T-cell acute lymphoblastic leukemia, B-cell acute lymphoblastic leukemia, and blastic NK cell leukemia. Sulforaphane caused a dose-dependent induction of apoptosis in blasts from patients diagnosed with acute lymphoblastic or myeloid leukemia. Moreover, it was able to cause apoptosis and to inhibit proliferation in hypoxic conditions on REH cells. As to its cytotoxic mechanism, we found that sulforaphane creates an oxidative cellular environment that induces DNA damage and Bax and p53 gene activation, which in turn helps trigger apoptosis. On the whole, our results raise hopes that sulforaphane might set the stage for a novel therapeutic principle complementing our growing armature against malignancies and advocate the exploration of sulforaphane in a broader population of leukemic patients.
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Affiliation(s)
- Carmela Fimognari
- Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, Rimini, Italy
| | - Eleonora Turrini
- Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, Rimini, Italy
| | - Piero Sestili
- Department of Biomolecular Sciences, University of Urbino "Carlo Bo", Urbino, Italy
| | - Cinzia Calcabrini
- Department of Biomolecular Sciences, University of Urbino "Carlo Bo", Urbino, Italy
| | - Giovanni Carulli
- Division of Hematology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Giulia Fontanelli
- Division of Hematology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Martina Rousseau
- Division of Hematology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Giorgio Cantelli-Forti
- Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, Rimini, Italy
| | - Patrizia Hrelia
- Department of Pharmacy and BioTechnology, Alma Mater Studiorum-University of Bologna, Bologna, Italy
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Azarenko O, Jordan MA, Wilson L. Erucin, the major isothiocyanate in arugula (Eruca sativa), inhibits proliferation of MCF7 tumor cells by suppressing microtubule dynamics. PLoS One 2014; 9:e100599. [PMID: 24950293 PMCID: PMC4065051 DOI: 10.1371/journal.pone.0100599] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2014] [Accepted: 05/28/2014] [Indexed: 01/25/2023] Open
Abstract
Consumption of cruciferous vegetables is associated with reduced risk of various types of cancer. Isothiocyanates including sulforaphane and erucin are believed to be responsible for this activity. Erucin [1-isothiocyanato-4-(methylthio)butane], which is metabolically and structurally related to sulforaphane, is present in large quantities in arugula (Eruca sativa, Mill.), kohlrabi and Chinese cabbage. However, its cancer preventive mechanisms remain poorly understood. We found that erucin inhibits proliferation of MCF7 breast cancer cells (IC50 = 28 µM) in parallel with cell cycle arrest at mitosis (IC50 = 13 µM) and apoptosis, by a mechanism consistent with impairment of microtubule dynamics. Concentrations of 5-15 µM erucin suppressed the dynamic instability of microtubules during interphase in the cells. Most dynamic instability parameters were inhibited, including the rates and extents of growing and shortening, the switching frequencies between growing and shortening, and the overall dynamicity. Much higher erucin concentrations were required to reduce the microtubule polymer mass. In addition, erucin suppressed dynamic instability of microtubules reassembled from purified tubulin in similar fashion. The effects of erucin on microtubule dynamics, like those of sulforaphane, are similar qualitatively to those of much more powerful clinically-used microtubule-targeting anticancer drugs, including taxanes and the vinca alkaloids. The results suggest that suppression of microtubule dynamics by erucin and the resulting impairment of critically important microtubule-dependent cell functions such as mitosis, cell migration and microtubule-based transport may be important in its cancer preventive activities.
