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1
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Tian F, Sun S, Ge Z, Ge Y, Ge X, Shi Z, Qian X. Understanding the Anticancer Effects of Phytochemicals: From Molecular Docking to Anticarcinogenic Signaling. J Nutr 2025; 155:431-444. [PMID: 39581266 DOI: 10.1016/j.tjnut.2024.11.015] [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: 11/13/2024] [Accepted: 11/20/2024] [Indexed: 11/26/2024] Open
Abstract
As nontraditional nutrients, the biological activity of phytochemicals have been extensively studied for their antioxidant, anti-inflammatory, and apoptosis-promoting effects in various diseases. The general anticancer benefits of phytochemicals have been demonstrated in both basic researches and clinical trials. However, researchers understanding of how phytochemicals target cancer-related signaling pathways is still in its infancy. Molecular docking simulation analyses have yielded a large amount of cellular target molecules of phytochemicals. Herein, we review the potential signaling pathways that may be involved in the phytochemical-driven cancer benefits. We expect these findings to help in the design of potential cancer treatments designed by manipulating the binding modes and sites of these plant chemicals.
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Affiliation(s)
- Fuwei Tian
- Department of Nutrition and Food Hygiene, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Shuhong Sun
- Department of Nutrition and Food Hygiene, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Zehe Ge
- Department of Nutrition and Food Hygiene, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yuqian Ge
- Department of Nutrition and Food Hygiene, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xin Ge
- Department of Nutrition and Food Hygiene, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Zhumei Shi
- Department of Nutrition and Food Hygiene, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China; Department of Neurosurgery of the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xu Qian
- Department of Nutrition and Food Hygiene, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China; Department of Neurosurgery of the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
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Rowghani K, Patel B, Martinez-Guryn K. Dietary impact on the gut microbiome and epigenome and regulation of gut inflammation. NUTRITION IN THE CONTROL OF INFLAMMATION 2025:369-398. [DOI: 10.1016/b978-0-443-18979-1.00014-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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3
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Deng X, Yang Z, Han M, Ismail N, Esa NM, Razis AFA, Bakar MZA, Chan KW. Comprehensive Insights Into the Combinatorial Uses of Selected Phytochemicals in Colorectal Cancer Prevention and Treatment: Isothiocyanates, Quinones, Carotenoids, and Alkaloids. Phytother Res 2025; 39:413-452. [PMID: 39557422 DOI: 10.1002/ptr.8378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Revised: 10/01/2024] [Accepted: 10/24/2024] [Indexed: 11/20/2024]
Abstract
Despite the advancement in cancer diagnosis and treatment, colorectal cancer remains the leading cause of cancer-related death worldwide. Given the high recurrence rate of colorectal cancer even after surgical resection, chemotherapy has been clinically used to improve the treatment outcomes of colorectal cancer. However, chemotherapy is well-known for its toxic side effects. Thus, phytochemicals have been widely studied in recent years as preventive and therapeutic agents for colorectal cancer owing to their relatively low toxicity. Moreover, combinatorial uses of phytochemicals with other natural compounds or with drugs may amplify the positive outcomes of colorectal cancer prevention and treatment by intervening in multiple signaling pathways and targets. This review summarized the combinatorial use of several well-studied groups of phytochemicals, that is, isothiocyanates, quinones, carotenoids, and alkaloids, in the prevention and treatment of colorectal cancer, and suggested it as a potential approach to improve the anticancer efficacy of single compounds and minimize the toxic side effects associated with conventional drugs. Notably, we generalized the in vitro, in vivo, and clinical experiments-based molecular mechanisms whereby the selected phytochemicals in combination with other compounds exerted anti-colorectal cancer effects by inhibiting cancer cell proliferation, cell apoptosis, cell invasion, and tumor growth. Overall, this review provides a reference and new perspective to propel further advancements in research and development of preventative and therapeutic strategies for colorectal cancer.
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Affiliation(s)
- Xi Deng
- Natural Medicines and Products Research Laboratory, Institute of Bioscience, Universiti Putra Malaysia, Serdang, Selangor, Malaysia
| | - Zhongming Yang
- Natural Medicines and Products Research Laboratory, Institute of Bioscience, Universiti Putra Malaysia, Serdang, Selangor, Malaysia
| | - Mingzhao Han
- Department of Land Management, Faculty of Agriculture, Universiti Putra Malaysia, Serdang, Selangor, Malaysia
| | - Norsharina Ismail
- Natural Medicines and Products Research Laboratory, Institute of Bioscience, Universiti Putra Malaysia, Serdang, Selangor, Malaysia
| | - Norhaizan Mohd Esa
- Department of Nutrition, Faculty of Medicine and Health Science, Universiti Putra Malaysia, Serdang, Selangor, Malaysia
- UPM-MAKNA Cancer Research Laboratory, Institute of Bioscience, Universiti Putra Malaysia, Serdang, Selangor, Malaysia
| | - Ahmad Faizal Abdull Razis
- Natural Medicines and Products Research Laboratory, Institute of Bioscience, Universiti Putra Malaysia, Serdang, Selangor, Malaysia
- Department of Food Science, Faculty of Food Science and Technology, Universiti Putra Malaysia, Serdang, Selangor, Malaysia
| | - Md Zuki Abu Bakar
- Natural Medicines and Products Research Laboratory, Institute of Bioscience, Universiti Putra Malaysia, Serdang, Selangor, Malaysia
- Department of Veterinary Preclinical Science, Faculty of Veterinary Medicine, Universiti Putra Malaysia, Serdang, Selangor, Malaysia
| | - Kim Wei Chan
- Natural Medicines and Products Research Laboratory, Institute of Bioscience, Universiti Putra Malaysia, Serdang, Selangor, Malaysia
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Mohan N, Johnson GS, Tovar Perez JE, Dashwood WM, Rajendran P, Dashwood RH. Alternative splicing of BAZ1A in colorectal cancer disrupts the DNA damage response and increases chemosensitization. Cell Death Dis 2024; 15:570. [PMID: 39112459 PMCID: PMC11306231 DOI: 10.1038/s41419-024-06954-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Revised: 07/23/2024] [Accepted: 07/25/2024] [Indexed: 08/10/2024]
Abstract
Bromodomain Adjacent to Zinc Finger Domain 1A (BAZ1A) is a critical regulator of chromatin remodeling. We sought to clarify the roles of BAZ1A in the etiology of colorectal cancer, including the mechanisms of its alternatively spliced variants. Public databases were examined and revealed high BAZ1A expression in the majority of colorectal cancer patients, which was corroborated in a panel of human colon cancer cell lines. BAZ1A silencing reduced cell viability and increased markers of DNA damage, apoptosis, and senescence, along with the downregulation of Wnt/β-catenin signaling. The corresponding molecular changes resulted in tumor growth inhibition when BAZ1A-knockout cells were implanted into nude mice. In rescue experiments, a short isoform of BAZ1A that was associated with alternative splicing by the DBIRD complex failed to restore DNA repair activity in colon cancer cells and maintained chemosensitivity to phleomycin treatment, unlike the full-length BAZ1A. A working model proposes that a buried domain in the N-terminus of the BAZ1A short isoform lacks the ability to access linker DNA, thereby disrupting the activity of the associated chromatin remodeling complexes. Given the current interest in RNA splicing deregulation and cancer etiology, additional mechanistic studies are warranted with new lead compounds targeting BAZ1A, and other members of the BAZ family, with a view to improved therapeutic interventions.
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Affiliation(s)
- Nivedhitha Mohan
- Center for Epigenetics & Disease Prevention, Texas A&M Health, Houston, TX, USA
| | - Gavin S Johnson
- Center for Epigenetics & Disease Prevention, Texas A&M Health, Houston, TX, USA
- CRISPR Therapeutics, South Boston, MA, USA
| | | | | | - Praveen Rajendran
- Center for Epigenetics & Disease Prevention, Texas A&M Health, Houston, TX, USA.
- Department of Translational Medical Sciences, Texas A&M College of Medicine, Houston, TX, USA.
| | - Roderick H Dashwood
- Center for Epigenetics & Disease Prevention, Texas A&M Health, Houston, TX, USA.
- Department of Translational Medical Sciences, Texas A&M College of Medicine, Houston, TX, USA.
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5
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DeBenedictis JN, Murrell C, Hauser D, van Herwijnen M, Elen B, de Kok TM, van Breda SG. Effects of Different Combinations of Phytochemical-Rich Fruits and Vegetables on Chronic Disease Risk Markers and Gene Expression Changes: Insights from the MiBLEND Study, a Randomized Trial. Antioxidants (Basel) 2024; 13:915. [PMID: 39199161 PMCID: PMC11351619 DOI: 10.3390/antiox13080915] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 07/13/2024] [Accepted: 07/19/2024] [Indexed: 09/01/2024] Open
Abstract
Adequate fruit and vegetable (F and V) intake, as recommended by the World Health Organization (over 400 g/day), is linked to reduced chronic disease risk. However, human intervention trials, especially with whole F and V and in complex combinations, are lacking. The MiBlend Study explored the effects of various phytochemical-rich F and V combinations on chronic disease risk markers, phytochemical absorption, and gene expression in blood. This randomized cross-over study involved participants consuming two of seven different F and V blends for 2 weeks (450 g/day), following a 2-week low F and V intake period (50 g/day). Each blend represented major phytochemical classes (flavonoids, anthocyanins, carotenoids, and glucosinolates) or combinations thereof. Markers of chronic disease risk, including DNA damage, oxidative stress, and retinal microvasculature, were measured. Increasing F and V intake significantly improved plasma antioxidant capacity, DNA damage protection, and retinal arteriolar dilation. Flavonoid-rich, carotenoid-rich, and complex blends notably reduced DNA damage susceptibility. Anthocyanin-rich and carotenoid-rich interventions were most effective in boosting antioxidant capacity, while blends high in flavonoids, especially combined with anthocyanins, significantly improved retinal microvasculature. Gene expression analysis revealed changes in DNA repair, signal transduction, and transcription processes, indicating mechanisms for these health benefits. The study suggests specific F and V blends can provide targeted health improvements, emphasizing the importance of both overall F and V intake and the specific phytochemical composition for personalized preventive strategies.
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Affiliation(s)
- Julia N. DeBenedictis
- Toxicogenomics Department, GROW School of Oncology & Reproduction, Faculty of Health, Medicine & Life Sciences, Maastricht University, 6229 ER Maastricht, The Netherlands
| | - Courtney Murrell
- Toxicogenomics Department, GROW School of Oncology & Reproduction, Faculty of Health, Medicine & Life Sciences, Maastricht University, 6229 ER Maastricht, The Netherlands
| | - Duncan Hauser
- Toxicogenomics Department, GROW School of Oncology & Reproduction, Faculty of Health, Medicine & Life Sciences, Maastricht University, 6229 ER Maastricht, The Netherlands
| | - Marcel van Herwijnen
- Toxicogenomics Department, GROW School of Oncology & Reproduction, Faculty of Health, Medicine & Life Sciences, Maastricht University, 6229 ER Maastricht, The Netherlands
| | - Bart Elen
- Flemish Institute for Technological Research (VITO), 2400 Mol, Belgium
| | - Theo M. de Kok
- Toxicogenomics Department, GROW School of Oncology & Reproduction, Faculty of Health, Medicine & Life Sciences, Maastricht University, 6229 ER Maastricht, The Netherlands
| | - Simone G. van Breda
- Toxicogenomics Department, GROW School of Oncology & Reproduction, Faculty of Health, Medicine & Life Sciences, Maastricht University, 6229 ER Maastricht, The Netherlands
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Maycotte P, Illanes M, Moreno DA. Glucosinolates, isothiocyanates, and their role in the regulation of autophagy and cellular function. PHYTOCHEMISTRY REVIEWS 2024. [DOI: 10.1007/s11101-024-09944-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Accepted: 02/27/2024] [Indexed: 01/04/2025]
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7
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Zhang F, Wan X, Zhan J, Shen M, Li R. Sulforaphane inhibits the growth of prostate cancer by regulating the microRNA-3919/DJ-1 axis. Front Oncol 2024; 14:1361152. [PMID: 38515566 PMCID: PMC10955061 DOI: 10.3389/fonc.2024.1361152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2023] [Accepted: 02/13/2024] [Indexed: 03/23/2024] Open
Abstract
Background Prostate cancer (PCa) is the second most common solid cancer among men worldwide and the fifth leading cause of cancer-related deaths in men. Sulforaphane (SFN), an isothiocyanate compound, has been shown to exert inhibitory effects on a variety of cancers. However, the biological function of SFN in PCa has not been fully elucidated. The objective of this study was conducted to further investigate the possible underlying mechanism of SFN in PCa using in vitro cell culture and in vivo tumor model experiments. Methods Cell viability, migration, invasion, and apoptosis were analyzed by Cell Counting Kit-8 (CCK-8), wound healing assay, transwell assay, or flow cytometry. Expression of microRNA (miR)-3919 was detected by quantitative real-time polymerase chain reaction (qRT-PCR) or in situ hybridization assay. Xenograft assay was conducted to validated the antitumor effect of miR-3919. The targeting relationship between miR-3919 and DJ-1 was verified by dual-luciferase reporter assay. The level of DJ-1was measured by qRT-PCR or western blotting (WB). Results In the present study, SFN downregulated mRNA and protein expression of DJ-1, an oncogenic gene. Small RNA sequencing analysis and dual-luciferase reporter assay confirmed that microRNA (miR)-3919 directly targeted DJ-1 to inhibition its expression. Furthermore, miR-3919 overexpression impeded viability, migration, and invasion and promoted apoptosis of PCa cells. Tumor growth in nude mice was also inhibited by miR-3919 overexpression, and miR-3919 expression in PCa tissues was lower than that in peritumoral tissues in an in situ hybridization assay. Transfection with miR-3919 inhibitors partially reversed the effects of SFN on cell viability, migration, invasion, and apoptosis. Conclusion Overall, the miR-3919/DJ-1 axis may be involved in the effects of SFN on the malignant biological behavior of PCa cells, which might be a new therapeutic target in PCa.
