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Wang L, Hu L, Sun J, Zhao J, Zhou S, Liu L, Yu W, Hu Y, Zhou D, Meng X, Yuan Z, Zhang H, Farrington S, Timofeeva M, Ding K, Little J, Dunlop M, Theodoratou E, Li X. Trans-ancestry transcriptome-wide association and functional studies to uncover novel susceptibility genes and therapeutic targets for colorectal cancer. NPJ Precis Oncol 2025; 9:124. [PMID: 40301637 PMCID: PMC12041606 DOI: 10.1038/s41698-025-00906-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Accepted: 04/07/2025] [Indexed: 05/01/2025] Open
Abstract
By integrating findings from large-scale omics analyses with experimental tests, this study aims to decipher susceptibility genes and the underlying biological mechanisms involved in the development of colorectal cancer (CRC). We first conducted a trans-ancestry transcriptome-wide association study (TWAS) among 57,402 CRC cases and 119,110 controls, aiming to examine how altered gene expression influences CRC risk in European and Asian populations. Then, functional experiments in (i) CRC cell lines and (ii) tumor xenografts were conducted to examine potential underlying mechanisms involved in colorectal carcinogenesis. Further, a drug sensitivity test was employed to explore possible clinical implications for CRC treatment. The TWAS identified 67 genes highly associated with CRC risk, 23 of which were novel findings. Functional annotation of variants within TWAS-identified loci revealed that the majority (93.6%) showed evidence of transcriptional regulatory mechanisms via proximal promoter or distal enhancer-promoter interactions. Among the identified susceptibility genes, splicing factor 3a subunit 3 (SF3A3) may act as an oncogene on the basis that overexpression of this gene was significantly associated with increased risk of CRC (P = 5.75 × 10-11). Further cell and animal experiments confirmed that SF3A3 plays an oncogenic role in CRC development, and the underlying biological mechanism is likely to be related to its anti-apoptosis effect. The drug sensitivity test suggested that phenethyl isothiocyanate (PEITC) targeting SF3A3 can inhibit CRC progression. This study identified novel CRC susceptibility genes and potential biological mechanisms of SF3A3 involved in CRC development, providing important insight into the etiology and potential leads to the treatment of CRC.
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Affiliation(s)
- Lijuan Wang
- School of Public Health, the Second affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Centre for Global Health, Usher Institute, University of Edinburgh, Edinburgh, UK
| | - Lidan Hu
- Department of Nephrology, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China.
| | - Jing Sun
- School of Public Health, the Second affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jianhui Zhao
- School of Public Health, the Second affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Siyun Zhou
- School of Public Health, the Second affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Lexin Liu
- Department of Nephrology, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| | - Wei Yu
- Department of Nephrology, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| | - Yeting Hu
- Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Dan Zhou
- School of Public Health, the Second affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiangrui Meng
- Division of Psychiatry, University College of London, London, UK
| | - Zhongshang Yuan
- Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Honghe Zhang
- Department of Pathology and Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Susan Farrington
- Colon Cancer Genetics Group, Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
| | - Maria Timofeeva
- Colon Cancer Genetics Group, Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
- Danish Institute for Advanced Study (DIAS), Epidemiology, Biostatistics and Biodemography Research Unit, Institute of Public Health, University of Southern Denmark, Odense, Denmark
| | - Kefeng Ding
- Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Center for Medical Research and Innovation in Digestive System Tumors, Ministry of Education, Hangzhou, China
- Zhejiang Provincial Clinical Research Center for CANCER, Hangzhou, China
| | - Julian Little
- School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada
| | - Malcolm Dunlop
- Colon Cancer Genetics Group, Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
| | - Evropi Theodoratou
- Centre for Global Health, Usher Institute, University of Edinburgh, Edinburgh, UK
- Cancer Research UK Edinburgh Centre, Medical Research Council Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK
| | - Xue Li
- School of Public Health, the Second affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
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Zhang X, Jia Q, Jia X, Li J, Sun X, Min L, Liu Z, Ma W, Zhao J. Brassica vegetables-an undervalued nutritional goldmine. HORTICULTURE RESEARCH 2025; 12:uhae302. [PMID: 39949883 PMCID: PMC11822409 DOI: 10.1093/hr/uhae302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Accepted: 10/16/2024] [Indexed: 02/16/2025]
Abstract
The genus Brassica includes six species and over 15 types of vegetables that are widely cultivated and consumed globally. This group of vegetables is rich in bioactive compounds, including glucosinolates, vitamins (such as vitamin C, folate, tocopherol, and phylloquinone), carotenoids, phenols, and minerals, which are crucial for enriching diets and maintaining human health. However, the full extent of these phytonutrients and their significant health benefits remain to be fully elucidated. This review highlights the nutrient compositions and health advantages of Brassica vegetables and discusses the impacts of various processing methods on their nutritional value. Additionally, we discuss potential strategies for enhancing the nutrition of Brassica crops through agronomic biofortification, conventional breeding, and biotechnological or metabolic engineering approaches. This review lays the foundation for the nutritional improvement of Brassica crops.
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Affiliation(s)
- Xiaomeng Zhang
- State Key Laboratory of North China Crop Improvement and Regulation, Key Laboratory of Vegetable Germplasm Innovation and Utilization of Hebei, Collaborative Innovation Center of Vegetable Industry in Hebei, College of Horticulture, Hebei Agricultural University, No. 2596 Lekai South Street, Lianchi District, Baoding, Hebei 071000, China
| | - Qiong Jia
- State Key Laboratory of North China Crop Improvement and Regulation, Key Laboratory of Vegetable Germplasm Innovation and Utilization of Hebei, Collaborative Innovation Center of Vegetable Industry in Hebei, College of Horticulture, Hebei Agricultural University, No. 2596 Lekai South Street, Lianchi District, Baoding, Hebei 071000, China
| | - Xin Jia
- State Key Laboratory of North China Crop Improvement and Regulation, Key Laboratory of Vegetable Germplasm Innovation and Utilization of Hebei, Collaborative Innovation Center of Vegetable Industry in Hebei, College of Horticulture, Hebei Agricultural University, No. 2596 Lekai South Street, Lianchi District, Baoding, Hebei 071000, China
| | - Jie Li
- Department of Biochemistry and Metabolism, John Innes Centre, Norwich Research Park, Norwich NR4 7UH, United Kingdom
| | - Xiaoxue Sun
- State Key Laboratory of North China Crop Improvement and Regulation, Key Laboratory of Vegetable Germplasm Innovation and Utilization of Hebei, Collaborative Innovation Center of Vegetable Industry in Hebei, College of Horticulture, Hebei Agricultural University, No. 2596 Lekai South Street, Lianchi District, Baoding, Hebei 071000, China
| | - Leiguo Min
- State Key Laboratory of North China Crop Improvement and Regulation, Key Laboratory of Vegetable Germplasm Innovation and Utilization of Hebei, Collaborative Innovation Center of Vegetable Industry in Hebei, College of Horticulture, Hebei Agricultural University, No. 2596 Lekai South Street, Lianchi District, Baoding, Hebei 071000, China
| | - Zhaokun Liu
- Vegetable Research Institute, Suzhou Academy of Agricultural Sciences, No. 2351 Dongshan Avenue, Linhu Town, Wuzhong District, Suzhou, Jiangsu 215155, China
| | - Wei Ma
- State Key Laboratory of North China Crop Improvement and Regulation, Key Laboratory of Vegetable Germplasm Innovation and Utilization of Hebei, Collaborative Innovation Center of Vegetable Industry in Hebei, College of Horticulture, Hebei Agricultural University, No. 2596 Lekai South Street, Lianchi District, Baoding, Hebei 071000, China
| | - Jianjun Zhao
- State Key Laboratory of North China Crop Improvement and Regulation, Key Laboratory of Vegetable Germplasm Innovation and Utilization of Hebei, Collaborative Innovation Center of Vegetable Industry in Hebei, College of Horticulture, Hebei Agricultural University, No. 2596 Lekai South Street, Lianchi District, Baoding, Hebei 071000, China
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Joković N, Pešić S, Vitorović J, Bogdanović A, Sharifi-Rad J, Calina D. Glucosinolates and Their Hydrolytic Derivatives: Promising Phytochemicals With Anticancer Potential. Phytother Res 2025; 39:1035-1089. [PMID: 39726346 DOI: 10.1002/ptr.8419] [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: 06/19/2024] [Revised: 10/29/2024] [Accepted: 12/10/2024] [Indexed: 12/28/2024]
Abstract
Recent research has increasingly focused on phytochemicals as promising anticancer agents, with glucosinolates (GSLs) and their hydrolytic derivatives playing a central role. These sulfur-containing compounds, found in plants of the Brassicales order, are converted by myrosinase enzymes into biologically active products, primarily isothiocyanates (ITCs) and indoles, which exhibit significant anticancer properties. Indole-3-carbinol, diindolylmethane, sulforaphane (SFN), phenethyl isothiocyanate (PEITC), benzyl isothiocyanate, and allyl isothiocyanate have shown potent anticancer effects in animal models, particularly in breast, prostate, lung, melanoma, bladder, hepatoma, and gastrointestinal cancers. Clinical studies further support the chemopreventive effects of SFN and PEITC, particularly in detoxifying carcinogens and altering biochemical markers in cancer patients. These compounds have demonstrated good bioavailability, low toxicity, and minimal adverse effects, supporting their potential therapeutic application. Their anticancer mechanisms include the modulation of reactive oxygen species, suppression of cancer-related signaling pathways, and direct interaction with tumor cell proteins. Additionally, semi-synthetic derivatives of GSLs have been developed to enhance anticancer efficacy. In conclusion, GSLs and their derivatives offer significant potential as both chemopreventive and therapeutic agents, warranting further clinical investigation to optimize their application in cancer treatment.