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Affiliation(s)
- Olga Azarenko
- Department of Molecular, Cellular, and Developmental Biology, and the Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, California, United States of America
| | - Mary Ann Jordan
- Department of Molecular, Cellular, and Developmental Biology, and the Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, California, United States of America
| | - Leslie Wilson
- Department of Molecular, Cellular, and Developmental Biology, and the Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, California, United States of America
- * E-mail:
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Ishida M, Hara M, Fukino N, Kakizaki T, Morimitsu Y. Glucosinolate metabolism, functionality and breeding for the improvement of Brassicaceae vegetables. BREEDING SCIENCE 2014; 64:48-59. [PMID: 24987290 PMCID: PMC4031110 DOI: 10.1270/jsbbs.64.48] [Citation(s) in RCA: 183] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/20/2013] [Accepted: 02/24/2014] [Indexed: 05/18/2023]
Abstract
Unique secondary metabolites, glucosinolates (S-glucopyranosyl thiohydroximates), are naturally occurring S-linked glucosides found mainly in Brassicaceae plants. They are enzymatically hydrolyzed to produce sulfate ions, D-glucose, and characteristic degradation products such as isothiocyanates. The functions of glucosinolates in the plants remain unclear, but isothiocyanates possessing a pungent or irritating taste and odor might be associated with plant defense from microbes. Isothiocyanates have been studied extensively in experimental in vitro and in vivo carcinogenesis models for their cancer chemopreventive properties. The beneficial isothiocyanates, glucosinolates that are functional for supporting human health, have received attention from many scientists studying plant breeding, plant physiology, plant genetics, and food functionality. This review presents a summary of recent topics related with glucosinolates in the Brassica family, along with a summary of the chemicals, metabolism, and genes of glucosinolates in Brassicaceae. The bioavailabilities of isothiocyanates from certain functional glucosinolates and the importance of breeding will be described with emphasis on glucosinolates.
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Affiliation(s)
- Masahiko Ishida
- NARO Institute of Vegetable and Tea Science, Tsukuba Vegetable Research Station,
3-1-1 Kannondai, Tsukuba, Ibaraki 305-8666,
Japan
- Corresponding author (e-mail: )
| | - Masakazu Hara
- Research Institute of Green Science and Technology, Shizuoka University,
836 Ohya, Shizuoka 422-8529,
Japan
| | - Nobuko Fukino
- NARO Institute of Vegetable and Tea Science,
360 Kusawa, Ano, Tsu, Mie 514-2392,
Japan
| | - Tomohiro Kakizaki
- NARO Institute of Vegetable and Tea Science,
360 Kusawa, Ano, Tsu, Mie 514-2392,
Japan
| | - Yasujiro Morimitsu
- The Department of Food and Nutritional Sciences, The Graduate School of Humanities and Sciences, Ochanomizu University,
2-1-1 Otsuka, Bunkyo, Tokyo 112-8610,
Japan
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Abstract
Cancer is a complex disease characterized by multiple genetic and molecular alterations involving transformation, deregulation of apoptosis, proliferation, invasion, angiogenesis, and metastasis. To grow, invade, and metastasize, tumors need host components and primary dysfunction in the tumor microenvironment, in addition to cell dysfunction, can be crucial for carcinogenesis. A great variety of phytochemicals have been shown to be potentially capable of inhibiting and modulating several relevant targets simultaneously and is therefore non-specific. Because of the enormous biological diversity of cancer, this pleiotropism might constitute an advantage. Phytochemicals, in particular diet-derived compounds, have therefore been proposed and applied in clinical trials as cancer chemopreventive/chemotherapeutic agents. Sulforaphane (SFN) is an isothiocyanate found in cruciferous vegetables. SFN has proved to be an effective chemoprotective agent in cell culture, in carcinogen-induced and genetic animal cancer models, as well as in xenograft models of cancer. It promoted potent cytostatic and cytotoxic effects orchestrated by the modulation of different molecular targets. Cell vulnerability to SFN-mediated apoptosis was subject to regulation by cell-cycle-dependent mechanisms but was independent of a mutated p53 status. Moreover, combination of SFN with cytotoxic therapy potentiated the cytotoxic effect mediated by chemotherapy in vitro, thus suggesting its potential therapeutic benefit in clinical settings. Overall, SFN appears to be an effective and safe chemopreventive molecule and a promising tool to fight cancer.