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Affiliation(s)
- Fangxi Zhang
- National Health Commission (NHC) Key Lab of Reproduction Regulation (Shanghai Institute for Biomedical and Pharmaceutical Technologies), School of Pharmacy, Fudan University, Shanghai, China
- Department of Pharmacy and Examination, Heze Medical Collge, Heze, China
| | - Xiaofeng Wan
- National Health Commission (NHC) Key Lab of Reproduction Regulation (Shanghai Institute for Biomedical and Pharmaceutical Technologies), School of Pharmacy, Fudan University, Shanghai, China
| | - Jianmin Zhan
- National Health Commission (NHC) Key Lab of Reproduction Regulation (Shanghai Institute for Biomedical and Pharmaceutical Technologies), School of Pharmacy, Fudan University, Shanghai, China
| | - Ming Shen
- National Health Commission (NHC) Key Lab of Reproduction Regulation (Shanghai Institute for Biomedical and Pharmaceutical Technologies), School of Pharmacy, Fudan University, Shanghai, China
| | - Runsheng Li
- National Health Commission (NHC) Key Lab of Reproduction Regulation (Shanghai Institute for Biomedical and Pharmaceutical Technologies), School of Pharmacy, Fudan University, Shanghai, China
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8
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Holczer M, Besze B, Lehel A, Kapuy O. The Dual Role of Sulforaphane-Induced Cellular Stress-A Systems Biological Study. Int J Mol Sci 2024; 25:1220. [PMID: 38279216 PMCID: PMC11154497 DOI: 10.3390/ijms25021220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Revised: 01/13/2024] [Accepted: 01/17/2024] [Indexed: 01/28/2024] Open
Abstract
The endoplasmic reticulum (ER) plays a crucial role in cellular homeostasis. When ER stress is generated, an autophagic self-digestive process is activated to promote cell survival; however, cell death is induced in the case of excessive levels of ER stress. The aim of the present study was to investigate the effect of a natural compound called sulforaphane (SFN) upon ER stress. Our goal was to investigate how SFN-dependent autophagy activation affects different stages of ER stress induction. We approached our scientific analysis from a systems biological perspective using both theoretical and molecular biological techniques. We found that SFN induced the various cell-death mechanisms in a concentration- and time-dependent manner. The short SFN treatment at low concentrations promoted autophagy, whereas the longer treatment at higher concentrations activated cell death. We proved that SFN activated autophagy in a mTORC1-dependent manner and that the presence of ULK1 was required for its function. A low concentration of SFN pre- or co-treatment combined with short and long ER stress was able to promote cell survival via autophagy induction in each treatment, suggesting the potential medical importance of SFN in ER stress-related diseases.
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Affiliation(s)
| | | | | | - Orsolya Kapuy
- Department of Molecular Biology, Institute of Biochemistry and Molecular Biology, Semmelweis University, 1085 Budapest, Hungary; (M.H.); (B.B.); (A.L.)
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9
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Targeting ACE2-BRD4 crosstalk in colorectal cancer and the deregulation of DNA repair and apoptosis. NPJ Precis Oncol 2023; 7:20. [PMID: 36801948 PMCID: PMC9938505 DOI: 10.1038/s41698-023-00361-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2022] [Accepted: 02/10/2023] [Indexed: 02/20/2023] Open
Abstract
ACE2 overexpression in colorectal cancer patients might increase susceptibility to SARS-CoV-2 infection. We report that knockdown, forced overexpression, and pharmacologic inhibition in human colon cancer cells targeted ACE2-BRD4 crosstalk to mediate marked changes in DNA damage/repair and apoptosis. In colorectal cancer patients for whom high ACE2 plus high BRD4 expression is predictive of poor survival, pan-BET inhibition would need to consider proviral/antiviral actions of different BET proteins during SARS-CoV-2 infection.
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10
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Kapoor S, Damiani E, Wang S, Dharmanand R, Tripathi C, Tovar Perez JE, Dashwood WM, Rajendran P, Dashwood RH. BRD9 Inhibition by Natural Polyphenols Targets DNA Damage/Repair and Apoptosis in Human Colon Cancer Cells. Nutrients 2022; 14:nu14204317. [PMID: 36297001 PMCID: PMC9610492 DOI: 10.3390/nu14204317] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 10/07/2022] [Accepted: 10/14/2022] [Indexed: 11/07/2022] Open
Abstract
Epigenetic mechanisms play an important role in the etiology of colorectal cancer (CRC) and other malignancies due, in part, to deregulated bromodomain (BRD) functions. Inhibitors of the bromodomain and extraterminal (BET) family have entered into clinical trials as anticancer agents, and interest has grown in other acetyl 'reader' proteins as therapeutic targets, including non-BET member bromodomain-containing protein 9 (BRD9). We report here that overexpression of BRD9 is associated with poor prognosis in CRC patients, and that siRNA-mediated knockdown of BRD9 decreased cell viability and activated apoptosis in human colon cancer cells, coincident with increased DNA damage. Seeking natural compounds as BRD9 antagonists, molecular docking in silico identified several polyphenols such as Epigallocatechin-3-gallate (EGCG), Equol, Quercetin, and Aspalathin, with favorable binding energies, supported by BROMOscan® (DiscoverX) and isothermal titration calorimetry experiments. Polyphenols mimicked BRD9 knockdown and iBRD9 treatment in reducing colon cancer cell viability, inhibiting colony formation, and enhancing DNA damage and apoptosis. Normal colonic epithelial cells were unaffected, signifying cancer-specific effects. These findings suggest that natural polyphenols recognize and target BRD9 for inhibition, and might serve as useful lead compounds for bromodomain therapeutics in the clinical setting.
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Affiliation(s)
- Sabeeta Kapoor
- Center for Epigenetics & Disease Prevention, Texas A&M Health, Houston, TX 77030, USA
| | - Elisabetta Damiani
- Department of Life and Environmental Sciences, Università Politecnica delle Marche, 60121 Ancona, Italy
| | - Shan Wang
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Hangzhou 310030, China
| | - Ravirajan Dharmanand
- Center for Infectious & Inflammatory Diseases, Texas A&M Health, Houston, TX 77030, USA
| | - Chakrapani Tripathi
- Center for Epigenetics & Disease Prevention, Texas A&M Health, Houston, TX 77030, USA
| | | | - Wan Mohaiza Dashwood
- Center for Epigenetics & Disease Prevention, Texas A&M Health, Houston, TX 77030, USA
| | - Praveen Rajendran
- Center for Epigenetics & Disease Prevention, Texas A&M Health, Houston, TX 77030, USA
- Department of Translational Medical Sciences, Texas A&M College of Medicine, Houston, TX 77030, USA
- Correspondence: (P.R.); (R.H.D.); Tel.: +1-713-677-7803 (P.R.); +1-713-677-7806 (R.H.D.)
| | - Roderick Hugh Dashwood
- Center for Epigenetics & Disease Prevention, Texas A&M Health, Houston, TX 77030, USA
- Department of Translational Medical Sciences, Texas A&M College of Medicine, Houston, TX 77030, USA
- Correspondence: (P.R.); (R.H.D.); Tel.: +1-713-677-7803 (P.R.); +1-713-677-7806 (R.H.D.)
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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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12
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Huang M, Liu C, Shao Y, Zhou S, Hu G, Yin S, Pu W, Yu H. Anti-tumor pharmacology of natural products targeting mitosis. Cancer Biol Med 2022; 19:j.issn.2095-3941.2022.0006. [PMID: 35699421 PMCID: PMC9257311 DOI: 10.20892/j.issn.2095-3941.2022.0006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Cancer has been an insurmountable problem in the history of medical science. The uncontrollable proliferation of cancer cells is one of cancer’s main characteristics, which is closely associated with abnormal mitosis. Targeting mitosis is an effective method for cancer treatment. This review summarizes several natural products with anti-tumor effects related to mitosis, focusing on targeting microtubulin, inducing DNA damage, and modulating mitosis-associated kinases. Furthermore, the main disadvantages of several typical compounds, including drug resistance, toxicity to non-tumor tissues, and poor aqueous solubility and pharmacokinetic properties, are also discussed, together with strategies to address them. Improved understanding of cancer cell mitosis and natural products may pave the way to drug development for the treatment of cancer.
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Affiliation(s)
- Manru Huang
- Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China.,State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Caiyan Liu
- Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China.,State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Yingying Shao
- Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China.,State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Shiyue Zhou
- Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China.,State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Gaoyong Hu
- Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China.,State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Shuangshuang Yin
- Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China.,State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Weiling Pu
- Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China.,State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Haiyang Yu
- Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China.,State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
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Sulforaphane Enhanced Proliferation of Porcine Satellite Cells via Epigenetic Augmentation of SMAD7. Animals (Basel) 2022; 12:ani12111365. [PMID: 35681828 PMCID: PMC9179638 DOI: 10.3390/ani12111365] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Revised: 05/22/2022] [Accepted: 05/24/2022] [Indexed: 12/10/2022] Open
Abstract
Satellite cells take an indispensable place in skeletal muscle regeneration, maintenance, and growth. However, only limited works have investigated effects of dietary compounds on the proliferation of porcine satellite cells (PSCs) and related mechanisms. Sulforaphane (SFN) at multiple levels was applied to PSCs. The PSCs’ viability and HDAC activity were measured with a WST-1 cell proliferation kit and Color-de-Lys® HDAC colorimetric activity assay kit. Gene expression and epigenetics modification were tested with qRT-PCR, Western blot, bisulfite sequencing, and ChIP-qPCR. This study found that SFN enhanced PSC proliferation and altered mRNA expression levels of myogenic regulatory factors. In addition, SFN inhibited histone deacetylase (HDAC) activity, disturbed mRNA levels of HDAC family members, and elevated acetylated histone H3 and H4 abundance in PSCs. Furthermore, both mRNA and protein levels of the Smad family member 7 (SMAD7) in PSCs were upregulated after SFN treatment. Finally, it was found that SFN increased the acetylation level of histone H4 in the SMAD7 promoter, decreased the expression of microRNAs, including ssc-miR-15a, ssc-miR-15b, ssc-miR-92a, ssc-miR-17-5p, ssc-miR-20a-5p, and ssc-miR-106a, targeting SMAD7, but did not impact on the SMAD7 promoter’s methylation status in PSCs. In summary, SFN was found to boost PSC proliferation and epigenetically increase porcine SMAD7 expression, which indicates a potential application of SFN in modulation of skeletal muscle growth.
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14
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Metabolomics of Acute vs. Chronic Spinach Intake in an Apc-Mutant Genetic Background: Linoleate and Butanoate Metabolites Targeting HDAC Activity and IFN-γ Signaling. Cells 2022; 11:cells11030573. [PMID: 35159382 PMCID: PMC8834217 DOI: 10.3390/cells11030573] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Revised: 01/27/2022] [Accepted: 02/04/2022] [Indexed: 02/08/2023] Open
Abstract
There is growing interest in the crosstalk between the gut microbiome, host metabolomic features, and disease pathogenesis. The current investigation compared long-term (26 week) and acute (3 day) dietary spinach intake in a genetic model of colorectal cancer. Metabolomic analyses in the polyposis in rat colon (Pirc) model and in wild-type animals corroborated key contributions to anticancer outcomes by spinach-derived linoleate bioactives and a butanoate metabolite linked to increased α-diversity of the gut microbiome. Combining linoleate and butanoate metabolites in human colon cancer cells revealed enhanced apoptosis and reduced cell viability, paralleling the apoptosis induction in colon tumors from rats given long-term spinach treatment. Mechanistic studies in cell-based assays and in vivo implicated the linoleate and butanoate metabolites in targeting histone deacetylase (HDAC) activity and the interferon-γ (IFN-γ) signaling axis. Clinical translation of these findings to at-risk patients might provide valuable quality-of-life benefits by delaying surgical interventions and drug therapies with adverse side effects.
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15
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Wang X, Zhao J. Targeted Cancer Therapy Based on Acetylation and Deacetylation of Key Proteins Involved in Double-Strand Break Repair. Cancer Manag Res 2022; 14:259-271. [PMID: 35115826 PMCID: PMC8800007 DOI: 10.2147/cmar.s346052] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2021] [Accepted: 01/13/2022] [Indexed: 12/22/2022] Open
Abstract
DNA double-strand breaks (DSBs) play an important role in promoting genomic instability and cell death. The precise repair of DSBs is essential for maintaining genome integrity during cancer progression, and inducing genomic instability or blocking DNA repair is an important mechanism through which chemo/radiotherapies exert killing effects on cancer cells. The two main pathways that facilitate the repair of DSBs in cancer cells are homologous recombination (HR) and non-homologous end-joining (NHEJ). Accumulating data suggest that the acetylation and deacetylation of DSB repair proteins regulate the initiation and progression of the cellular response to DNA DSBs, which may further affect the chemosensitivity or radiosensitivity of cancer cells. Here, we focus on the role of acetylation/deacetylation in the regulation of ataxia-telangiectasia mutated, Rad51, and 53BP1 in the HR pathway, as well as the relevant roles of PARP1 and Ku70 in NHEJ. Notably, several histone deacetylase (HDAC) inhibitors targeting HR or NHEJ have been demonstrated to enhance chemo/radiosensitivity in preclinical studies. This review highlights the essential role of acetylation/deacetylation in the regulation of DSB repair proteins, suggesting that HDAC inhibitors targeting the HR or NHEJ pathways that downregulate DNA DSB repair genes may be worthwhile cancer therapeutic agents.
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Affiliation(s)
- Xiwen Wang
- Department of Thoracic Surgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning, 110004, People’s Republic of China
| | - Jungang Zhao
- Department of Thoracic Surgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning, 110004, People’s Republic of China
- Correspondence: Jungang Zhao, Department of Thoracic Surgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning, 110004, People’s Republic of China, Tel/Fax +86 13889311066, Email
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16
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Zimmermann C, Wagner AE. Impact of Food-Derived Bioactive Compounds on Intestinal Immunity. Biomolecules 2021; 11:biom11121901. [PMID: 34944544 PMCID: PMC8699755 DOI: 10.3390/biom11121901] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 12/14/2021] [Accepted: 12/16/2021] [Indexed: 12/12/2022] Open
Abstract
The gastrointestinal system is responsible for the digestion and the absorption of nutrients. At the same time, it is essentially involved in the maintenance of immune homeostasis. The strongest antigen contact in an organism takes place in the digestive system showing the importance of a host to develop mechanisms allowing to discriminate between harmful and harmless antigens. An efficient intestinal barrier and the presence of a large and complex part of the immune system in the gut support the host to implement this task. The continuous ingestion of harmless antigens via the diet requires an efficient immune response to reliably identify them as safe. However, in some cases the immune system accidentally identifies harmless antigens as dangerous leading to various diseases such as celiac disease, inflammatory bowel diseases and allergies. It has been shown that the intestinal immune function can be affected by bioactive compounds derived from the diet. The present review provides an overview on the mucosal immune reactions in the gut and how bioactive food ingredients including secondary plant metabolites and probiotics mediate its health promoting effects with regard to the intestinal immune homeostasis.