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Affiliation(s)
- Nataša Joković
- Department of Biology and Ecology, Faculty of Science and Mathematics, University of Niš, Niš, Serbia
| | - Strahinja Pešić
- Department of Biology and Ecology, Faculty of Science and Mathematics, University of Niš, Niš, Serbia
| | - Jelena Vitorović
- Department of Biology and Ecology, Faculty of Science and Mathematics, University of Niš, Niš, Serbia
| | - Andrija Bogdanović
- Department of Biology and Ecology, Faculty of Science and Mathematics, University of Niš, Niš, Serbia
| | - Javad Sharifi-Rad
- Universidad Espíritu Santo, Samborondón, Ecuador
- Department of Medicine, College of Medicine, Korea University, Seoul, Republic of Korea
| | - Daniela Calina
- Department of Clinical Pharmacy, University of Medicine and Pharmacy of Craiova, Craiova, Romania
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Krisanits BA, Kaur B, Fahey JW, Turner DP. The Anti-AGEing and RAGEing Potential of Isothiocyanates. Molecules 2024; 29:5986. [PMID: 39770075 PMCID: PMC11677037 DOI: 10.3390/molecules29245986] [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: 11/15/2024] [Revised: 12/13/2024] [Accepted: 12/15/2024] [Indexed: 01/03/2025] Open
Abstract
Isothiocyanates (ITCs), found in edible plants such as cruciferous vegetables, are a group of reactive organo-sulfur phytochemicals produced by the hydrolysis of precursors known as glucosinolates. ITCs have been studied extensively both in vivo and in vitro to define their therapeutic potential for the treatment of chronic health conditions. Therapeutically, they have shown an intrinsic ability to inhibit oxidative and inflammatory phenotypes to support enhanced health. This review summarizes the current evidence supporting the observation that the antioxidant and anti-inflammatory activities of ITCs temper the pathogenic effects of a group of reactive metabolites called advanced glycation end products (AGEs). AGE exposure has significantly increased across the lifespan due to health risk factors that include dietary intake, a sedentary lifestyle, and comorbid conditions. By contributing to a chronic cycle of inflammatory stress through the aberrant activation of the transmembrane receptor for AGE (RAGE), increased AGE bioavailability is associated with chronic disease onset, progression, and severity. This review debates the potential molecular mechanisms by which ITCs may inhibit AGE bioavailability to reduce RAGE-mediated pro-oxidant and pro-inflammatory phenotypes. Bringing to light the molecular impact that ITCs may have on AGE biogenesis may stimulate novel intervention strategies for reversing or preventing the impact of lifestyle factors on chronic disease risk.
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Affiliation(s)
- Bradley A. Krisanits
- Department of Surgery, School of Medicine, Virginia Commonwealth University, Richmond, VA 23284, USA; (B.A.K.); (B.K.)
- Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23284, USA
| | - Bhoomika Kaur
- Department of Surgery, School of Medicine, Virginia Commonwealth University, Richmond, VA 23284, USA; (B.A.K.); (B.K.)
- Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23284, USA
| | - Jed W. Fahey
- Departments of Medicine, Pharmacology & Molecular Sciences, Psychiatry & Behavioral Sciences, and iMIND Hopkins, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA;
- Institute of Medicine, University of Maine, Orono, ME 04469, USA
| | - David P. Turner
- Department of Surgery, School of Medicine, Virginia Commonwealth University, Richmond, VA 23284, USA; (B.A.K.); (B.K.)
- Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23284, USA
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Na X, Li L, Liu D, He J, Zhang L, Zhou Y. Natural products targeting ferroptosis pathways in cancer therapy (Review). Oncol Rep 2024; 52:123. [PMID: 39054952 PMCID: PMC11292301 DOI: 10.3892/or.2024.8782] [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: 04/14/2024] [Accepted: 06/25/2024] [Indexed: 07/27/2024] Open
Abstract
Ferroptosis inducers (FIN) have a key role in cancer therapy and provide novel and innovative treatment strategies. Although many researchers have performed FIN screening of synthetic compounds, studies on the identification of FIN from natural products are limited, particularly in the field of drug development and combination therapy. In this review, this gap was addressed by comprehensively summarizing recent studies on ferroptosis. The causes of ferroptosis were categorized into driving and defensive factors, elucidating key pathways and targets. Next, through summarizing research on natural products that induce ferroptosis, the study elaborated in detail on the natural products that have FIN functions. Their discovery and development were also described and insight for clinical drug development was provided. In addition, the mechanisms of action were analyzed and potential combination therapies, resistance reversal and structural enhancements were presented. By highlighting the potential of natural products in inducing ferroptosis for cancer treatment, this review may serve as a reference for utilizing these compounds against cancer. It not only showed the significance of natural products but may also promote further investigation into their therapeutic effects, thus encouraging research in this field.
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Affiliation(s)
- Xin Na
- School of Pharmaceutical Sciences & Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, Yunnan 650500, P.R. China
| | - Lin Li
- Yunnan Cancer Hospital (Third Affiliated Hospital of Kunming Medical University), Kunming, Yunnan 650118, P.R. China
| | - Dongmei Liu
- School of Pharmaceutical Sciences & Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, Yunnan 650500, P.R. China
| | - Jiaqi He
- The First Clinical Medical College of Kunming Medical University, Kunming, Yunnan 650500, P.R. China
| | - Ling Zhang
- School of Pharmaceutical Sciences & Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, Yunnan 650500, P.R. China
| | - Yiping Zhou
- School of Pharmaceutical Sciences & Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, Yunnan 650500, P.R. China
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Rahman M, Khatun A, Liu L, Barkla BJ. Brassicaceae Mustards: Phytochemical Constituents, Pharmacological Effects, and Mechanisms of Action against Human Disease. Int J Mol Sci 2024; 25:9039. [PMID: 39201724 PMCID: PMC11354652 DOI: 10.3390/ijms25169039] [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: 07/07/2024] [Revised: 08/13/2024] [Accepted: 08/16/2024] [Indexed: 09/03/2024] Open
Abstract
The Brassicaceae genus consists of many economically important mustards of value for food and medicinal purposes, namely Asian mustard (Brassica juncea), ball mustard (Neslia paniculata), black mustard (B. nigra), garlic mustard (Alliaria petiolata), hedge mustard (Sisymbrium officinale), Asian hedge mustard (S. orientale), oilseed rape (B. napus), rapeseed (B. rapa), treacle mustard (Erysimum repandum), smooth mustard (S. erysimoides), white ball mustard (Calepina irregularis), white mustard (Sinapis alba), and Canola. Some of these are commercially cultivated as oilseeds to meet the global demand for a healthy plant-derived oil, high in polyunsaturated fats, i.e., B. napus and B. juncea. Other species are foraged from the wild where they grow on roadsides and as a weed of arable land, i.e., E. repandum and S. erysimoides, and harvested for medicinal uses. These plants contain a diverse range of bioactive natural products including sulfur-containing glucosinolates and other potentially valuable compounds, namely omega-3-fatty acids, terpenoids, phenylpropanoids, flavonoids, tannins, S-methyl cysteine sulfoxide, and trace-elements. Various parts of these plants and many of the molecules that are produced throughout the plant have been used in traditional medicines and more recently in the mainstream pharmaceutical and food industries. This study relates the uses of mustards in traditional medicines with their bioactive molecules and possible mechanisms of action and provides an overview of the current knowledge of Brassicaceae oilseeds and mustards, their phytochemicals, and their biological activities.
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Affiliation(s)
- Mahmudur Rahman
- Southern Cross Analytical Services, Southern Cross University, Lismore, NSW 2480, Australia; (M.R.); (A.K.)
- Faculty of Science and Engineering, Southern Cross University, Lismore, NSW 2480, Australia;
| | - Amina Khatun
- Southern Cross Analytical Services, Southern Cross University, Lismore, NSW 2480, Australia; (M.R.); (A.K.)