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Yamaguchi H, Kamiie K, Kidachi Y, Noshita T, Umetsu H, Fuke Y, Ryoyama K. Intracellular accumulation of structurally varied isothiocyanates correlates with inhibition of nitric oxide production in proinflammatory stimuli-activated tumorigenic macrophage-like cells. Bioorg Med Chem 2014; 22:440-6. [DOI: 10.1016/j.bmc.2013.11.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2013] [Revised: 11/03/2013] [Accepted: 11/04/2013] [Indexed: 12/01/2022]
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Lee YR, Noh EM, Han JH, Kim JM, Hwang BM, Kim BS, Lee SH, Jung SH, Youn HJ, Chung EY, Kim JS. Sulforaphane controls TPA-induced MMP-9 expression through the NF-κB signaling pathway, but not AP-1, in MCF-7 breast cancer cells. BMB Rep 2013; 46:201-6. [PMID: 23615261 PMCID: PMC4133889 DOI: 10.5483/bmbrep.2013.46.4.160] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Sulforaphane [1-isothiocyanato-4-(methylsulfinyl)-butane] is an isothiocyanate found in some cruciferous vegetables, especially broccoli. Sulforaphane has been shown to display anti-cancer properties against various cancer cell lines. Matrix metalloproteinase-9 (MMP-9), which degrades the extracellular matrix (ECM), plays an important role in cancer cell invasion. In this study, we investigated the effect of sulforaphane on 12-O-tetradecanoyl phorbol-13-acetate (TPA)-induced MMP-9 expression and cell invasion in MCF-7 cells. TPA-induced MMP-9 expression and cell invasion were decreased by sulforaphane treatment. TPA substantially increased NF-κB and AP-1 DNA binding activity. Pre-treatment with sulforaphane inhibited TPA-stimulated NF-κB binding activity, but not AP-1 binding activity. In addition, we found that sulforaphane suppressed NF-κB activation, by inhibiting phosphorylation of IκB in TPA-treated MCF-7 cells. In this study, we demonstrated that the inhibition of TPA-induced MMP-9 expression and cell invasion by sulforaphane was mediated by the suppression of the NF-κB pathway in MCF-7 cells. [BMB Reports 2013; 46(4): 201-206]
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Affiliation(s)
- Young-Rae Lee
- Department of Anesthesiology and Pain Medicine, Bucheon St. Mary's Hospital, The Catholic University of Korea, Bucheon 420-717, Korea.
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Li Y, Saldanha SN, Tollefsbol TO. Impact of epigenetic dietary compounds on transgenerational prevention of human diseases. AAPS JOURNAL 2013; 16:27-36. [PMID: 24114450 DOI: 10.1208/s12248-013-9538-7] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 04/25/2013] [Accepted: 09/25/2013] [Indexed: 01/10/2023]
Abstract
The etiology of most human diseases involves complicated interactions of multiple environmental factors with individual genetic background which is initially generated early in human life, for example, during the processes of embryogenesis and fetal development in utero. Early embryogenesis includes a series of programming processes involving extremely accurate time-controlled gene activation/silencing expressions, and epigenetic control is believed to play a key role in regulating early embryonic development. Certain dietary components with properties in influencing epigenetic processes are believed to have preventive effects on many human diseases such as cancer. Evidence shows that in utero exposure to certain epigenetic diets may lead to reprogramming of primary epigenetic profiles such as DNA methylation and histone modifications on the key coding genes of the fetal genome, leading to different susceptibility to diseases later in life. In this review, we assess the current advances in dietary epigenetic intervention on transgenerational human disease control. Enhanced understanding of the important role of early life epigenetics control may lead to cost-effective translational chemopreventive potential by appropriate administration of prenatal and/or postnatal dietary supplements leading to early disease prevention.