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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: 78] [Impact Index Per Article: 19.5] [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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18
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ATM controls the extent of DNA end resection by eliciting sequential posttranslational modifications of CtIP. Proc Natl Acad Sci U S A 2021; 118:2022600118. [PMID: 33723063 DOI: 10.1073/pnas.2022600118] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
DNA end resection is a critical step in the repair of DNA double-strand breaks (DSBs) via homologous recombination (HR). However, the mechanisms governing the extent of resection at DSB sites undergoing homology-directed repair remain unclear. Here, we show that, upon DSB induction, the key resection factor CtIP is modified by the ubiquitin-like protein SUMO at lysine 578 in a PIAS4-dependent manner. CtIP SUMOylation occurs on damaged chromatin and requires prior hyperphosphorylation by the ATM protein kinase. SUMO-modified hyperphosphorylated CtIP is targeted by the SUMO-dependent E3 ubiquitin ligase RNF4 for polyubiquitination and subsequent degradation. Consequently, disruption of CtIP SUMOylation results in aberrant accumulation of CtIP at DSBs, which, in turn, causes uncontrolled excessive resection, defective HR, and increased cellular sensitivity to DSB-inducing agents. These findings reveal a previously unidentified regulatory mechanism that regulates CtIP activity at DSBs and thus the extent of end resection via ATM-dependent sequential posttranslational modification of CtIP.
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19
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Mitsiogianni M, Anestopoulos I, Kyriakou S, Trafalis DT, Franco R, Pappa A, Panayiotidis MI. Benzyl and phenethyl isothiocyanates as promising epigenetic drug compounds by modulating histone acetylation and methylation marks in malignant melanoma. Invest New Drugs 2021; 39:1460-1468. [PMID: 33963962 DOI: 10.1007/s10637-021-01127-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Accepted: 05/04/2021] [Indexed: 11/30/2022]
Abstract
Melanoma is an aggressive skin cancer with increasing incidence rates globally. On the other hand, isothiocyanates are derived from cruciferous vegetables and are known to exert a wide range of anti-cancer activities including, among others, their ability to interact with the epigenome in order to supress cancer progression. The aim of this study was to determine the role of phenethyl and benzyl isothiocyanates in modulating histone acetylation and methylation as a potential epigenetic therapeutic strategy in an in vitro model of malignant melanoma. We report that both isothiocyanates induced cytotoxicity and influenced acetylation and methylation status of specific lysine residues on histones H3 and H4 by modulating the expression of various histone acetyltransferases, deacetylases and methyltransferases in malignant melanoma cells. Our data highlight novel insights on the interaction of isothiocyanates with components of the histone regulatory machinery in order to exert their anti-cancer action in malignant melanoma.
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Affiliation(s)
- Melina Mitsiogianni
- Department of Applied Sciences, Northumbria University, Newcastle Upon Tyne, UK
| | - Ioannis Anestopoulos
- Department of Cancer Genetics, Therapeutics & Ultrastructural Pathology, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus.,The Cyprus School of Molecular Medicine, Nicosia, Cyprus
| | - Sotiris Kyriakou
- Department of Cancer Genetics, Therapeutics & Ultrastructural Pathology, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus.,The Cyprus School of Molecular Medicine, Nicosia, Cyprus
| | - Dimitrios T Trafalis
- Laboratory of Pharmacology, Clinical Pharmacology Unit, Medical School, National & Kapodistrian University of Athens, Athens, Greece
| | - Rodrigo Franco
- Redox Biology Centre, University of Nebraska-Lincoln, Lincoln, Nebraska, USA.,School of Veterinary Medicine & Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, Nebraska, USA
| | - Aglaia Pappa
- Department of Molecular Biology & Genetics, Democritus University of Thrace, Alexandroupolis, Greece
| | - Mihalis I Panayiotidis
- Department of Applied Sciences, Northumbria University, Newcastle Upon Tyne, UK. .,Department of Cancer Genetics, Therapeutics & Ultrastructural Pathology, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus. .,The Cyprus School of Molecular Medicine, Nicosia, Cyprus.
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20
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Kapoor S, Gustafson T, Zhang M, Chen YS, Li J, Nguyen N, Perez JET, Dashwood WM, Rajendran P, Dashwood RH. Deacetylase Plus Bromodomain Inhibition Downregulates ERCC2 and Suppresses the Growth of Metastatic Colon Cancer Cells. Cancers (Basel) 2021; 13:cancers13061438. [PMID: 33809839 PMCID: PMC8004213 DOI: 10.3390/cancers13061438] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Accepted: 03/19/2021] [Indexed: 01/14/2023] Open
Abstract
There is growing evidence that DNA repair factors have clinical value for cancer treatment. Nucleotide excision repair (NER) proteins, including excision repair cross-complementation group 2 (ERCC2), play a critical role in maintaining genome integrity. Here, we examined ERCC2 expression following epigenetic combination drug treatment. Attention was drawn to ERCC2 for three reasons. First, from online databases, colorectal cancer (CRC) patients exhibited significantly reduced survival when ERCC2 was overexpressed in colon tumors. Second, ERCC2 was the most highly downregulated RNA transcript in human colon cancer cells, plus Ercc2 in rat tumors, after treatment with the histone deacetylase 3 (HDAC3) inhibitor sulforaphane (SFN) plus JQ1, which is an inhibitor of the bromodomain and extraterminal domain (BET) family. Third, as reported here, RNA-sequencing of polyposis in rat colon (Pirc) polyps following treatment of rats with JQ1 plus 6-methylsulfinylhexyl isothiocyanate (6-SFN) identified Ercc2 as the most highly downregulated gene. The current work also defined promising second-generation epigenetic drug combinations with enhanced synergy and efficacy, especially in metastasis-lineage colon cancer cells cultured as 3D spheroids and xenografts. This investigation adds to the growing interest in combination approaches that target epigenetic 'readers', 'writers', and 'erasers' that are deregulated in cancer and other pathologies, providing new avenues for precision oncology and cancer interception.
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Affiliation(s)
- Sabeeta Kapoor
- Center for Epigenetics & Disease Prevention, Texas A&M Health, Department of Translational Medical Sciences, Texas A&M College of Medicine, Houston, TX 77030, USA; (S.K.); (T.G.); (M.Z.); (Y.-S.C.); (J.L.); (N.N.); (J.E.T.P.); (W.M.D.)
| | - Trace Gustafson
- Center for Epigenetics & Disease Prevention, Texas A&M Health, Department of Translational Medical Sciences, Texas A&M College of Medicine, Houston, TX 77030, USA; (S.K.); (T.G.); (M.Z.); (Y.-S.C.); (J.L.); (N.N.); (J.E.T.P.); (W.M.D.)
| | - Mutian Zhang
- Center for Epigenetics & Disease Prevention, Texas A&M Health, Department of Translational Medical Sciences, Texas A&M College of Medicine, Houston, TX 77030, USA; (S.K.); (T.G.); (M.Z.); (Y.-S.C.); (J.L.); (N.N.); (J.E.T.P.); (W.M.D.)
| | - Ying-Shiuan Chen
- Center for Epigenetics & Disease Prevention, Texas A&M Health, Department of Translational Medical Sciences, Texas A&M College of Medicine, Houston, TX 77030, USA; (S.K.); (T.G.); (M.Z.); (Y.-S.C.); (J.L.); (N.N.); (J.E.T.P.); (W.M.D.)
| | - Jia Li
- Center for Epigenetics & Disease Prevention, Texas A&M Health, Department of Translational Medical Sciences, Texas A&M College of Medicine, Houston, TX 77030, USA; (S.K.); (T.G.); (M.Z.); (Y.-S.C.); (J.L.); (N.N.); (J.E.T.P.); (W.M.D.)
| | - Nhung Nguyen
- Center for Epigenetics & Disease Prevention, Texas A&M Health, Department of Translational Medical Sciences, Texas A&M College of Medicine, Houston, TX 77030, USA; (S.K.); (T.G.); (M.Z.); (Y.-S.C.); (J.L.); (N.N.); (J.E.T.P.); (W.M.D.)
| | - Jorge Enrique Tovar Perez
- Center for Epigenetics & Disease Prevention, Texas A&M Health, Department of Translational Medical Sciences, Texas A&M College of Medicine, Houston, TX 77030, USA; (S.K.); (T.G.); (M.Z.); (Y.-S.C.); (J.L.); (N.N.); (J.E.T.P.); (W.M.D.)
| | - Wan Mohaiza Dashwood
- Center for Epigenetics & Disease Prevention, Texas A&M Health, Department of Translational Medical Sciences, Texas A&M College of Medicine, Houston, TX 77030, USA; (S.K.); (T.G.); (M.Z.); (Y.-S.C.); (J.L.); (N.N.); (J.E.T.P.); (W.M.D.)
| | - Praveen Rajendran
- Center for Epigenetics & Disease Prevention, Texas A&M Health, Department of Translational Medical Sciences, Texas A&M College of Medicine, Houston, TX 77030, USA; (S.K.); (T.G.); (M.Z.); (Y.-S.C.); (J.L.); (N.N.); (J.E.T.P.); (W.M.D.)
- Antibody & Biopharmaceuticals Core, Texas A&M Health, Houston, TX 77030, USA
- Correspondence: (P.R.); (R.H.D.)
| | - Roderick H. Dashwood
- Center for Epigenetics & Disease Prevention, Texas A&M Health, Department of Translational Medical Sciences, Texas A&M College of Medicine, Houston, TX 77030, USA; (S.K.); (T.G.); (M.Z.); (Y.-S.C.); (J.L.); (N.N.); (J.E.T.P.); (W.M.D.)
- Correspondence: (P.R.); (R.H.D.)
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21
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Harris CM, Zamperoni KE, Sernoskie SC, Chow NSM, Massey TE. Effects of in vivo treatment of mice with sulforaphane on repair of DNA pyridyloxylbutylation. Toxicology 2021; 454:152753. [PMID: 33741493 DOI: 10.1016/j.tox.2021.152753] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 03/08/2021] [Accepted: 03/12/2021] [Indexed: 01/08/2023]
Abstract
The phytochemical sulforaphane (SF) has gained interest for its apparent association with reduced cancer risk and other cytoprotective properties, at least some of which are attributed to activation of the transcription factor Nrf2. Repair of bulky DNA adducts is important for mitigating carcinogenesis from exogenous DNA damaging agents, but it is unknown whether in vivo treatment with SF affects adduct repair. At 12 h following a single oral dose of 100 mg/kg SF, an almost doubling in activity for repair of pyridyloxobutylated DNA was observed in CD-1 mouse liver nuclear extracts, but not in lung extracts. This change at 12 h in repair activity was preceded by the induction of Nrf2-regulated genes but not accompanied by changes in levels of the specific nucleotide excision repair (NER) proteins XPC, XPA, XPB and p53 or in binding of hepatic XPC, XPA and XPB to damaged DNA. SF also did not significantly alter histone deacetylase activity as measured by acetylated histone H3 levels, or stimulate formation of γ-H2A.X, a marker of DNA damage. A significant reduction in oxidative DNA damage, as measured by 8-OHdG (a biomarker of oxidative DNA damage), was observed only in DNA from the lungs of SF-treated mice 3 h post-dosing. These results suggest that the ability of SF to increase bulky adduct repair activity is organ-selective and is consistent with activation of the Nrf2 signaling pathway.
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Affiliation(s)
- Christopher M Harris
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, K7L 3N6, Canada
| | - Kristen E Zamperoni
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, K7L 3N6, Canada
| | - Samantha C Sernoskie
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, K7L 3N6, Canada
| | - Natalie S M Chow
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, K7L 3N6, Canada
| | - Thomas E Massey
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, K7L 3N6, Canada.
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22
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Dietary isothiocyanates inhibit cancer progression by modulation of epigenome. Semin Cancer Biol 2021; 83:353-376. [PMID: 33434642 DOI: 10.1016/j.semcancer.2020.12.021] [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: 09/01/2020] [Revised: 12/13/2020] [Accepted: 12/27/2020] [Indexed: 12/15/2022]
Abstract
Cell cycle, growth, survival and metabolism are tightly regulated together and failure in cellular regulation leads to carcinogenesis. Several signaling pathways like the PI3K, WNT, MAPK and NFKb pathway exhibit aberrations in cancer and help achieve hallmark capabilities. Clinical research and in vitro studies have highlighted the role of epigenetic alterations in cancer onset and development. Altered gene expression patterns enabled by changes in DNA methylation, histone modifications and RNA processing have proven roles in cancer hallmark acquisition. The reversible nature of epigenetic processes offers robust therapeutic targets. Dietary bioactive compounds offer a vast compendium of effective therapeutic moieties. Isothiocyanates (ITCs) sourced from cruciferous vegetables demonstrate anti-proliferative, pro-apoptotic, anti-inflammatory, anti-migratory and anti-angiogenic effect against several cancers. ITCs also modulate the redox environment, modulate signaling pathways including PI3K, MAPK, WNT, and NFkB. They also modulate the epigenetic machinery by regulating the expression and activity of DNA methyltransferases, histone modifiers and miRNA. This further enhances their transcriptional modulation of key cellular regulators. In this review, we comprehensively assess the impact of ITCs such as sulforaphane, phenethyl isothiocyanate, benzyl isothiocyanate and allyl isothiocyanate on cancer and document their effect on various molecular targets. Overall, this will facilitate consolidation of the current understanding of the anti-cancer and epigenetic modulatory potential of these compounds and recognize the gaps in literature. Further, we discuss avenues of future research to develop these compounds as potential therapeutic entities.