- Faculty of Science and Engineering, Southern Cross University, Lismore, NSW 2480, Australia;
| | - Lei Liu
- Faculty of Science and Engineering, Southern Cross University, Lismore, NSW 2480, Australia;
| | - Bronwyn J. Barkla
- Faculty of Science and Engineering, Southern Cross University, Lismore, NSW 2480, Australia;
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M Ezzat S, M Merghany R, M Abdel Baki P, Ali Abdelrahim N, M Osman S, A Salem M, Peña-Corona SI, Cortés H, Kiyekbayeva L, Leyva-Gómez G, Sharifi-Rad J, Calina D. Nutritional Sources and Anticancer Potential of Phenethyl Isothiocyanate: Molecular Mechanisms and Therapeutic Insights. Mol Nutr Food Res 2024; 68:e2400063. [PMID: 38600885 DOI: 10.1002/mnfr.202400063] [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: 01/24/2024] [Indexed: 04/12/2024]
Abstract
Phenethyl isothiocyanate (PEITC), a compound derived from cruciferous vegetables, has garnered attention for its anticancer properties. This review synthesizes existing research on PEITC, focusing on its mechanisms of action in combatting cancer. PEITC has been found to be effective against various cancer types, such as breast, prostate, lung, colon, and pancreatic cancers. Its anticancer activities are mediated through several mechanisms, including the induction of apoptosis (programmed cell death), inhibition of cell proliferation, suppression of angiogenesis (formation of new blood vessels that feed tumors), and reduction of metastasis (spread of cancer cells to new areas). PEITC targets crucial cellular signaling pathways involved in cancer progression, notably the Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB), Protein Kinase B (Akt), and Mitogen-Activated Protein Kinase (MAPK) pathways. These findings suggest PEITC's potential as a therapeutic agent against cancer. However, further research is necessary to determine the optimal dosage, understand its bioavailability, and assess potential side effects. This will be crucial for developing PEITC-based treatments that are both effective and safe for clinical use in cancer therapy.
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Affiliation(s)
- Shahira M Ezzat
- Pharmacognosy Department, Faculty of Pharmacy, Cairo University, Kasr El-Ainy Street, Cairo, 11562, Egypt
- Department of Pharmacognosy, Faculty of Pharmacy, October University for Modern Sciences and Arts (MSA), Giza, 12451, Egypt
| | - Rana M Merghany
- Pharmacognosy Department, Pharmaceutical and Drug Industries Research Institute, National Research Centre (NRC), 33 El-Bohouth Street, Dokki, Giza, Egypt
| | - Passent M Abdel Baki
- Pharmacognosy Department, Faculty of Pharmacy, Cairo University, Kasr El-Ainy Street, Cairo, 11562, Egypt
| | - Nariman Ali Abdelrahim
- Department of Pharmacognosy, Faculty of Pharmacy, October University for Modern Sciences and Arts (MSA), Giza, 12451, Egypt
| | - Sohaila M Osman
- Faculty of Pharmacy, October University for Modern Sciences and Arts (MSA), Giza, 12451, Egypt
| | - Mohamed A Salem
- Department of Pharmacognosy and Natural Products, Faculty of Pharmacy, Menoufia University, Gamal Abd El Nasr St., Shibin El Kom, Menoufia, 32511, Egypt
| | - Sheila I Peña-Corona
- Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Ciudad de México, 04510, Mexico
| | - Hernán Cortés
- Laboratorio de Medicina Genómica, Departamento de Genómica, Instituto Nacional de Rehabilitación Luis Guillermo Ibarra Ibarra, Ciudad de México, Mexico
| | - Lashyn Kiyekbayeva
- Department of Pharmaceutical Technology, Pharmaceutical School, Asfendiyarov Kazakh National Medical University, Almaty, Kazakhstan
| | - Gerardo Leyva-Gómez
- Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Ciudad de México, 04510, Mexico
| | | | - Daniela Calina
- Department of Clinical Pharmacy, University of Medicine and Pharmacy of Craiova, Craiova, 200349, Romania
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Allyl-, Butyl- and Phenylethyl-Isothiocyanate Modulate Akt–mTOR and Cyclin–CDK Signaling in Gemcitabine- and Cisplatin-Resistant Bladder Cancer Cell Lines. Int J Mol Sci 2022; 23:ijms231910996. [PMID: 36232303 PMCID: PMC9570347 DOI: 10.3390/ijms231910996] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 09/12/2022] [Accepted: 09/14/2022] [Indexed: 11/17/2022] Open
Abstract
Combined cisplatin–gemcitabine treatment causes rapid resistance development in patients with advanced urothelial carcinoma. The present study investigated the potential of the natural isothiocyanates (ITCs) allyl-isothiocyanate (AITC), butyl-isothiocyanate (BITC), and phenylethyl-isothiocyanate (PEITC) to suppress growth and proliferation of gemcitabine- and cisplatin-resistant bladder cancer cells lines. Sensitive and gemcitabine- and cisplatin-resistant RT112, T24, and TCCSUP cells were treated with the ITCs, and tumor cell growth, proliferation, and clone formation were evaluated. Apoptosis induction and cell cycle progression were investigated as well. The molecular mode of action was investigated by evaluating cell cycle-regulating proteins (cyclin-dependent kinases (CDKs) and cyclins A and B) and the mechanistic target of the rapamycin (mTOR)-AKT signaling pathway. The ITCs significantly inhibited growth, proliferation and clone formation of all tumor cell lines (sensitive and resistant). Cells were arrested in the G2/M phase, independent of the type of resistance. Alterations of both the CDK–cyclin axis and the Akt–mTOR signaling pathway were observed in AITC-treated T24 cells with minor effects on apoptosis induction. In contrast, AITC de-activated Akt–mTOR signaling and induced apoptosis in RT112 cells, with only minor effects on CDK expression. It is concluded that AITC, BITC, and PEITC exert tumor-suppressive properties on cisplatin- and gemcitabine-resistant bladder cancer cells, whereby the molecular action may differ among the cell lines. The integration of these ITCs into the gemcitabine-/cisplatin-based treatment regimen might optimize bladder cancer therapy.
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Peres A, Branchini G, Marmett B, Nunes FB, Romão PRT, Olean-Oliveira T, Minuzzi L, Cavalcante M, Elsner V, Lira FS, Dorneles GP. Potential Anticarcinogenic Effects From Plasma of Older Adults After Exercise Training: An Exploratory Study. Front Physiol 2022; 13:855133. [PMID: 35874516 PMCID: PMC9298496 DOI: 10.3389/fphys.2022.855133] [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] [Received: 01/14/2022] [Accepted: 05/23/2022] [Indexed: 11/28/2022] Open
Abstract
Aim: To evaluate the impact of exercise training plasma on in vitro prostate cancer cell viability and proliferation. Methods: PC3 prostate cancer cells were incubated with plasma obtained from young men with high and low physical fitness (PF) (high PF, n = 5; low PF, n = 5) and with the plasma collected from institutionalized older adults (n = 8) before and after multimodal exercise training. Cell viability and proliferation, mitochondria membrane polarization, reactive oxygen species (ROS) generation, and apoptosis were evaluated after the cell treatment with plasma. Systemic cytokines were evaluated in the plasma of institutionalized older adults submitted to an exercise training protocol. Results: Plasma from high-PF men lowers both cell viability and proliferation after the incubation time. PC3 cells also presented lower cell viability and diminished rates of cell proliferation after the incubation with post-training plasma samples of the older adults. The incubation of PC3 cells with post-training plasma of older adults depolarized the mitochondrial membrane potential and increased mitochondrial reactive oxygen species production. Post-training plasma did not change apoptosis or necrosis rates in the PC3 cell line. Multimodal exercise training increased the plasma levels of IL-2, IL-10, IFN-α, and FGF-1 and decreased TNF-α concentrations in institutionalized older adults. Conclusion: Adaptations in blood factors of institutionalized older adults may alter cell viability and proliferation by targeting mitochondrial ROS in a prostate cancer cell line.