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Affiliation(s)
- Yuanyuan Li
- Department of Biology, University of Alabama at Birmingham, Birmingham, Alabama, 35294, USA,
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Mokhtari RB, Kumar S, Islam SS, Yazdanpanah M, Adeli K, Cutz E, Yeger H. Combination of carbonic anhydrase inhibitor, acetazolamide, and sulforaphane, reduces the viability and growth of bronchial carcinoid cell lines. BMC Cancer 2013; 13:378. [PMID: 23927827 PMCID: PMC3848757 DOI: 10.1186/1471-2407-13-378] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2012] [Accepted: 07/15/2013] [Indexed: 12/31/2022] Open
Abstract
Background Bronchial carcinoids are pulmonary neuroendocrine cell-derived tumors comprising typical (TC) and atypical (AC) malignant phenotypes. The 5-year survival rate in metastatic carcinoid, despite multiple current therapies, is 14-25%. Hence, we are testing novel therapies that can affect the proliferation and survival of bronchial carcinoids. Methods In vitro studies were used for the dose–response (AlamarBlue) effects of acetazolamide (AZ) and sulforaphane (SFN) on clonogenicity, serotonin-induced growth effect and serotonin content (LC-MS) on H-727 (TC) and H-720 (AC) bronchial carcinoid cell lines and their derived NOD/SCID mice subcutaneous xenografts. Tumor ultra structure was studied by electron microscopy. Invasive fraction of the tumors was determined by matrigel invasion assay. Immunohistochemistry was conducted to study the effect of treatment(s) on proliferation (Ki67, phospho histone-H3) and neuroendocrine phenotype (chromogranin-A, tryptophan hydroxylase). Results Both compounds significantly reduced cell viability and colony formation in a dose-dependent manner (0–80 μM, 48 hours and 7 days) in H-727 and H-720 cell lines. Treatment of H-727 and H-720 subcutaneous xenografts in NOD/SCID mice with the combination of AZ + SFN for two weeks demonstrated highly significant growth inhibition and reduction of 5-HT content and reduced the invasive capacity of H-727 tumor cells. In terms of the tumor ultra structure, a marked reduction in secretory vesicles correlated with the decrease in 5-HT content. Conclusions The combination of AZ and SFN was more effective than either single agent. Since the effective doses are well within clinical range and bioavailability, our results suggest a potential new therapeutic strategy for the treatment of bronchial carcinoids.
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Affiliation(s)
- Reza Bayat Mokhtari
- Developmental and Stem Cell Biology, University of Toronto, Toronto, ON, Canada.
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SAWAI YASUSHI, MURATA HIROAKI, HORII MOTOYUKI, KOTO KAZUTAKA, MATSUI TAKAAKI, HORIE NAOYUKI, TSUJI YOSHIRO, ASHIHARA EISHI, MAEKAWA TAIRA, KUBO TOSHIKAZU, FUSHIKI SHINJI. Effectiveness of sulforaphane as a radiosensitizer for murine osteosarcoma cells. Oncol Rep 2012; 29:941-5. [DOI: 10.3892/or.2012.2195] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2012] [Accepted: 11/19/2012] [Indexed: 11/05/2022] Open
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Suppipat K, Park CS, Shen Y, Zhu X, Lacorazza HD. Sulforaphane induces cell cycle arrest and apoptosis in acute lymphoblastic leukemia cells. PLoS One 2012; 7:e51251. [PMID: 23251470 PMCID: PMC3521002 DOI: 10.1371/journal.pone.0051251] [Citation(s) in RCA: 74] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2012] [Accepted: 10/29/2012] [Indexed: 12/12/2022] Open
Abstract
Acute lymphoblastic leukemia (ALL) is the most common hematological cancer in children. Although risk-adaptive therapy, CNS-directed chemotherapy, and supportive care have improved the survival of ALL patients, disease relapse is still the leading cause of cancer-related death in children. Therefore, new drugs are needed as frontline treatments in high-risk disease and as salvage agents in relapsed ALL. In this study, we report that purified sulforaphane, a natural isothiocyanate found in cruciferous vegetables, has anti-leukemic properties in a broad range of ALL cell lines and primary lymphoblasts from pediatric T-ALL and pre-B ALL patients. The treatment of ALL leukemic cells with sulforaphane resulted in dose-dependent apoptosis and G2/M cell cycle arrest, which was associated with the activation of caspases (3, 8, and 9), inactivation of PARP, p53-independent upregulation of p21(CIP1/WAF1), and inhibition of the Cdc2/Cyclin B1 complex. Interestingly, sulforaphane also inhibited the AKT and mTOR survival pathways in most of the tested cell lines by lowering the levels of both total and phosphorylated proteins. Finally, the administration of sulforaphane to the ALL xenograft models resulted in a reduction of tumor burden, particularly following oral administration, suggesting a potential role as an adjunctive agent to improve the therapeutic response in high-risk ALL patients with activated AKT signaling.