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23
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Ullah MF, Usmani S, Shah A, Abuduhier FM. Dietary molecules and experimental evidence of epigenetic influence in cancer chemoprevention: An insight. Semin Cancer Biol 2020; 83:319-334. [PMID: 33152485 DOI: 10.1016/j.semcancer.2020.10.011] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 10/26/2020] [Accepted: 10/27/2020] [Indexed: 12/17/2022]
Abstract
The world-wide rate of incidence of cancer disease has been only modestly contested by the past and current preventive and interventional strategies. Hence, the global effort towards novel ideas to contain the disease still continues. Constituents of human diets have in recent years emerged as key regulators of carcinogenesis, with studies reporting their inhibitory potential against all the three stages vis-a-vis initiation, promotion and progression. Unlike drugs which usually act on single targets, these dietary factors have an advantage of multi-targeted effects and pleiotropic action mechanisms, which are effective against cancer that manifest as a micro-evolutionary and multi-factorial disease. Since most of the cellular targets have been identified and their consumption considered relatively safe, these diet-derived agents often appear as molecules of interest in repurposing strategies. Currently, many of these molecules are being investigated for their ability to influence the aberrant alterations in cell's epigenome for epigenetic therapy against cancer. Targeting the epigenetic regulators is a new paradigm in cancer chemoprevention which acts to reverse the warped-up epigenetic alterations in a cancer cell, thereby directing it towards a normal phenotype. In this review, we discuss the significance of dietary factors and natural products as chemopreventive agents. Further, we corroborate the experimental evidence from existing literature, reflecting the ability of a series of such molecules to act as epigenetic modifiers in cancer cells, by interfering with molecular events that map the epigenetic imprints such as DNA methylation, histone acetylation and non-coding RNA mediated gene regulation.
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Affiliation(s)
- Mohammad Fahad Ullah
- Prince Fahad Research Chair, Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk, 71491, Saudi Arabia.
| | - Shazia Usmani
- Faculty of Pharmacy, Integral University, Lucknow, India
| | - Aaliya Shah
- Department of Biochemistry, SKIMS Medical College, Srinagar, India
| | - Faisel M Abuduhier
- Prince Fahad Research Chair, Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk, 71491, Saudi Arabia
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24
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Kumari A, Bhawal S, Kapila S, Yadav H, Kapila R. Health-promoting role of dietary bioactive compounds through epigenetic modulations: a novel prophylactic and therapeutic approach. Crit Rev Food Sci Nutr 2020; 62:619-639. [PMID: 33081489 DOI: 10.1080/10408398.2020.1825286] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The epigenome is an overall epigenetic state of an organism, which is as important as that of the genome for normal development and functioning of an individual. Epigenetics involves heritable but reversible changes in gene expression through alterations in DNA methylation, histone modifications and regulation of non-coding RNAs in cells, without any change in the DNA sequence. Epigenetic changes are owned by various environmental factors including pollution, microbiota and diet, which have profound effects on epigenetic modifiers. The bioactive compounds present in the diet mainly include curcumin, resveratrol, catechins, quercetin, genistein, sulforaphane, epigallocatechin-3-gallate, alkaloids, vitamins, and peptides. Bioactive compounds released during fermentation by the action of microbes also have a significant effect on the host epigenome. Besides, recent studies have explored the new insights in vitamin's functions through epigenetic regulation. These bioactive compounds exert synergistic, preventive and therapeutic effects when combined as well as when used with chemotherapeutic agents. Therefore, these compounds have potential of therapeutic agents that could be used as "Epidrug" to treat many inflammatory diseases and various cancers where chemotherapy results have many side effects. In this review, the effect of diet derived bioactive compounds through epigenetic modulations on in vitro and in vivo models is discussed.
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Affiliation(s)
- Ankita Kumari
- Animal Biochemistry Division, ICAR-National Dairy Research Institute, Karnal, India
| | - Shalaka Bhawal
- Animal Biochemistry Division, ICAR-National Dairy Research Institute, Karnal, India
| | - Suman Kapila
- Animal Biochemistry Division, ICAR-National Dairy Research Institute, Karnal, India
| | - Hariom Yadav
- Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
| | - Rajeev Kapila
- Animal Biochemistry Division, ICAR-National Dairy Research Institute, Karnal, India
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25
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Hudlikar R, Wang L, Wu R, Li S, Peter R, Shannar A, Chou PJ, Liu X, Liu Z, Kuo HCD, Kong AN. Epigenetics/Epigenomics and Prevention of Early Stages of Cancer by Isothiocyanates. Cancer Prev Res (Phila) 2020; 14:151-164. [PMID: 33055265 DOI: 10.1158/1940-6207.capr-20-0217] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2020] [Revised: 07/26/2020] [Accepted: 10/05/2020] [Indexed: 12/17/2022]
Abstract
Cancer is a complex disease and cancer development takes 10-50 years involving epigenetics. Evidence suggests that approximately 80% of human cancers are linked to environmental factors impinging upon genetics/epigenetics. Because advanced metastasized cancers are resistant to radiotherapy/chemotherapeutic drugs, cancer prevention by relatively nontoxic chemopreventive "epigenetic modifiers" involving epigenetics/epigenomics is logical. Isothiocyanates are relatively nontoxic at low nutritional and even higher pharmacologic doses, with good oral bioavailability, potent antioxidative stress/antiinflammatory activities, possess epigenetic-modifying properties, great anticancer efficacy in many in vitro cell culture and in vivo animal models. This review summarizes the latest advances on the role of epigenetics/epigenomics by isothiocyanates in prevention of skin, colon, lung, breast, and prostate cancers. The exact molecular mechanism how isothiocyanates modify the epigenetic/epigenomic machinery is unclear. We postulate "redox" processes would play important roles. In addition, isothiocyanates sulforaphane and phenethyl isothiocyanate, possess multifaceted molecular mechanisms would be considered as "general" cancer preventive agents not unlike chemotherapeutic agents like platinum-based or taxane-based drugs. Analogous to chemotherapeutic agents, the isothiocyanates would need to be used in combination with other nontoxic chemopreventive phytochemicals or drugs such as NSAIDs, 5-α-reductase/aromatase inhibitors targeting different signaling pathways would be logical for the prevention of progression of tumors to late advanced metastatic states.
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Affiliation(s)
- Rasika Hudlikar
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey
| | - Lujing Wang
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey.,Graduate Program in Pharmaceutical Science, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey
| | - Renyi Wu
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey
| | - Shanyi Li
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey
| | - Rebecca Peter
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey.,Graduate Program in Pharmaceutical Science, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey
| | - Ahmad Shannar
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey.,Graduate Program in Pharmaceutical Science, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey
| | - Pochung Jordan Chou
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey.,Graduate Program in Pharmaceutical Science, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey
| | - Xia Liu
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey.,Department of Pharmacology, School of Basic Medical Science, Lanzhou University, Lanzhou, China
| | - Zhigang Liu
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey.,Department of Food and Pharmaceutical Engineering, Guiyang University, Guiyang, China
| | - Hsiao-Chen Dina Kuo
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey.,Graduate Program in Pharmaceutical Science, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey
| | - Ah-Ng Kong
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey.
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26
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Nandini DB, Rao RS, Deepak BS, Reddy PB. Sulforaphane in broccoli: The green chemoprevention!! Role in cancer prevention and therapy. J Oral Maxillofac Pathol 2020; 24:405. [PMID: 33456268 PMCID: PMC7802872 DOI: 10.4103/jomfp.jomfp_126_19] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2019] [Revised: 09/06/2019] [Accepted: 03/05/2020] [Indexed: 02/06/2023] Open
Abstract
Isothicyanates present in cruciferous vegetables are known to exhibit chemoprevention by various mechanisms. Presently, there is growing evidence that a phytochemical compound known as sulforaphane in these green leafy vegetables is found to be effective in preventing and treating various cancers such as prostate cancer, breast cancer, colon cancer, skin, urinary bladder and oral cancers. This component is naturally present in the broccoli sprouts, kale, cabbage, cauliflower and garden cress and is available as a commercial supplementary pill called Broccoli extract. Availability of many bioactive substances such as vitamins, polyphenols, sulfides, glucosinolates and antioxidants makes broccoli consumption important in daily diet regularly. Researchers have named it as "Green chemoprevention." It is easily affordable and more cost-effective than the traditional chemopreventive drugs. Results from the epidemiological and experimental studies have emphasized the role of sulforophane as a complementary or alternative chemopreventive agent.
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Affiliation(s)
- D B Nandini
- Department of Oral Pathology and Microbiology, Dental College, Regional Institute of Medical Sciences, Imphal, Manipur, India
| | - Roopa S Rao
- Department of Oral Pathology and Microbiology, M. S. Ramaiah Dental College, Bengaluru, Karnataka, India
| | - B S Deepak
- Department of Conservative Dentistry, Dental College, Regional Institute of Medical Sciences, Imphal, Manipur, India
| | - Praveen B Reddy
- Department of Oral and Maxillofacial Surgery, Dental College, Regional Institute of Medical Sciences, Imphal, Manipur, India
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27
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Esteve M. Mechanisms Underlying Biological Effects of Cruciferous Glucosinolate-Derived Isothiocyanates/Indoles: A Focus on Metabolic Syndrome. Front Nutr 2020; 7:111. [PMID: 32984393 PMCID: PMC7492599 DOI: 10.3389/fnut.2020.00111] [Citation(s) in RCA: 64] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Accepted: 06/16/2020] [Indexed: 12/13/2022] Open
Abstract
An inverse correlation between vegetable consumption and the incidence of cancer has long been described. This protective effect is stronger when cruciferous vegetables are specifically consumed. The beneficial properties of vegetables are attributed to their bioactive components like fiber, antioxidants vitamins, antioxidants, minerals, and phenolic compounds. Cruciferous vegetables contain all these molecules; however, what makes them different are their sulfurous components, called glucosinolates, responsible for their special smell and taste. Glucosinolates are inactive biologically in the organism but are hydrolyzed by the enzyme myrosinase released as a result of chewing, leading to the formation of active derivatives such as isothiocyanates and indoles. A considerable number of in vitro and in vivo studies have reported that isothiocyanates and indoles elicit chemopreventive potency through multiple mechanisms that include modulation of phases I and II detoxification pathway enzymes, regulation of cell cycle arrest, and control of cell growth, induction of apoptosis, antioxidant activity, anti-angiogenic effects, and epigenetic regulation. Nuclear erythroid 2-related factor 2 (Nrf2) and Nuclear factor-κB (NF-κB) are key and central regulators in all these processes with a main role in oxidative stress and inflammation control. It has been described that isothiocyanates and indoles regulate their activity directly and indirectly. Today, the metabolic syndrome (central obesity, insulin resistance, hyperlipidemia, and hypertension) is responsible for a majority of deaths worldwide. All components of metabolic syndrome are characterized by chronic inflammation with deregulation of the PI3K/AKT/mTOR, MAPK/EKR/JNK, Nrf2, and NF-κB signaling pathways. The effects of GLSs derivatives controlling these pathways have been widely described in relation to cancer. Changes in food consumption patterns observed in the last decades to higher consumption of ultra-processed foods, with elevation in simple sugar and saturated fat contents and lower consumption of vegetables and fruits have been directly correlated with metabolic syndrome prevalence. In this review, it is summarized the knowledge regarding the mechanisms by which cruciferous glucosinolate derivatives (isothiocyanates and indoles) directly and indirectly regulate these pathways. However, the review places a special focus on the knowledge of the effects of glucosinolates derivatives in metabolic syndrome, since this has not been reviewed before.
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Affiliation(s)
- Montserrat Esteve
- Department of Biochemistry and Molecular Biomedicine, University of Barcelona, Barcelona, Spain
- Biomedical Research Centre in Physiopathology of Obesity and Nutrition (CIBERobn), Institute of Health Carlos III, Madrid, Spain
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Akone SH, Ntie-Kang F, Stuhldreier F, Ewonkem MB, Noah AM, Mouelle SEM, Müller R. Natural Products Impacting DNA Methyltransferases and Histone Deacetylases. Front Pharmacol 2020; 11:992. [PMID: 32903500 PMCID: PMC7438611 DOI: 10.3389/fphar.2020.00992] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2020] [Accepted: 06/19/2020] [Indexed: 12/24/2022] Open
Abstract
Epigenetics refers to heritable changes in gene expression and chromatin structure without change in a DNA sequence. Several epigenetic modifications and respective regulators have been reported. These include DNA methylation, chromatin remodeling, histone post-translational modifications, and non-coding RNAs. Emerging evidence has revealed that epigenetic dysregulations are involved in a wide range of diseases including cancers. Therefore, the reversible nature of epigenetic modifications concerning activation or inhibition of enzymes involved could be promising targets and useful tools for the elucidation of cellular and biological phenomena. In this review, emphasis is laid on natural products that inhibit DNA methyltransferases (DNMTs) and histone deacetylases (HDACs) making them promising candidates for the development of lead structures for anticancer-drugs targeting epigenetic modifications. However, most of the natural products targeting HDAC and/or DNMT lack isoform selectivity, which is important for determining their potential use as therapeutic agents. Nevertheless, the structures presented in this review offer the well-founded basis that screening and chemical modifications of natural products will in future provide not only leads to the identification of more specific inhibitors with fewer side effects, but also important features for the elucidation of HDAC and DNMT function with respect to cancer treatment.