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Affiliation(s)
- Alessandra Peres
- Laboratório de Imunologia Celular e Molecular, Departamento de Ciências Básicas da Saúde, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, Brazil
| | - Gisele Branchini
- Programa de Pós-graduação em Patologia, Universidade Federal de Ciências da Saúde de Porto Alegre-UFCSPA, Porto Alegre, Brazil
| | - Bruna Marmett
- Laboratório de Imunologia Celular e Molecular, Departamento de Ciências Básicas da Saúde, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, Brazil
| | - Fernanda Bordignon Nunes
- Programa de Pós-graduação em Patologia, Universidade Federal de Ciências da Saúde de Porto Alegre-UFCSPA, Porto Alegre, Brazil
| | - Pedro R T Romão
- Laboratório de Imunologia Celular e Molecular, Departamento de Ciências Básicas da Saúde, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, Brazil
| | - Tiago Olean-Oliveira
- Exercise and Immunometabolism Research Group, Postgraduation Program in Movement Sciences, Department of Physical Education, Universidade Estadual Paulista (UNESP), Presidente Prudente, Brazil.,Faculty of Sports Science and Physical Education, Research Center for Sports and Physical Activity, University of Coimbra, Coimbra, Portugal
| | - Luciele Minuzzi
- Exercise and Immunometabolism Research Group, Postgraduation Program in Movement Sciences, Department of Physical Education, Universidade Estadual Paulista (UNESP), Presidente Prudente, Brazil
| | - Mateus Cavalcante
- Programa de Pós-graduação em Fisiologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Viviane Elsner
- Laboratório de Imunologia Celular e Molecular, Departamento de Ciências Básicas da Saúde, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, Brazil
| | - Fabio Santos Lira
- Exercise and Immunometabolism Research Group, Postgraduation Program in Movement Sciences, Department of Physical Education, Universidade Estadual Paulista (UNESP), Presidente Prudente, Brazil.,Faculty of Sports Science and Physical Education, Research Center for Sports and Physical Activity, University of Coimbra, Coimbra, Portugal
| | - Gilson Pires Dorneles
- Laboratório de Imunologia Celular e Molecular, Departamento de Ciências Básicas da Saúde, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, Brazil
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10
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Khattak S, Rauf MA, Khan NH, Zhang QQ, Chen HJ, Muhammad P, Ansari MA, Alomary MN, Jahangir M, Zhang CY, Ji XY, Wu DD. Hydrogen Sulfide Biology and Its Role in Cancer. Molecules 2022; 27:3389. [PMID: 35684331 PMCID: PMC9181954 DOI: 10.3390/molecules27113389] [Citation(s) in RCA: 55] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 04/27/2022] [Accepted: 05/01/2022] [Indexed: 02/07/2023] Open
Abstract
Hydrogen sulfide (H2S) is an endogenous biologically active gas produced in mammalian tissues. It plays a very critical role in many pathophysiological processes in the body. It can be endogenously produced through many enzymes analogous to the cysteine family, while the exogenous source may involve inorganic sulfide salts. H2S has recently been well investigated with regard to the onset of various carcinogenic diseases such as lung, breast, ovaries, colon cancer, and neurodegenerative disorders. H2S is considered an oncogenic gas, and a potential therapeutic target for treating and diagnosing cancers, due to its role in mediating the development of tumorigenesis. Here in this review, an in-detail up-to-date explanation of the potential role of H2S in different malignancies has been reported. The study summarizes the synthesis of H2S, its roles, signaling routes, expressions, and H2S release in various malignancies. Considering the critical importance of this active biological molecule, we believe this review in this esteemed journal will highlight the oncogenic role of H2S in the scientific community.
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Affiliation(s)
- Saadullah Khattak
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China; (S.K.); (N.H.K.); (Q.-Q.Z.); (H.-J.C.)
| | - Mohd Ahmar Rauf
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL 33136, USA;
| | - Nazeer Hussain Khan
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China; (S.K.); (N.H.K.); (Q.-Q.Z.); (H.-J.C.)
| | - Qian-Qian Zhang
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China; (S.K.); (N.H.K.); (Q.-Q.Z.); (H.-J.C.)
| | - Hao-Jie Chen
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China; (S.K.); (N.H.K.); (Q.-Q.Z.); (H.-J.C.)
| | - Pir Muhammad
- Henan-Macquarie University Joint Centre for Biomedical Innovation, School of Life Sciences, Henan University, Kaifeng 475004, China;
| | - Mohammad Azam Ansari
- Department of Epidemic Disease Research, Institute for Research & Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Saudi Arabia;
| | - Mohammad N. Alomary
- National Centre for Biotechnology, King Abdulaziz City for Science and Technology (KACST), P.O. Box 6086, Riyadh 11442, Saudi Arabia;
| | - Muhammad Jahangir
- Department of Psychiatric and Mental Health, Central South University, Changsha 410078, China;
| | - Chun-Yang Zhang
- Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
- Department of General Thoracic Surgery, Hami Central Hospital, Hami 839000, China
| | - Xin-Ying Ji
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China; (S.K.); (N.H.K.); (Q.-Q.Z.); (H.-J.C.)
- Kaifeng Key Laboratory of Infection and Biological Safety, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China
| | - Dong-Dong Wu
- Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China; (S.K.); (N.H.K.); (Q.-Q.Z.); (H.-J.C.)
- School of Stomatology, Henan University, Kaifeng 475004, China
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11
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Henklewska M, Pawlak A, Li RF, Yi J, Zbyryt I, Obmińska-Mrukowicz B. Benzyl Isothiocyanate, a Vegetable-Derived Compound, Induces Apoptosis via ROS Accumulation and DNA Damage in Canine Lymphoma and Leukemia Cells. Int J Mol Sci 2021; 22:ijms222111772. [PMID: 34769202 PMCID: PMC8583731 DOI: 10.3390/ijms222111772] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 10/22/2021] [Accepted: 10/27/2021] [Indexed: 12/12/2022] Open
Abstract
Treatment of neoplastic diseases in companion animals is one of the most important problems of modern veterinary medicine. Given the growing interest in substances of natural origin as potential anti-cancer drugs, our goal was to examine the effectiveness of benzyl isothiocyanate (BITC), a compound found in cruciferous vegetables, against canine lymphoma and leukemia. These are the one of the most common canine cancer types, and chemotherapy is the only treatment option. The study involved established cell lines originating from various hematopoietic malignancies: CLBL-1, GL-1, CLB70 and CNK-89, immortalized noncancerous cell lines: MDCK and NIH-3T3 and canine peripheral blood mononuclear cells (PBMCs). The cytotoxic activity of BITC, apoptosis induction, caspase activity and ROS generation were evaluated by flow cytometry. H2AX phosphorylation was assessed by western blot. The study showed that the compound was especially active against B lymphocyte-derived malignant cells. Their death resulted from caspase-dependent apoptosis. BITC induced ROS accumulation, and glutathione precursor N-acetyl-l-cysteine reversed the effect of the compound, thus proving the role of oxidative stress in BITC activity. In addition, exposure to the compound induced DNA damage in the tested cells. This is the first study that provides information on the activity of BITC in canine hematopoietic malignancies and suggests that the compound may be particularly useful in B-cell neoplasms treatment.
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Affiliation(s)
- Marta Henklewska
- Department of Pharmacology and Toxicology, Wrocław University of Environmental and Life Sciences, C.K. Norwida 31, 50-375 Wrocław, Poland; (A.P.); (B.O.-M.)
- Correspondence:
| | - Aleksandra Pawlak
- Department of Pharmacology and Toxicology, Wrocław University of Environmental and Life Sciences, C.K. Norwida 31, 50-375 Wrocław, Poland; (A.P.); (B.O.-M.)
| | - Rong-Fang Li
- Hunan Engineering Research Center of Livestock and Poultry Health Care, Colleges of Veterinary Medicine, Hunan Agricultural University, Changsha 410128, China; (R.-F.L.); (J.Y.)
| | - Jine Yi
- Hunan Engineering Research Center of Livestock and Poultry Health Care, Colleges of Veterinary Medicine, Hunan Agricultural University, Changsha 410128, China; (R.-F.L.); (J.Y.)
| | - Iwona Zbyryt
- Department of Epizootiology and Clinic of Birds and Exotic Animals, Wrocław University of Environmental and Life Sciences, C.K. Norwida 31, 50-375 Wrocław, Poland;
| | - Bożena Obmińska-Mrukowicz
- Department of Pharmacology and Toxicology, Wrocław University of Environmental and Life Sciences, C.K. Norwida 31, 50-375 Wrocław, Poland; (A.P.); (B.O.-M.)
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12
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Cerqueni G, Scalzone A, Licini C, Gentile P, Mattioli-Belmonte M. Insights into oxidative stress in bone tissue and novel challenges for biomaterials. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2021; 130:112433. [PMID: 34702518 DOI: 10.1016/j.msec.2021.112433] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 09/08/2021] [Accepted: 09/11/2021] [Indexed: 12/28/2022]
Abstract
The presence of Reactive Oxygen Species (ROS) in bone can influence resident cells behaviour as well as the extra-cellular matrix composition and the tissue architecture. Aging, in addition to excessive overloads, unbalanced diet, smoking, predisposing genetic factors, lead to an increase of ROS and, if it is accompanied with an inappropriate production of scavengers, promotes the generation of oxidative stress that encourages bone catabolism. Furthermore, bone injuries can be triggered by numerous events such as road and sports accidents or tumour resection. Although bone tissue possesses a well-known repair and regeneration capacity, these mechanisms are inefficient in repairing large size defects and bone grafts are often necessary. ROS play a fundamental role in response after the implant introduction and can influence its success. This review provides insights on the mechanisms of oxidative stress generated by an implant in vivo and suitable ways for its modulation. The local delivery of active molecules, such as polyphenols, enhanced bone biomaterial integration evidencing that the management of the oxidative stress is a target for the effectiveness of an implant. Polyphenols have been widely used in medicine for cardiovascular, neurodegenerative, bone disorders and cancer, thanks to their antioxidant and anti-inflammatory properties. In addition, the perspective of new smart biomaterials and molecular medicine for the oxidative stress modulation in a programmable way, by the use of ROS responsive materials or by the targeting of selective molecular pathways involved in ROS generation, will be analysed and discussed critically.