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Affiliation(s)
- Koramit Suppipat
- Texas Children’s Cancer and Hematology Centers, Texas Children’s Hospital, Houston, Texas, United States of America
| | - Chun Shik Park
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, United States of America
| | - Ye Shen
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, United States of America
| | - Xiao Zhu
- Summer Medical and Research Training Program, Baylor College of Medicine, Houston, Texas, United States of America
| | - H. Daniel Lacorazza
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, United States of America
- Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States of America
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JEONG HEEJEONG, YU SEONMI, JUNG JAECHANG, KIM SONGJA. Sulforaphane inhibits proliferation by causing cell cycle arrest at the G2/M phase in rabbit articular chondrocytes. Mol Med Rep 2012; 6:1199-203. [DOI: 10.3892/mmr.2012.1057] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2012] [Accepted: 08/20/2012] [Indexed: 11/05/2022] Open
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Azizi Naser S, Amiri-Besheli B, Sharifi-Mehr S. The Isolation and Determination of Sulforaphane from Broccoli Tissues by Reverse Phase-High Performance Liquid Chromatography. J CHIN CHEM SOC-TAIP 2011. [DOI: 10.1002/jccs.201190143] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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Fimognari C, Turrini E, Ferruzzi L, Lenzi M, Hrelia P. Natural isothiocyanates: genotoxic potential versus chemoprevention. Mutat Res 2011; 750:107-131. [PMID: 22178957 DOI: 10.1016/j.mrrev.2011.12.001] [Citation(s) in RCA: 76] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2011] [Revised: 12/01/2011] [Accepted: 12/02/2011] [Indexed: 12/12/2022]
Abstract
Isothiocyanates, occurring in many dietary cruciferous vegetables, show interesting chemopreventive activities against several chronic-degenerative diseases, including cancer, cardiovascular diseases, neurodegeneration, diabetes. The electrophilic carbon residue in the isothiocyanate moiety reacts with biological nucleophiles and modification of proteins is recognized as a key mechanism underlying the biological activity of isothiocyanates. The nuclear factor-erythroid-2-related factor 2 system, which orchestrates the expression of a wide array of antioxidant genes, plays a role in the protective effect of isothiocyanates against almost all the pathological conditions reported above. Recent emerging findings suggest a further common mechanism. Chronic inflammation plays a central role in many human diseases and isothiocyanates inhibit the activity of many inflammation components, suppress cyclooxygenase 2, and irreversibly inactivate the macrophage migration inhibitory factor. Due to their electrophilic reactivity, some isothiocyanates are able to form adducts with DNA and induce gene mutations and chromosomal aberrations. DNA damage has been demonstrated to be involved in the pathogenesis of various chronic-degenerative diseases of epidemiological relevance. Thus, the genotoxicity of the isothiocyanates should be carefully considered. In addition, the dose-response relationship for genotoxic compounds does not suggest evidence of a threshold. Thus, chemicals that are genotoxic pose a greater potential risk to humans than non-genotoxic compounds. Dietary consumption levels of isothiocyanates appear to be several orders of magnitude lower than the doses used in the genotoxicity studies and thus it is highly unlikely that such toxicities would occur in humans. However, the beneficial properties of isothiocyanates stimulated an increase of dietary supplements and functional foods with highly enriched isothiocyanate concentrations on the market. Whether such concentrations may exert a potential health risk cannot be excluded with certainty and an accurate evaluation of the toxicological profile of isothiocyanates should be prompted before any major increase in their consumption be recommended or their clinical use suggested.
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Affiliation(s)
- Carmela Fimognari
- Department of Pharmacology, University of Bologna, via Irnerio 48, 40126 Bologna, Italy.
| | - Eleonora Turrini
- Department of Pharmacology, University of Bologna, via Irnerio 48, 40126 Bologna, Italy
| | - Lorenzo Ferruzzi
- Department of Pharmacology, University of Bologna, via Irnerio 48, 40126 Bologna, Italy
| | - Monia Lenzi
- Department of Pharmacology, University of Bologna, via Irnerio 48, 40126 Bologna, Italy
| | - Patrizia Hrelia
- Department of Pharmacology, University of Bologna, via Irnerio 48, 40126 Bologna, Italy
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