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Affiliation(s)
- Sergi Herve Akone
- Department of Chemistry, Faculty of Science, University of Douala, Douala, Cameroon
- Department of Microbial Natural Products, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research and Department of Pharmacy, Saarland University, Saarbrücken, Germany
| | - Fidele Ntie-Kang
- Department of Chemistry, Faculty of Science, University of Buea, Buea, Cameroon
- Institute for Pharmacy, Martin-Luther-Universität Halle-Wittenberg, Halle (Saale), Germany
- Institut für Botanik, Technische Universität Dresden, Dresden, Germany
| | - Fabian Stuhldreier
- Medical Faculty, Institute of Molecular Medicine I, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | | | - Alexandre Mboene Noah
- Department of Biochemistry, Faculty of Science, University of Douala, Douala, Cameroon
| | | | - Rolf Müller
- Department of Microbial Natural Products, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research and Department of Pharmacy, Saarland University, Saarbrücken, Germany
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Mitsiogianni M, Trafalis DT, Franco R, Zoumpourlis V, Pappa A, Panayiotidis MI. Sulforaphane and iberin are potent epigenetic modulators of histone acetylation and methylation in malignant melanoma. Eur J Nutr 2020; 60:147-158. [PMID: 32215717 DOI: 10.1007/s00394-020-02227-y] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Accepted: 03/09/2020] [Indexed: 12/21/2022]
Abstract
OBJECTIVE(S) Growing evidence supports that isothiocyanates exert a wide range of bioactivities amongst of which is their capacity to interact with the epigenetic machinery in various cancers including melanoma. Our aim was to characterise the effect of sulforaphane and iberin on histone acetylation and methylation as a potential anti-melanoma strategy. METHODS We have utilised an in vitro model of malignant melanoma [consisting of human (A375, Hs294T, VMM1) and murine (B16F-10) melanoma cell lines as well as a non-melanoma (A431) and a non-tumorigenic immortalised keratinocyte (HaCaT) cell line] exposed to sulforaphane or iberin. Cell viability was evaluated by the Alamar blue assay whilst total histone deacetylases and acetyltransferases activities were determined by the Epigenase HDAC Activity/Inhibition and EpiQuik HAT Activity/Inhibition assay kits, respectively. The expression levels of specific histone deacetylases and acetyltransferases together with those of lysine acetylation and methylation marks were obtained by western immunoblotting. RESULTS Overall, both sulforaphane and iberin were able to (1) reduce cell viability, (2) decrease total histone deacetylase activity and (3) modulate the expression levels of various histone deacetylases as well as acetyl and methyl transferases thus modulating the acetylation and methylation status of specific lysine residues on histones 3 and 4 in malignant melanoma cells. CONCLUSIONS Our findings highlight novel insights as to how sulforaphane and iberin differentially regulate the epigenetic response in ways compatible with their anticancer action in malignant melanoma.
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Affiliation(s)
- Melina Mitsiogianni
- Faculty of Health and Life Sciences, Department of Applied Sciences, Group of Translational Biosciences, Northumbria University, Newcastle Upon Tyne, NE1 8ST, UK
| | - Dimitrios T Trafalis
- Laboratory of Pharmacology, Clinical Pharmacology Unit, Medical School, National and Kapodistrian University of Athens, 11527, Athens, Greece
| | - Rodrigo Franco
- Redox Biology Centre, University of Nebraska-Lincoln, Lincoln, NE, 68588, USA
- School of Veterinary Medicine & 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
| | - Aglaia Pappa
- Department of Molecular Biology and Genetics, Democritus University of Thrace, 68100, Alexandroupolis, Greece
| | - Mihalis I Panayiotidis
- Faculty of Health and Life Sciences, Department of Applied Sciences, Group of Translational Biosciences, Northumbria University, Newcastle Upon Tyne, NE1 8ST, UK.
- Department of Electron Microscopy and Molecular Pathology, The Cyprus Institute of Neurology and Genetics, 2371, Nicosia, Cyprus.
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30
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Samec M, Liskova A, Koklesova L, Mestanova V, Franekova M, Kassayova M, Bojkova B, Uramova S, Zubor P, Janikova K, Danko J, Samuel SM, Büsselberg D, Kubatka P. Fluctuations of Histone Chemical Modifications in Breast, Prostate, and Colorectal Cancer: An Implication of Phytochemicals as Defenders of Chromatin Equilibrium. Biomolecules 2019; 9:E829. [PMID: 31817446 PMCID: PMC6995638 DOI: 10.3390/biom9120829] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Revised: 11/29/2019] [Accepted: 12/02/2019] [Indexed: 02/07/2023] Open
Abstract
Natural substances of plant origin exert health beneficiary efficacy due to the content of various phytochemicals. Significant anticancer abilities of natural compounds are mediated via various processes such as regulation of a cell's epigenome. The potential antineoplastic activity of plant natural substances mediated by their action on posttranslational histone modifications (PHMs) is currently a highly evaluated area of cancer research. PHMs play an important role in maintaining chromatin structure and regulating gene expression. Aberrations in PHMs are directly linked to the process of carcinogenesis in cancer such as breast (BC), prostate (PC), and colorectal (CRC) cancer, common malignant diseases in terms of incidence and mortality among both men and women. This review summarizes the effects of plant phytochemicals (isolated or mixtures) on cancer-associated PHMs (mainly modulation of acetylation and methylation) resulting in alterations of chromatin structure that are related to the regulation of transcription activity of specific oncogenes, which are crucial in the development of BC, PC, and CRC. Significant effectiveness of natural compounds in the modulation of aberrant PHMs were confirmed by a number of in vitro or in vivo studies in preclinical cancer research. However, evidence concerning PHMs-modulating abilities of plant-based natural substances in clinical trials is insufficient.
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Affiliation(s)
- Marek Samec
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia; (M.S.); (A.L.); (L.K.); (J.D.)
| | - Alena Liskova
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia; (M.S.); (A.L.); (L.K.); (J.D.)
| | - Lenka Koklesova
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia; (M.S.); (A.L.); (L.K.); (J.D.)
| | - Veronika Mestanova
- Department of Histology and Embryology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia;
| | - Maria Franekova
- Department of Medical Biology and Biomedical Center Martin, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia;
| | - Monika Kassayova
- Department of Animal Physiology, Institute of Biology and Ecology, Faculty of Science, Pavol Jozef Safarik University, 04001 Kosice, Slovakia; (M.K.); (B.B.)
| | - Bianka Bojkova
- Department of Animal Physiology, Institute of Biology and Ecology, Faculty of Science, Pavol Jozef Safarik University, 04001 Kosice, Slovakia; (M.K.); (B.B.)
| | - Sona Uramova
- Biomedical Center Martin, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia;
| | - Pavol Zubor
- OBGY Health & Care, Ltd., 01026 Zilina, Slovakia;
| | - Katarina Janikova
- Department of Pathological Anatomy, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia
| | - Jan Danko
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia; (M.S.); (A.L.); (L.K.); (J.D.)
| | - Samson Mathews Samuel
- Department of Physiology and Biophysics, Weill Cornell Medicine in Qatar, Education City, Qatar Foundation, Doha 24144, Qatar;
| | - Dietrich Büsselberg
- Department of Physiology and Biophysics, Weill Cornell Medicine in Qatar, Education City, Qatar Foundation, Doha 24144, Qatar;
| | - Peter Kubatka
- Department of Medical Biology and Biomedical Center Martin, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia;
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Pocasap P, Weerapreeyakul N, Thumanu K. Alyssin and Iberin in Cruciferous Vegetables Exert Anticancer Activity in HepG2 by Increasing Intracellular Reactive Oxygen Species and Tubulin Depolymerization. Biomol Ther (Seoul) 2019; 27:540-552. [PMID: 31405267 PMCID: PMC6824623 DOI: 10.4062/biomolther.2019.027] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Revised: 05/19/2019] [Accepted: 06/17/2019] [Indexed: 11/23/2022] Open
Abstract
To determine the chemopreventive potential of alyssin and iberin, the in vitro anticancer activities and molecular targets of isothiocyanates (ITCs) were measured and compared to sulforaphane in hepatocellular carcinoma cell HepG2. The SR-FTIR spectra observed a similar pattern vis-à-vis the biomolecular alteration amongst the ITCs-treated cells suggesting a similar mode of action. All of the ITCs in this study cause cancer cell death through both apoptosis and necrosis in concentration dependent manner (20–80 μM). We found no interactions of any of the ITCs studied with DNA. Notwithstanding, all of the ITCs studied increased intracellular reactive oxygen species (ROS) and suppressed tubulin polymerization, which led to cell-cycle arrest in the S and G2/M phase. Alyssin possessed the most potent anticancer ability; possibly due to its ability to increase intracellular ROS rather than tubulin depolymerization. Nevertheless, the structural influence of alkyl chain length on anticancer capabilities of ITCs remains inconclusive. The results of this study indicate an optional, potent ITC (viz., alyssin) because of its underlying mechanisms against hepatic cancer. As a consequence, further selection and development of effective chemotherapeutic ITCs is recommended.
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Affiliation(s)
- Piman Pocasap
- Research and Development in Pharmaceuticals Program, Graduate School, Faculty of Pharmaceutical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Natthida Weerapreeyakul
- Division of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand.,Human High Performance and Health Promotion Research Institute (HHP&HP), Khon Kaen University, Khon Kaen 40002, Thailand
| | - Kanjana Thumanu
- Synchrotron Light Research Institute (Public Organization), Nakhon Ratchasima 30000, Thailand
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32
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Montgomery M, Srinivasan A. Epigenetic Gene Regulation by Dietary Compounds in Cancer Prevention. Adv Nutr 2019; 10:1012-1028. [PMID: 31100104 PMCID: PMC6855955 DOI: 10.1093/advances/nmz046] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Revised: 03/07/2019] [Accepted: 04/03/2019] [Indexed: 02/06/2023] Open
Abstract
Traditionally, cancer has been viewed as a set of diseases that are driven by the accumulation of genetic mutations, but we now understand that disruptions in epigenetic regulatory mechanisms are prevalent in cancer as well. Unlike genetic mutations, however, epigenetic alterations are reversible, making them desirable therapeutic targets. The potential for diet, and bioactive dietary components, to target epigenetic pathways in cancer is now widely appreciated, but our understanding of how to utilize these compounds for effective chemopreventive strategies in humans is in its infancy. This review provides a brief overview of epigenetic regulation and the clinical applications of epigenetics in cancer. It then describes the capacity for dietary components to contribute to epigenetic regulation, with a focus on the efficacy of dietary epigenetic regulators as secondary cancer prevention strategies in humans. Lastly, it discusses the necessary precautions and challenges that will need to be overcome before the chemopreventive power of dietary-based intervention strategies can be fully harnessed.
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Affiliation(s)
- McKale Montgomery
- Department of Nutritional Sciences, Oklahoma State University, Stillwater, OK,Address correspondence to MM (E-mail: )
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Raut N, Wicks SM, Lawal TO, Mahady GB. Epigenetic regulation of bone remodeling by natural compounds. Pharmacol Res 2019; 147:104350. [PMID: 31315065 PMCID: PMC6733678 DOI: 10.1016/j.phrs.2019.104350] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2018] [Revised: 06/27/2019] [Accepted: 07/10/2019] [Indexed: 12/12/2022]
Abstract
Osteoporosis and osteopenia impact more than 54 million Americans, resulting in significant morbidity and mortality. Alterations in bone remodeling are the hallmarks for osteoporosis, and thus the development of novel treatments that will prevent or treat bone diseases would be clinically significant, and improve the quality of life for these patients. Bone remodeling involves the removal of old bone by osteoclasts and the formation of new bone by osteoblasts. This process is tightly coupled, and is essential for the maintenance of bone strength and integrity. Since the osteoclast is the only cell capable of bone resorption, the development of drugs to treat bone disorders has primarily focused on reducing osteoclast differentiation, maturation, and bone resorption mechanisms, and there are few treatments that actually increase bone formation. Evidence from observational, experimental, and clinical studies demonstrate a positive link between naturally occurring compounds and improved indices of bone health. While many natural extracts and compounds are reported to have beneficial effects on bone, only resveratrol, sulforaphane, specific phenolic acids and anthocyanins, have been shown to both increase bone formation and reduce resorption through their effects on the bone epigenome. Each of these compounds alters specific aspects of the bone epigenome to improve osteoblast differentiation, reduce osteoblast apoptosis, improve bone mineralization, and reduce osteoclast differentiation and function. This review focuses on these specific natural compounds and their epigenetic regulation of bone remodeling.
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Affiliation(s)
- Nishikant Raut
- Department of Pharmacy Practice, College of Pharmacy, WHO/PAHO Collaborating Centre for Traditional Medicine, University of Illinois at Chicago, USA; Department of Pharmaceutical Sciences, Rashtrasant Tukadoji Maharaj Nagpur University, Nagpur, India
| | - Sheila M Wicks
- Department of Cellular and Molecular Medicine, Rush University, Chicago, IL 60612, USA
| | - Tempitope O Lawal
- Department of Pharmaceutical Microbiology, University of Ibadan, Ibadan, Nigeria
| | - Gail B Mahady
- Department of Pharmacy Practice, College of Pharmacy, WHO/PAHO Collaborating Centre for Traditional Medicine, University of Illinois at Chicago, USA.
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Huang C, Wu XF, Wang XL. Trichostatin a inhibits phenotypic transition and induces apoptosis of the TAF-treated normal colonic epithelial cells through regulation of TGF-β pathway. Int J Biochem Cell Biol 2019; 114:105565. [PMID: 31278993 DOI: 10.1016/j.biocel.2019.105565] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Revised: 06/24/2019] [Accepted: 07/03/2019] [Indexed: 12/15/2022]
Abstract
Tumor-associated fibroblasts (TAFs) contribute to transdifferentiation of stromal cells in tumor microenvironment. Epithelial-mesenchymal transition (EMT) is a procedure of phenotypic remodeling of epithelial cells and extensively exists in local tumoral stroma. Histone deacetylase (HDAC) inhibitor Tricostatin A (TSA) and sodium butyrate (SB) are reported to play important roles in the regulation of biological behaviour of cancer cells. However, whether TSA or SB is involved in control of EMT in colon epithelial cells induced by TAFs remains unidentified. In present study, we used conditioned medium (CM) form TAF-like CCD-18Co cells to stimulate 2D- and 3D-cultured colon epithelial HCoEpiC cells for 24 h and 4 d. We found that the CCD-18Co CM triggered multiple morphological changes in HCoEpiCs including prolonged cell diameters, down-regulation of E-cadherin and up-regulation of vimentin and α-SMA. Besides, ZEB1 and Snail expression and migration were also promoted by the CM. These phenomena were abolised by 5 μg/ml LY364947, a TGF-β receptor inhibitor. CCD-18Co induced up-regulation of HDAC1 and HDAC2 in the 2D and 3D models, while no change of HDAC4 exprerssion was found. Treatment of 2 μg/ml TSA reversed the CCD-18Co-induced morphological changes and migration of the HCoEpiCs, and suppressed the downregulation of E-cadherin and upregulation of vimentin, α-SMA, ZEB1 and Snail. However, the suppressive effect of 4 mg/ml SB on the EMT was not observed. TSA down-regulated the expressions of Smad2/3, p-Smad2/3 amd HDAC4. Besides, TSA promoted the apoptosis rate (36.84 ± 6.52%) comparing with the CCD-18Co-treated HCoEpiCs (3.52 ± 0.85%, P < 0.05), with promotion of Bax (0.5893±0.0498 in 2D and 0.8867±0.0916 in 3D) and reduction of Bcl-2 (0.0476±0.0053 in 2D and 0.0294±0.0075 in 3D). TSA stimulated expression of phosphorylated-p38 MAPK in 2D (0.3472±0.0249) and 3D (0.3188±0.0248). After pre-treatment with p38 MAPK inhibitor VX-702 (0.5 mg/ml), the apoptosis rate of TSA was decreased in 2D (10.32%) and 3D (5.26%). Our observations demonstrate that epigenetic treatment with HDAC inhibitor TSA may be a useful therapeutic tool for the reversion of TAF-induced EMT in colon epithelium through mediating canonical Smads pathway and non-canonical p38 MAPK signalling.