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Affiliation(s)
- Giorgia Cerqueni
- Department of Clinical and Molecular Sciences (DISCLIMO), Università Politecnica delle Marche, Via Tronto 10/a, Ancona 60126, Italy
| | - Annachiara Scalzone
- School of Engineering, Newcastle University, Stephenson Building, Claremont Road, Newcastle upon Tyne NE1 7RU, UK
| | - Caterina Licini
- Department of Clinical and Molecular Sciences (DISCLIMO), Università Politecnica delle Marche, Via Tronto 10/a, Ancona 60126, Italy; Department of Applied Science and Technology, Politecnico di Torino, Corso Duca degli Abruzzi 204, 10129 Torino, Italy
| | - Piergiorgio Gentile
- School of Engineering, Newcastle University, Stephenson Building, Claremont Road, Newcastle upon Tyne NE1 7RU, UK
| | - Monica Mattioli-Belmonte
- Department of Clinical and Molecular Sciences (DISCLIMO), Università Politecnica delle Marche, Via Tronto 10/a, Ancona 60126, Italy.
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13
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Flores P, Pedreño M, Almagro L, Hernández V, Fenoll J, Hellín P. Increasing nutritional value of broccoli with seaweed extract and trilinolein. J Food Compost Anal 2021. [DOI: 10.1016/j.jfca.2021.103834] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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14
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Mitsiogianni M, Kyriakou S, Anestopoulos I, Trafalis DT, Deligiorgi MV, Franco R, Pappa A, Panayiotidis MI. An Evaluation of the Anti-Carcinogenic Response of Major Isothiocyanates in Non-Metastatic and Metastatic Melanoma Cells. Antioxidants (Basel) 2021; 10:antiox10020284. [PMID: 33668498 PMCID: PMC7918923 DOI: 10.3390/antiox10020284] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Revised: 02/07/2021] [Accepted: 02/10/2021] [Indexed: 12/28/2022] Open
Abstract
Malignant melanoma is one of the most deadly types of solid cancers, a property mainly attributed to its highly aggressive metastatic form. On the other hand, different classes of isothiocyanates, a class of phytochemicals, present in cruciferous vegetables have been characterized by considerable anti-cancer activity in both in vitro and in vivo experimental models. In the current study, we investigated the anti-cancer response of five isothiocyanates in an in vitro model of melanoma consisting of non-metastatic (A375, B16F-10) and metastatic (VMM1, Hs294T) malignant melanoma as well as non-melanoma epidermoid carcinoma (A431) and non-tumorigenic melanocyte-neighboring keratinocyte (HaCaT) cells. Our aim was to compare different endpoints of cytotoxicity (e.g., reactive oxygen species, intracellular glutathione content, cell cycle growth arrest, apoptosis and necrosis) descriptive of an anti-cancer response between non-metastatic and metastatic melanoma as well as non-melanoma epidermoid carcinoma and non-tumorigenic cells. Our results showed that exposure to isothiocyanates induced an increase in intracellular reactive oxygen species and glutathione contents between non-metastatic and metastatic melanoma cells. The distribution of cell cycle phases followed a similar pattern in a manner where non-metastatic and metastatic melanoma cells appeared to be growth arrested at the G2/M phase while elevated levels of metastatic melanoma cells were shown to be at sub G1 phase, an indicator of necrotic cell death. Finally, metastatic melanoma cells were more sensitive apoptosis and/or necrosis as higher levels were observed compared to non-melanoma epidermoid carcinoma and non-tumorigenic cells. In general, non-melanoma epidermoid carcinoma and non-tumorigenic cells were more resistant under any experimental exposure condition. Overall, our study provides further evidence for the potential development of isothiocyanates as promising anti-cancer agents against non-metastatic and metastatic melanoma cells, a property specific for these cells and not shared by non-melanoma epidermoid carcinoma or non-tumorigenic melanocyte cells.
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Affiliation(s)
- Melina Mitsiogianni
- Department of Applied Sciences, Northumbria University, Newcastle Upon Tyne NE1 8ST, UK;
| | - Sotiris Kyriakou
- Department of Electron Microscopy & Molecular Pathology, The Cyprus Institute of Neurology & Genetics, Nicosia 2371, Cyprus; (S.K.); (I.A.)
- The Cyprus School of Molecular Medicine, P.O. Box 23462, Nicosia 1683, Cyprus
| | - Ioannis Anestopoulos
- Department of Electron Microscopy & Molecular Pathology, The Cyprus Institute of Neurology & Genetics, Nicosia 2371, Cyprus; (S.K.); (I.A.)
- The Cyprus School of Molecular Medicine, P.O. Box 23462, Nicosia 1683, Cyprus
| | - Dimitrios T. Trafalis
- Laboratory of Pharmacology, Medical School, National & Kapodistrian University of Athens, 11527 Athens, Greece; (D.T.T.); (M.V.D.)
| | - Maria V. Deligiorgi
- Laboratory of Pharmacology, Medical School, National & Kapodistrian University of Athens, 11527 Athens, Greece; (D.T.T.); (M.V.D.)
| | - Rodrigo Franco
- Redox Biology Centre, University of Nebraska-Lincoln, Lincoln, NE 68583, USA;
- Department of Veterinary Medicine & Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE 68583, USA
| | - Aglaia Pappa
- Department of Molecular Biology & Genetics, Democritus University of Thrace, 68100 Alexandroupolis, Greece;
| | - Mihalis I. Panayiotidis
- Department of Applied Sciences, Northumbria University, Newcastle Upon Tyne NE1 8ST, UK;
- Department of Electron Microscopy & Molecular Pathology, The Cyprus Institute of Neurology & Genetics, Nicosia 2371, Cyprus; (S.K.); (I.A.)
- The Cyprus School of Molecular Medicine, P.O. Box 23462, Nicosia 1683, Cyprus
- Correspondence: ; Tel.: +357-223-92626
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15
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Li H, Hu B, Hu S, Luo W, Sun D, Yang M, Liao Z, Wei H, Zhao C, Li D, Shi M, Luo Q, Zhang D, Nie Q, Zhang X. High expression of BCL6 inhibits the differentiation and development of hematopoietic stem cells and affects the growth and development of chickens. J Anim Sci Biotechnol 2021; 12:18. [PMID: 33541426 PMCID: PMC7863511 DOI: 10.1186/s40104-020-00541-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Accepted: 12/20/2020] [Indexed: 12/22/2022] Open
Abstract
Background B-cell CLL/lymphoma 6 (BCL6) is a transcriptional master regulator that represses more than 1200 potential target genes. Our previous study showed that a decline in blood production in runting and stunting syndrome (RSS) affected sex-linked dwarf (SLD) chickens compared to SLD chickens. However, the association between BCL6 gene and hematopoietic function remains unknown in chickens. Methods In this study, we used RSS affected SLD (RSS-SLD) chickens, SLD chickens and normal chickens as research object and overexpression of BCL6 in hematopoietic stem cells (HSCs), to investigate the effect of the BCL6 on differentiation and development of HSCs. Results The results showed that comparison of RSS-SLD chickens with SLD chickens, the BCL6 was highly expressed in RSS-SLD chickens bone marrow. The bone marrow of RSS-SLD chickens was exhausted and red bone marrow was largely replaced by yellow bone marrow, bone density was reduced, and the levels of immature erythrocytes in peripheral blood were increased. At the same time, the hematopoietic function of HSCs decreased in RSS-SLD chickens, which was manifested by a decrease in the hematopoietic growth factors (HGFs) EPO, SCF, TPO, and IL-3, as well as hemoglobin α1 and hemoglobin β expression. Moreover, mitochondrial function in the HSCs of RSS-SLD chickens was damaged, including an increase in ROS production, decrease in ATP concentration, and decrease in mitochondrial membrane potential (ΔΨm). The same results were also observed in SLD chickens compared with normal chickens; however, the symptoms were more serious in RSS-SLD chickens. Additionally, after overexpression of the BCL6 in primary HSCs, the secretion of HGFs (EPO, SCF, TPO and IL-3) was inhibited and the expression of hemoglobin α1 and hemoglobin β was decreased. However, cell proliferation was accelerated, apoptosis was inhibited, and the HSCs entered a cancerous state. The function of mitochondria was also abnormal, ROS production was decreased, and ATP concentration and ΔΨm were increased, which was related to the inhibition of apoptosis of stem cells. Conclusions Taken together, we conclude that the high expression of BCL6 inhibits the differentiation and development of HSCs by affecting mitochondrial function, resulting in impaired growth and development of chickens. Moreover, the abnormal expression of BCL6 might be a cause of the clinical manifestations of chicken comb, pale skin, stunted growth and development, and the tendency to appear RSS in SLD chickens.