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Affiliation(s)
- Chao Huang
- Department of Traditional Chinese Medicine, Affiliated Bao'an Hospital of Shenzhen, Southern Medical University, Shenzhen, 518100, China.
| | - Xiao-Fen Wu
- Department of Endocrinology, The 940th Hospital of Joint Logistics Support Force of Chinese People's Liberation Army, Lanzhou, 730050, China
| | - Xiu-Lian Wang
- Health Management Centre, Affiliated Bao'an Hospital of Traditional Chinese Medicine of Shenzhen, Traditional Chinese Medicine University Of Guangzhou, Shenzhen, 518100, China
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Hać A, Brokowska J, Rintz E, Bartkowski M, Węgrzyn G, Herman-Antosiewicz A. Mechanism of selective anticancer activity of isothiocyanates relies on differences in DNA damage repair between cancer and healthy cells. Eur J Nutr 2019; 59:1421-1432. [PMID: 31123866 PMCID: PMC7230056 DOI: 10.1007/s00394-019-01995-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Accepted: 05/11/2019] [Indexed: 12/14/2022]
Abstract
Purpose Isothiocyanates (ITCs) are compounds derived from Brassica plants with documented anticancer activity. Molecular mechanisms of their selective activity against cancer cells are still underexplored. In this work, the impact of ITC on DNA replication and damage was compared between PC-3 prostate cancer cells and HDFa normal fibroblasts as well as PNT2 prostate epithelial cells. Methods Cells were treated with sulforaphane or phenethyl isothiocyanate. [3H]thymidine incorporation and the level of histone γH2A.X were estimated as indicators of DNA replication and double-strand breaks (DSB), respectively. Levels of HDAC3, CtIP, and p-RPA were investigated by immunoblotting. Comet assay was performed to visualize DNA damage. Results ITCs inhibited DNA replication in all tested cell lines, and this activity was independent of reactive oxygen species of mitochondrial origin. It was followed by DSB which were more pronounced in cancer than noncancerous cells. This difference was independent of HDAC activity which was decreased in both cell lines when treated with ITCs. On the other hand, it correlated with faster removal of DSB, and thus, transient activation of repair proteins in normal cells, while in PC-3 prostate cancer, cell DNA repair was significantly less effective. Conclusion DNA damage induced by ITCs is a consequence of the block in DNA replication which is observed in both, cancer and normal cells. Selective antiproliferative activity of ITCs towards cancer cells results from less efficient DNA repair in cancer cells relative to normal cells.
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Affiliation(s)
- Aleksandra Hać
- Department of Medical Biology and Genetics, Faculty of Biology, University of Gdańsk, Wita Stwosza 59, 80-308, Gdańsk, Poland
| | - Joanna Brokowska
- Department of Medical Biology and Genetics, Faculty of Biology, University of Gdańsk, Wita Stwosza 59, 80-308, Gdańsk, Poland
- Department of Molecular Biology, Faculty of Biology, University of Gdańsk, Wita Stwosza 59, 80-308, Gdańsk, Poland
| | - Estera Rintz
- Department of Medical Biology and Genetics, Faculty of Biology, University of Gdańsk, Wita Stwosza 59, 80-308, Gdańsk, Poland
- Department of Molecular Biology, Faculty of Biology, University of Gdańsk, Wita Stwosza 59, 80-308, Gdańsk, Poland
| | - Michał Bartkowski
- Department of Medical Biology and Genetics, Faculty of Biology, University of Gdańsk, Wita Stwosza 59, 80-308, Gdańsk, Poland
- Department of Molecular Biology, Faculty of Biology, University of Gdańsk, Wita Stwosza 59, 80-308, Gdańsk, Poland
| | - Grzegorz Węgrzyn
- Department of Molecular Biology, Faculty of Biology, University of Gdańsk, Wita Stwosza 59, 80-308, Gdańsk, Poland
| | - Anna Herman-Antosiewicz
- Department of Medical Biology and Genetics, Faculty of Biology, University of Gdańsk, Wita Stwosza 59, 80-308, Gdańsk, Poland.
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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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Allyl isothiocyanate regulates lysine acetylation and methylation marks in an experimental model of malignant melanoma. Eur J Nutr 2019; 59:557-569. [PMID: 30762097 PMCID: PMC7058602 DOI: 10.1007/s00394-019-01925-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2018] [Accepted: 02/05/2019] [Indexed: 12/19/2022]
Abstract
Objective(s) Isothiocyanates (ITCs) are biologically active plant secondary metabolites capable of mediating various biological effects including modulation of the epigenome. Our aim was to characterize the effect of allyl isothiocyanate (AITC) on lysine acetylation and methylation marks as a potential epigenetic-induced anti-melanoma strategy. Methods Our malignant melanoma model consisted of (1) human (A375) and murine (B16-F10) malignant melanoma as well as of human; (2) brain (VMM1) and lymph node (Hs 294T) metastatic melanoma; (3) non-melanoma epidermoid carcinoma (A431) and (4) immortalized keratinocyte (HaCaT) cells subjected to AITC. Cell viability, histone deacetylases (HDACs) and acetyltransferases (HATs) activities were evaluated by the Alamar blue, Epigenase HDAC Activity/Inhibition and EpiQuik HAT Activity/Inhibition assay kits, respectively, while their expression levels together with those of lysine acetylation and methylation marks by western immunoblotting. Finally, apoptotic gene expression was assessed by an RT-PCR-based gene expression profiling methodology. Results AITC reduces cell viability, decreases HDACs and HATs activities and causes changes in protein expression levels of various HDACs, HATs, and histone methyl transferases (HMTs) all of which have a profound effect on specific lysine acetylation and methylation marks. Moreover, AITC regulates the expression of a number of genes participating in various apoptotic cascades thus indicating its involvement in apoptotic induction. Conclusions AITC exerts a potent epigenetic effect suggesting its potential involvement as a promising epigenetic-induced bioactive for the treatment of malignant melanoma.
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Rajendran P, Johnson G, Li L, Chen YS, Dashwood M, Nguyen N, Ulusan A, Ertem F, Zhang M, Li J, Sun D, Huang Y, Wang S, Leung HC, Lieberman D, Beaver L, Ho E, Bedford M, Chang K, Vilar E, Dashwood R. Acetylation of CCAR2 Establishes a BET/BRD9 Acetyl Switch in Response to Combined Deacetylase and Bromodomain Inhibition. Cancer Res 2019; 79:918-927. [PMID: 30643017 DOI: 10.1158/0008-5472.can-18-2003] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Revised: 10/19/2018] [Accepted: 01/09/2019] [Indexed: 12/15/2022]
Abstract
There continues to be interest in targeting epigenetic "readers, writers, and erasers" for the treatment of cancer and other pathologies. However, a mechanistic understanding is frequently lacking for the synergy observed when combining deacetylase and bromodomain inhibitors. Here we identify cell cycle and apoptosis regulator 2 (CCAR2) as an early target for acetylation in colon cancer cells treated with sulforaphane. N-terminal acetylation of CCAR2 diminished its interactions with histone deacetylase 3 and β-catenin, interfering with Wnt coactivator functions of CCAR2, including in cells harboring genetically encoded CCAR2 acetylation. Protein domain arrays and pull-down assays identified acetyl "reader" proteins that recognized CCAR2 acetylation sites, including BRD9 and members of the bromodomain and extraterminal domain (BET) family. Treatment with the BET inhibitor JQ1 synergized with sulforaphane in colon cancer cells and suppressed tumor development effectively in a preclinical model of colorectal cancer. Studies with sulforaphane+JQ1 in combination implicated a BET/BRD9 acetyl switch and a shift in the pool of acetyl "reader" proteins in favor of BRD9-regulated target genes. SIGNIFICANCE: These results highlight the competition that exists among the "readers" of acetylated histone and nonhistone proteins and provide a mechanistic basis for potential new therapeutic avenues involving epigenetic combination treatments.
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Affiliation(s)
- Praveen Rajendran
- Center for Epigenetics & Disease Prevention, Texas A&M College of Medicine, Houston, Texas.
| | - Gavin Johnson
- Center for Epigenetics & Disease Prevention, Texas A&M College of Medicine, Houston, Texas
| | - Li Li
- Center for Epigenetics & Disease Prevention, Texas A&M College of Medicine, Houston, Texas
| | - Ying-Shiuan Chen
- Center for Epigenetics & Disease Prevention, Texas A&M College of Medicine, Houston, Texas
| | - Mohaiza Dashwood
- Center for Epigenetics & Disease Prevention, Texas A&M College of Medicine, Houston, Texas
| | - Nhung Nguyen
- Center for Epigenetics & Disease Prevention, Texas A&M College of Medicine, Houston, Texas
| | - Ahmet Ulusan
- Center for Epigenetics & Disease Prevention, Texas A&M College of Medicine, Houston, Texas
| | - Furkan Ertem
- Center for Epigenetics & Disease Prevention, Texas A&M College of Medicine, Houston, Texas
| | - Mutian Zhang
- Center for Epigenetics & Disease Prevention, Texas A&M College of Medicine, Houston, Texas
| | - Jia Li
- Center for Epigenetics & Disease Prevention, Texas A&M College of Medicine, Houston, Texas
| | - Deqiang Sun
- Center for Epigenetics & Disease Prevention, Texas A&M College of Medicine, Houston, Texas
| | - Yun Huang
- Center for Epigenetics & Disease Prevention, Texas A&M College of Medicine, Houston, Texas
| | - Shan Wang
- Center for Epigenetics & Disease Prevention, Texas A&M College of Medicine, Houston, Texas
| | - Hon-Chiu Leung
- Mass Spectrometry-Proteomics Core, Baylor College of Medicine, Houston, Texas
| | - David Lieberman
- Division of Gastroenterology and Hepatology, Oregon Health & Science University, Portland, Oregon
| | - Laura Beaver
- College of Public Health and Human Sciences, Oregon State University, Corvallis, Oregon
| | - Emily Ho
- College of Public Health and Human Sciences, Oregon State University, Corvallis, Oregon
| | - Mark Bedford
- The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Kyle Chang
- The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Eduardo Vilar
- The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Roderick Dashwood
- Center for Epigenetics & Disease Prevention, Texas A&M College of Medicine, Houston, Texas. .,The University of Texas MD Anderson Cancer Center, Houston, Texas
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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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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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Okonkwo A, Mitra J, Johnson GS, Li L, Dashwood WM, Hegde ML, Yue C, Dashwood RH, Rajendran P. Heterocyclic Analogs of Sulforaphane Trigger DNA Damage and Impede DNA Repair in Colon Cancer Cells: Interplay of HATs and HDACs. Mol Nutr Food Res 2018; 62:e1800228. [PMID: 29924908 DOI: 10.1002/mnfr.201800228] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2018] [Revised: 06/03/2018] [Indexed: 01/29/2023]
Abstract
SCOPE DNA repair inhibitors have broad clinical applications in tumor types with DNA repair defects, including colorectal cancer (CRC). Structural analogs of the anticancer agent sulforaphane (SFN) were investigated as modifiers of histone deacetylase (HDAC) and histone acetyltransferase (HAT) activity, and for effects on DNA damage/repair pertinent to human CRC. METHODS AND RESULTS In the polyposis in rat colon (Pirc) model, single oral administration of SFN and structurally related long-chain isothiocyanates (ITCs) decreased histone deacetylase 3 (HDAC3) expression and increased pH2AX levels markedly in adenomatous colon polyps, extending prior observations on HDAC3 inhibition/turnover in cell-based assays. Colon cancer cells at a high initial plating density had diminished cytotoxicity from SFN, whereas novel tetrazole-containing heterocyclic analogs of SFN retained their efficacy. The potent SFN analogs triggered DNA damage, cell cycle arrest, apoptosis, and loss of a key DNA repair regulator, C-terminal binding protein (CtBP) interacting protein (CtIP). These SFN analogs also altered HAT/HDAC activities and histone acetylation status, lowered the expression of HDAC3, P300/CBP-associated factor (PCAF) and lysine acetyltransferase 2A (KAT2A/GCN5), and attenuated homologous recombination (HR)/non-homologous end joining (NHEJ) repair activities in colon cancer cells. CONCLUSION Novel tetrazole-containing heterocyclic analogs of SFN provide a new avenue for chemosensitization in colon cancer cells via modulation of HAT/HDAC activities and associated DNA damage/repair signaling pathways.