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Affiliation(s)
- Hongmei Li
- Department of Animal Genetics, Breeding and Reproduction, College of Animal Science, South China Agricultural University, Guangzhou, 510642, Guangdong Province, China.,Guangdong Provincial Key Lab of AgroAnimal Genomics and Molecular Breeding and Key Lab of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture, Guangzhou, 510642, Guangdong, China.,State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, South China Agricultural University, Guangzhou, 510642, Guangdong, China
| | - Bowen Hu
- Department of Animal Genetics, Breeding and Reproduction, College of Animal Science, South China Agricultural University, Guangzhou, 510642, Guangdong Province, China.,Guangdong Provincial Key Lab of AgroAnimal Genomics and Molecular Breeding and Key Lab of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture, Guangzhou, 510642, Guangdong, China.,State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, South China Agricultural University, Guangzhou, 510642, Guangdong, China
| | - Shang Hu
- Department of Animal Genetics, Breeding and Reproduction, College of Animal Science, South China Agricultural University, Guangzhou, 510642, Guangdong Province, China.,Guangdong Provincial Key Lab of AgroAnimal Genomics and Molecular Breeding and Key Lab of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture, Guangzhou, 510642, Guangdong, China.,State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, South China Agricultural University, Guangzhou, 510642, Guangdong, China
| | - Wen Luo
- Department of Animal Genetics, Breeding and Reproduction, College of Animal Science, South China Agricultural University, Guangzhou, 510642, Guangdong Province, China.,Guangdong Provincial Key Lab of AgroAnimal Genomics and Molecular Breeding and Key Lab of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture, Guangzhou, 510642, Guangdong, China.,State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, South China Agricultural University, Guangzhou, 510642, Guangdong, China
| | - Donglei Sun
- Division of Immunology, Virginia-Maryland College of Veterinary Medicine, University of Maryland, College Park, MD, USA
| | - Minmin Yang
- Department of Animal Genetics, Breeding and Reproduction, College of Animal Science, South China Agricultural University, Guangzhou, 510642, Guangdong Province, China.,Guangdong Provincial Key Lab of AgroAnimal Genomics and Molecular Breeding and Key Lab of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture, Guangzhou, 510642, Guangdong, China.,State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, South China Agricultural University, Guangzhou, 510642, Guangdong, China
| | - Zhiying Liao
- Department of Animal Genetics, Breeding and Reproduction, College of Animal Science, South China Agricultural University, Guangzhou, 510642, Guangdong Province, China.,Guangdong Provincial Key Lab of AgroAnimal Genomics and Molecular Breeding and Key Lab of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture, Guangzhou, 510642, Guangdong, China.,State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, South China Agricultural University, Guangzhou, 510642, Guangdong, China
| | - Haohui Wei
- Department of Animal Genetics, Breeding and Reproduction, College of Animal Science, South China Agricultural University, Guangzhou, 510642, Guangdong Province, China.,Guangdong Provincial Key Lab of AgroAnimal Genomics and Molecular Breeding and Key Lab of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture, Guangzhou, 510642, Guangdong, China.,State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, South China Agricultural University, Guangzhou, 510642, Guangdong, China
| | - Changbin Zhao
- Department of Animal Genetics, Breeding and Reproduction, College of Animal Science, South China Agricultural University, Guangzhou, 510642, Guangdong Province, China.,Guangdong Provincial Key Lab of AgroAnimal Genomics and Molecular Breeding and Key Lab of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture, Guangzhou, 510642, Guangdong, China.,State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, South China Agricultural University, Guangzhou, 510642, Guangdong, China
| | - Dajian Li
- Department of Animal Genetics, Breeding and Reproduction, College of Animal Science, South China Agricultural University, Guangzhou, 510642, Guangdong Province, China.,Guangdong Provincial Key Lab of AgroAnimal Genomics and Molecular Breeding and Key Lab of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture, Guangzhou, 510642, Guangdong, China.,State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, South China Agricultural University, Guangzhou, 510642, Guangdong, China
| | - Meiqing Shi
- Division of Immunology, Virginia-Maryland College of Veterinary Medicine, University of Maryland, College Park, MD, USA
| | - Qingbin Luo
- Department of Animal Genetics, Breeding and Reproduction, College of Animal Science, South China Agricultural University, Guangzhou, 510642, Guangdong Province, China.,Guangdong Provincial Key Lab of AgroAnimal Genomics and Molecular Breeding and Key Lab of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture, Guangzhou, 510642, Guangdong, China.,State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, South China Agricultural University, Guangzhou, 510642, Guangdong, China
| | - Dexiang Zhang
- Department of Animal Genetics, Breeding and Reproduction, College of Animal Science, South China Agricultural University, Guangzhou, 510642, Guangdong Province, China.,Guangdong Provincial Key Lab of AgroAnimal Genomics and Molecular Breeding and Key Lab of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture, Guangzhou, 510642, Guangdong, China.,State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, South China Agricultural University, Guangzhou, 510642, Guangdong, China
| | - Qinghua Nie
- Department of Animal Genetics, Breeding and Reproduction, College of Animal Science, South China Agricultural University, Guangzhou, 510642, Guangdong Province, China.,Guangdong Provincial Key Lab of AgroAnimal Genomics and Molecular Breeding and Key Lab of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture, Guangzhou, 510642, Guangdong, China.,State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, South China Agricultural University, Guangzhou, 510642, Guangdong, China
| | - Xiquan Zhang
- Department of Animal Genetics, Breeding and Reproduction, College of Animal Science, South China Agricultural University, Guangzhou, 510642, Guangdong Province, China. .,Guangdong Provincial Key Lab of AgroAnimal Genomics and Molecular Breeding and Key Lab of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture, Guangzhou, 510642, Guangdong, China. .,State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, South China Agricultural University, Guangzhou, 510642, Guangdong, China.
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16
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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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17
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Chiang JH, Tsai FJ, Hsu YM, Yin MC, Chiu HY, Yang JS. Sensitivity of allyl isothiocyanate to induce apoptosis via ER stress and the mitochondrial pathway upon ROS production in colorectal adenocarcinoma cells. Oncol Rep 2020; 44:1415-1424. [PMID: 32700751 PMCID: PMC7448487 DOI: 10.3892/or.2020.7700] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Accepted: 06/29/2020] [Indexed: 02/07/2023] Open
Abstract
Allyl isothiocyanate (AITC), a bioactive phytochemical compound that is a constituent of dietary cruciferous vegetables, possesses promising chemopreventive and anticancer effects. However, reports of AITC exerting antitumor effects on apoptosis induction of colorectal cancer (CRC) cells in vitro are not well elucidated. The present study focused on the functional mechanism of the endoplasmic reticulum (ER) stress-based apoptotic machinery induced by AITC in human colorectal cancer HT-29 cells. Our results indicated that AITC decreased cell growth and number, reduced viability, and facilitated morphological changes of apoptotic cell death. DNA analysis by flow cytometry showed G2/M phase arrest, and alterations in the modulated protein levels caused by AITC were detected via western blot analysis. AITC also triggered vital intrinsic apoptotic factors (caspase-9/caspase-3 activity), disrupted mitochondrial membrane potential, and stimulated mitochondrial-related apoptotic molecules (e.g., cytochrome c, apoptotic protease activating factor 1, apoptosis-inducing factor, and endonuclease G). Additionally, AITC prompted induced cytosolic Ca2+ release and Ca2+-dependent ER stress-related signals, such as calpain 1, activating transcription factor 6α, glucose-regulated proteins 78 and 94, growth arrest- and DNA damage-inducible protein 153 (GADD153), and caspase-4. The level of reactive oxygen species (ROS) production was found to induce the hallmark of ER stress GADD153, proapoptotic marker caspase-3, and calpain activity after AITC treatment. Our findings showed for the first time that AITC induced G2/M phase arrest and apoptotic death via ROS-based ER stress and the intrinsic pathway (mitochondrial-dependent) in HT-29 cells. Overall, AITC may exert an epigenetic effect and is a potential bioactive compound for CRC treatment.
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Affiliation(s)
- Jo-Hua Chiang
- Department of Nursing, Chung‑Jen Junior College of Nursing, Health Sciences and Management, Chiayi County 62241, Taiwan, R.O.C
| | - Fuu-Jen Tsai
- Human Genetics Center, Department of Medical Research, China Medical University Hospital, Taichung 40447, Taiwan, R.O.C
| | - Yuan-Man Hsu
- Department of Biological Science and Technology, China Medical University, Taichung 40402, Taiwan, R.O.C
| | - Mei-Chin Yin
- Department of Food Nutrition and Health Biotechnology, Asia University, Taichung 41354, Taiwan, R.O.C
| | - Hong-Yi Chiu
- Department of Pharmacy, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 97002, Taiwan, R.O.C
| | - Jai-Sing Yang
- Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 40442, Taiwan, R.O.C
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18
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Di A, Wu Y, Chen M, Nie D, Ge X. Chemical Characterization of Seasonal PM 2.5 Samples and Their Cytotoxicity in Human Lung Epithelial Cells (A549). INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2020; 17:ijerph17124599. [PMID: 32604837 PMCID: PMC7345009 DOI: 10.3390/ijerph17124599] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/10/2020] [Revised: 06/10/2020] [Accepted: 06/17/2020] [Indexed: 12/13/2022]
Abstract
In order to study the toxicity of fine particulate matter (PM2.5) sourced from different seasons on human health, we collected PM2.5 samples quarterly from March 2016 to February 2017 in Nanjing, China. The component analysis results showed that high proportions of water-soluble organic carbon (WSOC), SO42−, Ca2+ and Mg2+ were found in the summer samples, while high proportions of NO3−, NH4+ and heavy metals were observed in the spring and winter samples. Then human lung epithelial cells (A549) were exposed to the PM2.5 samples. The toxicological results indicated that reactive oxygen species (ROS) production in the spring and winter samples was higher than that in the summer and fall samples, which was related to the contribution of some heavy metals and inorganic ions (e.g., Pb and NO3−). However, the apoptosis rates of the cells showed the opposite seasonal changes as what the ROS did, which might be caused by the higher WSOC content in the summer. In addition, regression analysis also showed the importance of the PM2.5 components in ROS production and apoptosis. Particularly, Zn had the strongest correlation with ROS production (R = 0.863) and cell apoptosis (R = 0.675); thus, the specific toxicity of Zn in PM2.5 deserves further investigation. Our results could be beneficial for assessing the health risks and controlling the toxic components of PM2.5 in Nanjing.
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Affiliation(s)
- Ao Di
- Collaborative Innovation Center of Atmospheric Environment and Equipment Technology, Jiangsu Key Laboratory of Atmospheric Environment Monitoring and Pollution Control, School of Environmental Science and Engineering, Nanjing University of Information Science & Technology, Nanjing 210044, China; (A.D.); (X.G.)
| | - Yun Wu
- Collaborative Innovation Center of Atmospheric Environment and Equipment Technology, Jiangsu Key Laboratory of Atmospheric Environment Monitoring and Pollution Control, School of Environmental Science and Engineering, Nanjing University of Information Science & Technology, Nanjing 210044, China; (A.D.); (X.G.)
- Correspondence: (Y.W.); (M.C.); Tel.: +86-25-5873-1089 (M.C.)
| | - Mindong Chen
- Collaborative Innovation Center of Atmospheric Environment and Equipment Technology, Jiangsu Key Laboratory of Atmospheric Environment Monitoring and Pollution Control, School of Environmental Science and Engineering, Nanjing University of Information Science & Technology, Nanjing 210044, China; (A.D.); (X.G.)
- Correspondence: (Y.W.); (M.C.); Tel.: +86-25-5873-1089 (M.C.)
| | - Dongyang Nie
- School of Atmospheric Sciences, Nanjing University, Nanjing 210023, China;
| | - Xinlei Ge
- Collaborative Innovation Center of Atmospheric Environment and Equipment Technology, Jiangsu Key Laboratory of Atmospheric Environment Monitoring and Pollution Control, School of Environmental Science and Engineering, Nanjing University of Information Science & Technology, Nanjing 210044, China; (A.D.); (X.G.)
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19
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The Double-Faced Role of Nitric Oxide and Reactive Oxygen Species in Solid Tumors. Antioxidants (Basel) 2020; 9:antiox9050374. [PMID: 32365852 PMCID: PMC7278755 DOI: 10.3390/antiox9050374] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 04/24/2020] [Accepted: 04/27/2020] [Indexed: 02/08/2023] Open
Abstract
Disturbed redox homeostasis represents a hallmark of cancer phenotypes, affecting cellular metabolism and redox signaling. Since reactive oxygen and nitrogen species (ROS/RNS) are involved in regulation of proliferation and apoptosis, they may play a double-faced role in cancer, entailing protumorigenic and tumor-suppressing effects in early and later stages, respectively. In addition, ROS and RNS impact the activity and communication of all tumor constituents, mediating their reprogramming from anti- to protumorigenic phenotypes, and vice versa. An important role in this dichotomic action is played by the variable amounts of O2 in the tumor microenvironment, which dictates the ultimate outcome of the influence of ROS/RNS on carcinogenesis. Moreover, ROS/RNS levels remarkably influence the cancer response to therapy. The relevance of ROS/RNS signaling in solid tumors is witnessed by the emergence of novel targeted treatments of solid tumors with compounds that target ROS/RNS action and production, such as tyrosine kinase inhibitors and monoclonal antibodies, which might contribute to the complexity of redox regulation in cancer. Prospectively, the dual role of ROS/RNS in the different stages of tumorigenesis through different impact on oxidation and nitrosylation may also allow development of tailored diagnostic and therapeutic approaches.
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20
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Martelli A, Citi V, Testai L, Brogi S, Calderone V. Organic Isothiocyanates as Hydrogen Sulfide Donors. Antioxid Redox Signal 2020; 32:110-144. [PMID: 31588780 DOI: 10.1089/ars.2019.7888] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Significance: Hydrogen sulfide (H2S), the "new entry" in the series of endogenous gasotransmitters, plays a fundamental role in regulating the biological functions of various organs and systems. Consequently, the lack of adequate levels of H2S may represent the etiopathogenetic factor of multiple pathological alterations. In these diseases, the use of H2S donors represents a precious and innovative opportunity. Recent Advances: Natural isothiocyanates (ITCs), sulfur compounds typical of some botanical species, have long been investigated because of their intriguing pharmacological profile. Recently, the ITC moiety has been proposed as a new H2S-donor chemotype (with a l-cysteine-mediated reaction). Based on this recent discovery, we can clearly observe that almost all the effects of natural ITCs can be explained by the H2S release. Consistently, the ITC function was also used as an original H2S-releasing moiety for the design of synthetic H2S donors and original "pharmacological hybrids." Very recently, the chemical mechanism of H2S release, resulting from the reaction between l-cysteine and some ITCs, has been elucidated. Critical Issues: Available literature gives convincing demonstration that H2S is the real player in ITC pharmacology. Further, countless studies have been carried out on natural ITCs, but this versatile moiety has been used only rarely for the design of synthetic H2S donors with optimal drug-like properties. Future Directions: The development of more ITC-based synthetic H2S donors with optimal drug-like properties and selectivity toward specific tissues/pathologies seem to represent a stimulating and indispensable prospect of future experimental activities.