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Affiliation(s)
- Adaobi Okonkwo
- Center for Epigenetics and Disease Prevention, Institute of Biosciences and Technology, Texas A&M Health Science Center, Texas A&M College of Medicine, Houston, TX, USA, 77030
| | - Joy Mitra
- Department of Radiation Oncology, Houston Methodist Research Institute, Houston, TX, USA, 77030
| | - Gavin S Johnson
- Center for Epigenetics and Disease Prevention, Institute of Biosciences and Technology, Texas A&M Health Science Center, Texas A&M College of Medicine, Houston, TX, USA, 77030
| | - Li Li
- Center for Epigenetics and Disease Prevention, Institute of Biosciences and Technology, Texas A&M Health Science Center, Texas A&M College of Medicine, Houston, TX, USA, 77030
| | - Wan Mohaiza Dashwood
- Center for Epigenetics and Disease Prevention, Institute of Biosciences and Technology, Texas A&M Health Science Center, Texas A&M College of Medicine, Houston, TX, USA, 77030
| | - Muralidhar L Hegde
- Department of Radiation Oncology, Houston Methodist Research Institute, Houston, TX, USA, 77030.,Weill Cornell Medical College of Cornell University, NY, USA, 10065
| | - Chen Yue
- The State Key Laboratory of Elemento-Organic Chemistry, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), College of Pharmacy, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China, 300071
| | - Roderick H Dashwood
- Center for Epigenetics and Disease Prevention, Institute of Biosciences and Technology, Texas A&M Health Science Center, Texas A&M College of Medicine, Houston, TX, USA, 77030.,Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston, TX, USA, 77030.,Department of Nutrition and Food Science, Texas A&M University, College Station, TX, USA, 77843.,Department of Molecular and Cellular Medicine, Texas A&M College of Medicine, College Station, TX, USA, 77843
| | - Praveen Rajendran
- Center for Epigenetics and Disease Prevention, Institute of Biosciences and Technology, Texas A&M Health Science Center, Texas A&M College of Medicine, Houston, TX, USA, 77030
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Mirza-Aghazadeh-Attari M, Darband SG, Kaviani M, Mihanfar A, Aghazadeh Attari J, Yousefi B, Majidinia M. DNA damage response and repair in colorectal cancer: Defects, regulation and therapeutic implications. DNA Repair (Amst) 2018; 69:34-52. [PMID: 30055507 DOI: 10.1016/j.dnarep.2018.07.005] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2018] [Revised: 07/15/2018] [Accepted: 07/15/2018] [Indexed: 12/11/2022]
Abstract
DNA damage response, a key factor involved in maintaining genome integrity and stability, consists of several kinase-dependent signaling pathways, which sense and transduce DNA damage signal. The severity of damage appears to determine DNA damage responses, which can include cell cycle arrest, damage repair and apoptosis. A number of recent studies have demonstrated that defection in signaling through this network is thought to be an underlying mechanism behind the development and progression of various types of human malignancies, including colorectal cancer. In this review, colorectal cancer and its molecular pathology as well as DNA damage response is briefly introduced. Finally, the involvement of key components of this network in the initiation/progression, prognosis, response to treatment and development of drug resistance is comprehensively discussed.
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Affiliation(s)
- Mohammad Mirza-Aghazadeh-Attari
- Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran; Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Saber Ghazizadeh Darband
- Danesh Pey Hadi Co., Health Technology Development Center, Urmia University of Medical Sciences, Urmia, Iran
| | - Mojtaba Kaviani
- School of Nutrition and Dietetics, Acadia University, Wolfville, Nova Scotia, Canada
| | - Ainaz Mihanfar
- Stem Cell and Regenerative Medicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Bahman Yousefi
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Maryam Majidinia
- Solid Tumor Research Center, Urmia University of Medical Sciences, Urmia, Iran.
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Reddy DS, Wu X, Golub VM, Dashwood WM, Dashwood RH. Measuring Histone Deacetylase Inhibition in the Brain. ACTA ACUST UNITED AC 2018; 81:e41. [PMID: 29927058 DOI: 10.1002/cpph.41] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Histone deacetylases (HDACs) represent a family of enzymes that are targets for epigenetic modulation of genomic activity and may be beneficial in the treatment of many diseases, including cancer and central nervous system disorders. In animal models, HDAC inhibitors have neuroprotective, antiepileptogenic, and antidepressant effects. Assaying HDAC activity provides a robust method for identifying HDAC inhibitors and for assessing their effects under various physiological conditions or after pathological insults. In this unit, a simple and sensitive assay for measuring HDAC activity is described. HDAC activity in tissue lysates can be assessed fluorometrically using a Boc-Lys(Ac) HDAC activity kit. HDACs catalyze the deacetylation of the substrate Boc-Lys(Ac)-AMC. Addition of a trypsin-containing developer converts the deacetylated product to a quantifiable fluorophore that can be used both as a screening method to identify putative HDAC inhibitors and to assess the effects of these inhibitors on tissue and animal epigenetic-modulated phenotypes. © 2018 by John Wiley & Sons, Inc.
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Affiliation(s)
- Doodipala Samba Reddy
- Department of Neuroscience and Experimental Therapeutics, Texas A&M University Health Science Center, College of Medicine, Bryan, Texas
| | - Xin Wu
- Department of Neuroscience and Experimental Therapeutics, Texas A&M University Health Science Center, College of Medicine, Bryan, Texas
| | - Victoria M Golub
- Department of Neuroscience and Experimental Therapeutics, Texas A&M University Health Science Center, College of Medicine, Bryan, Texas
| | - W Mohaiza Dashwood
- Center for Epigenetics & Disease Prevention, Texas A&M University Health Science Center, College of Medicine, Houston, Texas
| | - Roderick H Dashwood
- Center for Epigenetics & Disease Prevention, Texas A&M University Health Science Center, College of Medicine, Houston, Texas
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Anticancer Activity of Sulforaphane: The Epigenetic Mechanisms and the Nrf2 Signaling Pathway. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2018; 2018:5438179. [PMID: 29977456 PMCID: PMC6011061 DOI: 10.1155/2018/5438179] [Citation(s) in RCA: 87] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/22/2018] [Revised: 04/27/2018] [Accepted: 05/08/2018] [Indexed: 12/21/2022]
Abstract
Sulforaphane (SFN), a compound derived from cruciferous vegetables that has been shown to be safe and nontoxic, with minimal/no side effects, has been extensively studied due to its numerous bioactivities, such as anticancer and antioxidant activities. SFN exerts its anticancer effects by modulating key signaling pathways and genes involved in the induction of apoptosis, cell cycle arrest, and inhibition of angiogenesis. SFN also upregulates a series of cytoprotective genes by activating nuclear factor erythroid-2- (NF-E2-) related factor 2 (Nrf2), a critical transcription factor activated in response to oxidative stress; Nrf2 activation is also involved in the cancer-preventive effects of SFN. Accumulating evidence supports that epigenetic modification is an important factor in carcinogenesis and cancer progression, as epigenetic alterations often contribute to the inhibition of tumor-suppressor genes and the activation of oncogenes, which enables cells to acquire cancer-promoting properties. Studies on the mechanisms underlying the anticancer effects of SFN have shown that SFN can reverse such epigenetic alterations in cancers by targeting DNA methyltransferases (DNMTs), histone deacetyltransferases (HDACs), and noncoding RNAs. Therefore, in this review, we will discuss the anticancer activities of SFN and its mechanisms, with a particular emphasis on epigenetic modifications, including epigenetic reactivation of Nrf2.
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Liu P, Wang W, Zhou Z, Smith AJO, Bowater RP, Wormstone IM, Chen Y, Bao Y. Chemopreventive Activities of Sulforaphane and Its Metabolites in Human Hepatoma HepG2 Cells. Nutrients 2018; 10:nu10050585. [PMID: 29747418 PMCID: PMC5986465 DOI: 10.3390/nu10050585] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Revised: 05/02/2018] [Accepted: 05/04/2018] [Indexed: 12/04/2022] Open
Abstract
Sulforaphane (SFN) exhibits chemopreventive effects through various mechanisms. However, few studies have focused on the bioactivities of its metabolites. Here, three metabolites derived from SFN were studied, known as sulforaphane glutathione, sulforaphane cysteine and sulforaphane-N-acetylcysteine. Their effects on cell viability, DNA damage, tumorigenicity, cell migration and adhesion were measured in human hepatoma HepG2 cells, and their anti-angiogenetic effects were determined in a 3D co-culture model of human umbilical vein endothelial cells (HUVECs) and pericytes. Results indicated that these metabolites at high doses decreased cancer cell viability, induced DNA damage and inhibited motility, and impaired endothelial cell migration and tube formation. Additionally, pre-treatment with low doses of SFN metabolites protected against H2O2 challenge. The activation of the nuclear factor E2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway and the induction of intracellular glutathione (GSH) played an important role in the cytoprotective effects of SFN metabolites. In conclusion, SFN metabolites exhibited similar cytotoxic and cytoprotective effects to SFN, which proves the necessity to study the mechanisms of action of not only SFN but also of its metabolites. Based on the different tissue distribution profiles of these metabolites, the most relevant chemical forms can be selected for targeted chemoprevention.
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Affiliation(s)
- Peng Liu
- Norwich Medical School, University of East Anglia, Norfolk, Norwich NR4 7UQ, UK.
| | - Wei Wang
- Norwich Medical School, University of East Anglia, Norfolk, Norwich NR4 7UQ, UK.
| | - Zhigang Zhou
- Norwich Medical School, University of East Anglia, Norfolk, Norwich NR4 7UQ, UK.
| | - Andrew J O Smith
- School of Biological Sciences, University of East Anglia, Norwich Research Park, Norwich, Norfolk NR4 7TJ, UK.
| | - Richard P Bowater
- School of Biological Sciences, University of East Anglia, Norwich Research Park, Norwich, Norfolk NR4 7TJ, UK.
| | - Ian Michael Wormstone
- School of Biological Sciences, University of East Anglia, Norwich Research Park, Norwich, Norfolk NR4 7TJ, UK.
| | - Yuqiong Chen
- College of Horticulture and Forestry Science Huazhong Agricultural University, Wuhan 430070, China.
| | - Yongping Bao
- Norwich Medical School, University of East Anglia, Norfolk, Norwich NR4 7UQ, UK.
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Komariah K, Manalu W, Kiranadi B, Winarto A, Handharyani E, Roeslan MO. Valproic Acid Exposure of Pregnant Rats During Organogenesis Disturbs Pancreas Development in Insulin Synthesis and Secretion of the Offspring. Toxicol Res 2018; 34:173-182. [PMID: 29686779 PMCID: PMC5903136 DOI: 10.5487/tr.2018.34.2.173] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2017] [Revised: 11/26/2017] [Accepted: 03/09/2018] [Indexed: 12/19/2022] Open
Abstract
Valproic acid (VPA) plays a role in histone modifications that eventually inhibit the activity of histone deacetylase (HDAC), and will affect the expressions of genes Pdx1, Nkx6.1, and Ngn3 during pancreatic organogenesis. This experiment was designed to study the effect of VPA exposure in pregnant rats on the activity of HDAC that controls the expression of genes regulating the development of beta cells in the pancreas to synthesize and secrete insulin. This study used 30 pregnant Sprague-Dawley rats, divided into 4 groups, as follows: (1) a control group of pregnant rats without VPA administration, (2) pregnant rats administered with 250 mg VPA on day 10 of pregnancy, (3) pregnant rats administered with 250 mg VPA on day 13 of pregnancy, and (4) pregnant rats administered with 250 mg VPA on day 16 of pregnancy. Eighty-four newborn rats born to control rats and rats administered with VPA on days 10, 13, and 16 of pregnancy were used to measure serum glucose, insulin, DNA, RNA, and ratio of RNA/DNA concentrations in the pancreas and to observe the microscopical condition of the pancreas at the ages of 4 to 32 weeks postpartum with 4-week intervals. The results showed that at the age of 32 weeks, the offspring of pregnant rats administered with 250 mg VPA on days 10, 13, and 16 of pregnancy had higher serum glucose concentrations and lower serum insulin concentrations, followed by decreased concentrations of RNA, and the ratio of RNA/DNA in the pancreas. Microscopical observations showed that the pancreas of the rats born to pregnant rats administered with VPA during pregnancy had low immunoreaction to insulin. The exposure of pregnant rats to VPA during pregnancy disturbs organogenesis of the pancreas of the embryos that eventually disturb the insulin production in the beta cells indicated by the decreased insulin secretion during postnatal life.
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Affiliation(s)
- Komariah Komariah
- Department of Histology, Faculty of Dentistry, Trisakti University, West Jakarta, Indonesia
| | - Wasmen Manalu
- Department of Anatomy, Physiology, and Pharmacology, Faculty of Veterinary Medicine, Bogor Agricultural University, West Java, Indonesia
| | - Bambang Kiranadi
- Department of Anatomy, Physiology, and Pharmacology, Faculty of Veterinary Medicine, Bogor Agricultural University, West Java, Indonesia
| | - Adi Winarto
- Department of Anatomy, Physiology, and Pharmacology, Faculty of Veterinary Medicine, Bogor Agricultural University, West Java, Indonesia
| | - Ekowati Handharyani
- Department of Clinic, Reproduction, and Pathology, Faculty of Veterinary Medicine, Bogor Agricultural University, West Java, Indonesia
| | - M Orliando Roeslan
- Department of Biology Oral, Faculty of Dentistry, Trisakti University, West Jakarta, Indonesia
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47
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Beaver LM, Lӧhr CV, Clarke JD, Glasser ST, Watson GW, Wong CP, Zhang Z, Williams DE, Dashwood RH, Shannon J, Thuillier P, Ho E. Broccoli Sprouts Delay Prostate Cancer Formation and Decrease Prostate Cancer Severity with a Concurrent Decrease in HDAC3 Protein Expression in Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) Mice. Curr Dev Nutr 2018; 2:nzy002. [PMID: 30019025 PMCID: PMC6041877 DOI: 10.1093/cdn/nzy002] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2017] [Revised: 12/21/2017] [Accepted: 12/21/2017] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND Cruciferous vegetables have been associated with the chemoprevention of cancer. Epigenetic regulators have been identified as important targets for prostate cancer chemoprevention. Treatment of human prostate cancer cells with sulforaphane (SFN), a chemical from broccoli and broccoli sprouts, inhibits epigenetic regulators such as histone deacetylase (HDAC) enzymes, but it is not known whether consumption of a diet high in broccoli sprouts impacts epigenetic mechanisms in an in vivo model of prostate cancer. OBJECTIVE In the transgenic adenocarcinoma of the mouse prostate (TRAMP) model, we tested the hypothesis that a broccoli sprout diet suppresses prostate cancer, inhibits HDAC expression, alters histone modifications, and changes the expression of genes regulated by HDACs. METHODS TRAMP mice were fed a 15% broccoli sprout or control AIN93G diet; tissue samples were collected at 12 and 28 wk of age. RESULTS Mice fed broccoli sprouts had detectable amounts of SFN metabolites in liver, kidney, colon, and prostate tissues. Broccoli sprouts reduced prostate cancer incidence and progression to invasive cancer by 11- and 2.4-fold at 12 and 28 wk of age, respectively. There was a significant decline in HDAC3 protein expression in the epithelial cells of prostate ventral and anterior lobes at age 12 wk. Broccoli sprout consumption also decreased histone H3 lysine 9 trimethylation in the ventral lobe (age 12 wk), and decreased histone H3 lysine 18 acetylation in all prostate lobes (age 28 wk). A decline in p16 mRNA levels, a gene regulated by HDAC3, was associated with broccoli sprout consumption, but no significant changes were noted at the protein level. CONCLUSIONS Broccoli sprout intake was associated with a decline in prostate cancer occurrence and HDAC3 protein expression in the prostate, extending prior work that implicated loss of HDAC3/ corepressor interactions as a key preventive mechanism by SFN in vivo.
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Affiliation(s)
- Laura M Beaver
- School of Biological and Population Health Sciences, Oregon State University, Corvallis, OR
- Linus Pauling Institute, Oregon State University, Corvallis, OR
| | - Christiane V Lӧhr
- Linus Pauling Institute, Oregon State University, Corvallis, OR
- Department of Biomedical Sciences, College of Veterinary Medicine, Oregon State University, Corvallis, OR
| | - John D Clarke
- School of Biological and Population Health Sciences, Oregon State University, Corvallis, OR
- Linus Pauling Institute, Oregon State University, Corvallis, OR
| | - Sarah T Glasser
- School of Biological and Population Health Sciences, Oregon State University, Corvallis, OR
| | - Greg W Watson
- School of Biological and Population Health Sciences, Oregon State University, Corvallis, OR
- Linus Pauling Institute, Oregon State University, Corvallis, OR
| | - Carmen P Wong
- School of Biological and Population Health Sciences, Oregon State University, Corvallis, OR
- Linus Pauling Institute, Oregon State University, Corvallis, OR
| | - Zhenzhen Zhang
- OHSU-PSU School of Public Health, Oregon Health & Science University, Portland, OR
| | - David E Williams
- Linus Pauling Institute, Oregon State University, Corvallis, OR
- Department of Environmental and Molecular Toxicology, College of Agricultural Sciences, Oregon State University, Corvallis, OR
| | - Roderick H Dashwood
- Linus Pauling Institute, Oregon State University, Corvallis, OR
- Department of Environmental and Molecular Toxicology, College of Agricultural Sciences, Oregon State University, Corvallis, OR
| | - Jackilen Shannon
- Department of Environmental and Molecular Toxicology, College of Agricultural Sciences, Oregon State University, Corvallis, OR
| | - Philippe Thuillier
- OHSU-PSU School of Public Health, Oregon Health & Science University, Portland, OR
- Department of Dermatology, Oregon Health & Science University, Portland, OR
| | - Emily Ho
- School of Biological and Population Health Sciences, Oregon State University, Corvallis, OR
- Linus Pauling Institute, Oregon State University, Corvallis, OR
- Moore Family Center for Whole Grain Foods, Nutrition and Preventive Health, Oregon State University, Corvallis, OR
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48
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Zhou Y, Yang G, Tian H, Hu Y, Wu S, Geng Y, Lin K, Wu W. Sulforaphane metabolites cause apoptosis via microtubule disruption in cancer. Endocr Relat Cancer 2018; 25:255-268. [PMID: 29431641 DOI: 10.1530/erc-17-0483] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2017] [Accepted: 12/19/2017] [Indexed: 12/17/2022]
Abstract
Sulforaphane (SFN) inhibited growth in many cancers, but its half-life is 2 h in circulation. However, its metabolites, sulforaphane-cysteine (SFN-Cys) and sulforaphane-N-acetyl-cysteine (SFN-NAC) had longer half-lives and decreased the cell viability in both dose- and time-dependent manners in human prostate cancer. Flow cytometry assay revealed that these two SFN metabolites induced apoptosis with the features such as vacuolization, disappeared nuclear envelope, nuclear agglutination and fragmentation via transmission electron microscopy observation. Western blot showed that the sustained phosphorylation of ERK1/2 mediated by SFN metabolites caused activation and upregulation of cleaved Caspase 3 and downregulation of α-tubulin. High expression of α-tubulin was demonstrated to be positively correlated with cancer pathological grading. Both co-immunoprecipitation and immunofluorescence staining implicated the interaction between SFN metabolite-induced phosphorylated ERK1/2 and α-tubulin, and Caspase 3 cleavage assay showed that α-tubulin might be the substrate for cleaved Caspase 3. More, the SFN metabolite-mediated reduction of α-tubulin increased the depolymerization and instability of microtubules by microtubule polymerization assay. Reversely, microtubule-associated protein Stathmin-1 phosphorylation was increased via phosphorylated ERK1/2 and total Stathmin-1 was reduced, which might promote over-stability of microtubules. Immunofluorescence staining also showed that SFN metabolites induced the 'nest-like' structures of microtubule distribution resulting from the disrupted and aggregated microtubules, and abnormal nuclear division, suggesting that the disturbance of spindle formation and mitosis turned up. Thus, SFN-Cys and SFN-NAC triggered the dynamic imbalance of microtubules, microtubule disruption leading to cell apoptosis. These findings provided a novel insight into the chemotherapy of human prostate cancer.
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Affiliation(s)
- Yan Zhou
- Department of Biochemistry and Molecular BiologySchool of Basic Medical Sciences, Beijing Key Laboratory of Tumor Invasion and Metastasis Research, Institute of Cancer Research, Capital Medical University, Beijing, China
| | - Gaoxiang Yang
- Department of Biochemistry and Molecular BiologySchool of Basic Medical Sciences, Beijing Key Laboratory of Tumor Invasion and Metastasis Research, Institute of Cancer Research, Capital Medical University, Beijing, China
| | - Hua Tian
- Department of Biochemistry and Molecular BiologySchool of Basic Medical Sciences, Beijing Key Laboratory of Tumor Invasion and Metastasis Research, Institute of Cancer Research, Capital Medical University, Beijing, China
| | - Yabin Hu
- Department of Biochemistry and Molecular BiologySchool of Basic Medical Sciences, Beijing Key Laboratory of Tumor Invasion and Metastasis Research, Institute of Cancer Research, Capital Medical University, Beijing, China
| | - Sai Wu
- Department of Biochemistry and Molecular BiologySchool of Basic Medical Sciences, Beijing Key Laboratory of Tumor Invasion and Metastasis Research, Institute of Cancer Research, Capital Medical University, Beijing, China
| | - Yang Geng
- Department of Biochemistry and Molecular BiologySchool of Basic Medical Sciences, Beijing Key Laboratory of Tumor Invasion and Metastasis Research, Institute of Cancer Research, Capital Medical University, Beijing, China
| | - Kai Lin
- Department of Biochemistry and Molecular BiologySchool of Basic Medical Sciences, Beijing Key Laboratory of Tumor Invasion and Metastasis Research, Institute of Cancer Research, Capital Medical University, Beijing, China
| | - Wei Wu
- Department of Biochemistry and Molecular BiologySchool of Basic Medical Sciences, Beijing Key Laboratory of Tumor Invasion and Metastasis Research, Institute of Cancer Research, Capital Medical University, Beijing, China
- Institute of Brain TumorBeijing Institute for Brain Disorders, Capital Medical University, Beijing, China
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49
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Housley L, Magana AA, Hsu A, Beaver LM, Wong CP, Stevens JF, Choi J, Jiang Y, Bella D, Williams DE, Maier CS, Shannon J, Dashwood RH, Ho E. Untargeted Metabolomic Screen Reveals Changes in Human Plasma Metabolite Profiles Following Consumption of Fresh Broccoli Sprouts. Mol Nutr Food Res 2018; 62:e1700665. [PMID: 29377494 DOI: 10.1002/mnfr.201700665] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2017] [Revised: 12/22/2017] [Indexed: 12/21/2022]
Abstract
SCOPE Several lines of evidence suggest that the consumption of cruciferous vegetables is beneficial to human health. Yet, underlying mechanisms and key molecular targets that are involved with achieving these benefits in humans are still not fully understood. To accelerate this research, we conduct a human study to identify potential molecular targets of crucifers for further study. This study aims to characterize plasma metabolite profiles in humans before and after consuming fresh broccoli sprouts (a rich dietary source of bioactive sulforaphane). METHODS AND RESULTS Ten healthy adults consume fresh broccoli sprouts (containing 200 μmol sulforaphane equivalents) at time 0 and provide blood samples at 0, 3, 6, 12, 24, and 48 h. An untargeted metabolomics screen reveals that levels of several plasma metabolites are significantly different before and after sprout intake, including fatty acids (14:0, 14:1, 16:0, 16:1, 18:0, and 18:1), glutathione, glutamine, cysteine, dehydroepiandrosterone, and deoxyuridine monophosphate. Evaluation of all time points is conducted using paired t-test (R software) and repeated measures analysis of variance for a within-subject design (Progenesis QI). CONCLUSION This investigation identifies several potential molecular targets of crucifers that may aid in studying established and emerging health benefits of consuming cruciferous vegetables and related bioactive compounds.
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Affiliation(s)
- Lauren Housley
- School of Biological and Population Health Sciences, Oregon State University, Corvallis, OR, USA.,Department of Nutrition and Food Science, California State University, Chico, CA, USA
| | - Armando Alcazar Magana
- Linus Pauling Institute, Oregon State University, Corvallis, OR, USA.,Department of Chemistry, Oregon State University, Corvallis, OR, USA
| | - Anna Hsu
- School of Biological and Population Health Sciences, Oregon State University, Corvallis, OR, USA
| | - Laura M Beaver
- School of Biological and Population Health Sciences, Oregon State University, Corvallis, OR, USA
| | - Carmen P Wong
- School of Biological and Population Health Sciences, Oregon State University, Corvallis, OR, USA
| | - Jan F Stevens
- Linus Pauling Institute, Oregon State University, Corvallis, OR, USA.,Department of Pharmaceutical Sciences, Oregon State University, Corvallis, OR, USA
| | - Jaewoo Choi
- Linus Pauling Institute, Oregon State University, Corvallis, OR, USA
| | - Yuan Jiang
- Department of Statistics, Oregon State University, Corvallis, OR, USA
| | - Deborah Bella
- School of Biological and Population Health Sciences, Oregon State University, Corvallis, OR, USA
| | - David E Williams
- Linus Pauling Institute, Oregon State University, Corvallis, OR, USA.,Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR, USA
| | - Claudia S Maier
- Department of Chemistry, Oregon State University, Corvallis, OR, USA
| | - Jackilen Shannon
- Department of Public Health & Preventive Medicine, Oregon Health and Science University, Portland, OR, USA
| | - Roderick H Dashwood
- Center for Epigenetics & Disease Prevention, Texas A&M Health Science Center, Houston, TX, USA
| | - Emily Ho
- School of Biological and Population Health Sciences, Oregon State University, Corvallis, OR, USA.,Linus Pauling Institute, Oregon State University, Corvallis, OR, USA.,Center for Epigenetics & Disease Prevention, Texas A&M Health Science Center, Houston, TX, USA.,Moore Family Center for Whole Grain Foods, Nutrition and Preventive Health, Oregon State University, Corvallis, OR, USA
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50
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Liu P, Behray M, Wang Q, Wang W, Zhou Z, Chao Y, Bao Y. Anti-cancer activities of allyl isothiocyanate and its conjugated silicon quantum dots. Sci Rep 2018; 8:1084. [PMID: 29348534 PMCID: PMC5773486 DOI: 10.1038/s41598-018-19353-7] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2017] [Accepted: 11/08/2017] [Indexed: 12/11/2022] Open
Abstract
Allyl isothiocyanate (AITC), a dietary phytochemical in some cruciferous vegetables, exhibits promising anticancer activities in many cancer models. However, previous data showed AITC to have a biphasic effect on cell viability, DNA damage and migration in human hepatoma HepG2 cells. Moreover, in a 3D co-culture of HUVEC with pericytes, it inhibited tube formation at high doses but promoted this at low doses, which confirmed its biphasic effect on angiogenesis. siRNA knockdown of Nrf2 and glutathione inhibition abolished the stimulation effect of AITC on cell migration and DNA damage. The biological activity of a novel AITC-conjugated silicon quantum dots (AITC-SiQDs) has been investigated for the first time. AITC-SiQDs showed similar anti-cancer properties to AITC at high doses while avoiding the low doses stimulation effect. In addition, AITC-SiQDs showed a lower and long-lasting activation of Nrf2 translocation into nucleus which correlated with their levels of cellular uptake, as detected by the intrinsic fluorescence of SiQDs. ROS production could be one of the mechanisms behind the anti-cancer effect of AITC-SiQDs. These data provide novel insights into the biphasic effect of AITC and highlight the application of nanotechnology to optimize the therapeutic potential of dietary isothiocyanates in cancer treatment.
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Affiliation(s)
- Peng Liu
- Norwich Medical School, University of East Anglia, Norwich, Norfolk, United Kingdom
| | - Mehrnaz Behray
- School of Chemistry, University of East Anglia, Norwich, Norfolk, United Kingdom
| | - Qi Wang
- Norwich Medical School, University of East Anglia, Norwich, Norfolk, United Kingdom
| | - Wei Wang
- Norwich Medical School, University of East Anglia, Norwich, Norfolk, United Kingdom
| | - Zhigang Zhou
- Norwich Medical School, University of East Anglia, Norwich, Norfolk, United Kingdom
| | - Yimin Chao
- School of Chemistry, University of East Anglia, Norwich, Norfolk, United Kingdom
| | - Yongping Bao
- Norwich Medical School, University of East Anglia, Norwich, Norfolk, United Kingdom.
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