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Affiliation(s)
- Alma Martelli
- Department of Pharmacy, University of Pisa, Pisa, Italy.,Interdepartmental Research Centre "Nutraceuticals and Food for Health (NUTRAFOOD)," University of Pisa, Pisa, Italy.,Interdepartmental Research Centre of "Ageing Biology and Pathology," University of Pisa, Pisa, Italy
| | | | - Lara Testai
- Department of Pharmacy, University of Pisa, Pisa, Italy.,Interdepartmental Research Centre "Nutraceuticals and Food for Health (NUTRAFOOD)," University of Pisa, Pisa, Italy.,Interdepartmental Research Centre of "Ageing Biology and Pathology," University of Pisa, Pisa, Italy
| | - Simone Brogi
- Department of Pharmacy, University of Pisa, Pisa, Italy
| | - Vincenzo Calderone
- Department of Pharmacy, University of Pisa, Pisa, Italy.,Interdepartmental Research Centre "Nutraceuticals and Food for Health (NUTRAFOOD)," University of Pisa, Pisa, Italy.,Interdepartmental Research Centre of "Ageing Biology and Pathology," University of Pisa, Pisa, Italy
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21
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Liu S, Zhu Y, Yan S, Xiao H, Yi J, Li R, Wu J, Wen L. Phenethyl isothiocyanate induces IPEC-J2 cells cytotoxicity and apoptosis via S-G 2/M phase arrest and mitochondria-mediated Bax/Bcl-2 pathway. Comp Biochem Physiol C Toxicol Pharmacol 2019; 226:108574. [PMID: 31446007 DOI: 10.1016/j.cbpc.2019.108574] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Revised: 06/23/2019] [Accepted: 07/16/2019] [Indexed: 11/27/2022]
Abstract
Phenethyl isothiocyanate (PEITC) is one of the glucosinolates (GLs) present in cruciferous vegetables. Although there are many reports of livestock and poultry poisoning caused by plants containing GLs, the actual dosage that causes poisoning and the characteristics of GLs and their metabolites are unclear. Herein, we investigated the inhibitory effects of PEITC on IPEC-J2 cells and examined the mechanisms of PEITC-induced apoptosis via the mitochondrial pathway. Cell viability was determined by the MTT assay, and the levels of reactive oxygen species, mitochondrial membrane potential (∆Ψ), intracellular Ca2+ concentration, and cell apoptosis were detected by flow cytometry. IPEC-J2 cells were collected to assess the activities of superoxide dismutase, catalase, and glutathione peroxidase, as well as the contents of glutathione, malondialdehyde, H2O2, ATP, and lactate dehydrogenase, using biochemical methods. The levels of cytochrome c, Bax, Bcl-2, caspase-3, caspase-9, poly (ADP-ribose) polymerase (PARP)-1, p53, CDC25C, and cyclin A2 were analyzed by western blotting. We found that PEITC effectively inhibited the growth of IPEC-J2 cells, causing apoptosis. PEITC suppressed the level of mitochondrial membrane potential; released cytochrome c from the mitochondria to the cytoplasm; reduced ATP levels; inhibited Bcl-2 expression; increased Bax expression; and activated caspase-9, caspase-3, and PARP-1, leading to apoptosis. PEITC also induced G2/M and S phase arrest by affecting cell cycle-associated proteins such as p53, CDC25C, and cyclin A2. We conclude that PEITC causes oxidative stress, cell cycle arrest, and apoptosis in IPEC-J2 cells via a mitochondrial-dependent Bax/Bcl-2 pathway.
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Affiliation(s)
- Shuiping Liu
- College of Veterinary Medicine, Hunan Agricultural University, No. 1 Nongda Road, Changsha City 410128, Hunan Province, PR China
| | - Yuanyuan Zhu
- College of Veterinary Medicine, Hunan Agricultural University, No. 1 Nongda Road, Changsha City 410128, Hunan Province, PR China
| | - Sisi Yan
- College of Veterinary Medicine, Hunan Agricultural University, No. 1 Nongda Road, Changsha City 410128, Hunan Province, PR China
| | - Haisi Xiao
- College of Veterinary Medicine, Hunan Agricultural University, No. 1 Nongda Road, Changsha City 410128, Hunan Province, PR China
| | - Jine Yi
- College of Veterinary Medicine, Hunan Agricultural University, No. 1 Nongda Road, Changsha City 410128, Hunan Province, PR China
| | - Rongfang Li
- College of Veterinary Medicine, Hunan Agricultural University, No. 1 Nongda Road, Changsha City 410128, Hunan Province, PR China
| | - Jing Wu
- College of Veterinary Medicine, Hunan Agricultural University, No. 1 Nongda Road, Changsha City 410128, Hunan Province, PR China.
| | - Lixin Wen
- College of Veterinary Medicine, Hunan Agricultural University, No. 1 Nongda Road, Changsha City 410128, Hunan Province, PR China; Hunan Collaborative Innovation Center of Animal Production Safety, No. 1 Nongda Road, Changsha City 410128, Hunan Province, PR China.
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22
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Ghaffarilaleh V, Fisher D, Henkel R. Carica papaya seed extract slows human sperm. JOURNAL OF ETHNOPHARMACOLOGY 2019; 241:111972. [PMID: 31128152 DOI: 10.1016/j.jep.2019.111972] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Revised: 05/13/2019] [Accepted: 05/22/2019] [Indexed: 06/09/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Traditional healers use Carica papaya seeds as a remedy for diseases and as a contraceptive for men and abortion in women. MATERIAL AND METHODS Semen samples from 35 healthy men were allowed to liquefy and subsequently incubated for 60 min in Human Tubular Fluid medium containing 1% bovine serum albumin with aqueous C. papaya seed extract at concentrations of zero, 0.025, 0.25, 2.5, 25, 250 and 2500 μg/ml. Afterwards, sperm were washed and used for assessment of capacitation and acrosome reaction, DNA fragmentation, vitality, motility, reactive oxygen species (ROS) and mitochondrial membrane potential (MMP). RESULTS The extract showed no effects on straight-line velocity, linearity, straightness, beat-cross frequency and the percentage of capacitated, acrosome-reacted sperm. In contrast, vitality, total motility, progressive motility, curvilinear velocity, average-path velocity and the percentages of hyper-activated, ROS-positive and MMP-intact sperm decreased significantly (P < 0.05), while the percentage of DNA-fragmented sperm increased (P < 0.05). CONCLUSIONS Our data show that aqueous C. papaya seed extract significantly and negatively affects sperm motility parameters crucial for fertility; and thus, poses as a likely candidate for male contraception.
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Affiliation(s)
- V Ghaffarilaleh
- Department of Medical Bioscience, University of the Western Cape, Robert Sobukwe Rd., Bellville, South Africa
| | - D Fisher
- Department of Medical Bioscience, University of the Western Cape, Robert Sobukwe Rd., Bellville, South Africa
| | - R Henkel
- Department of Medical Bioscience, University of the Western Cape, Robert Sobukwe Rd., Bellville, South Africa; American Centre for Reproductive Medicine, Cleveland Clinic, Carnegie Ave, Cleveland, OH, USA.
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23
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In Search of Panacea-Review of Recent Studies Concerning Nature-Derived Anticancer Agents. Nutrients 2019; 11:nu11061426. [PMID: 31242602 PMCID: PMC6627480 DOI: 10.3390/nu11061426] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Revised: 06/18/2019] [Accepted: 06/20/2019] [Indexed: 12/21/2022] Open
Abstract
Cancers are one of the leading causes of deaths affecting millions of people around the world, therefore they are currently a major public health problem. The treatment of cancer is based on surgical resection, radiotherapy, chemotherapy or immunotherapy, much of which is often insufficient and cause serious, burdensome and undesirable side effects. For many years, assorted secondary metabolites derived from plants have been used as antitumor agents. Recently, researchers have discovered a large number of new natural substances which can effectively interfere with cancer cells’ metabolism. The most famous groups of these compounds are topoisomerase and mitotic inhibitors. The aim of the latest research is to characterize natural compounds found in many common foods, especially by means of their abilities to regulate cell cycle, growth and differentiation, as well as epigenetic modulation. In this paper, we focus on a review of recent discoveries regarding nature-derived anticancer agents.
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24
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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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25
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Frieben EE, Amin S, Sharma AK. Development of Isoselenocyanate Compounds’ Syntheses and Biological Applications. J Med Chem 2019; 62:5261-5275. [DOI: 10.1021/acs.jmedchem.8b01698] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Emily E. Frieben
- Department of Pharmacology, Penn State Cancer Institute, CH72, Penn State College of Medicine, 500 University Drive, Hershey, Pennsylvania 17033, United States
| | - Shantu Amin
- Department of Pharmacology, Penn State Cancer Institute, CH72, Penn State College of Medicine, 500 University Drive, Hershey, Pennsylvania 17033, United States
| | - Arun K. Sharma
- Department of Pharmacology, Penn State Cancer Institute, CH72, Penn State College of Medicine, 500 University Drive, Hershey, Pennsylvania 17033, United States
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26
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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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27
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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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28
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N��ez-Iglesias M, Novio S, Garc�a-Santiago C, Cartea M, Soengas P, Velasco P, Freire-Garabal M. Effects of 3-butenyl isothiocyanate on phenotypically different prostate cancer cells. Int J Oncol 2018; 53:2213-2223. [DOI: 10.3892/ijo.2018.4545] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2018] [Accepted: 06/27/2018] [Indexed: 11/05/2022] Open
Affiliation(s)
- M.j. N��ez-Iglesias
- Screening of New Libraries Laboratory, School of Medicine and Dentistry, University of Santiago de Compostela, 15782 A Coru�a, Spain
| | - S. Novio
- Screening of New Libraries Laboratory, School of Medicine and Dentistry, University of Santiago de Compostela, 15782 A Coru�a, Spain
| | - C. Garc�a-Santiago
- Screening of New Libraries Laboratory, School of Medicine and Dentistry, University of Santiago de Compostela, 15782 A Coru�a, Spain
| | - M.e. Cartea
- Group of Genetics, Breeding and Biochemistry of Brassicas, Biological Mission of Galicia, CSIC, 36143 Pontevedra, Spain
| | - P. Soengas
- Group of Genetics, Breeding and Biochemistry of Brassicas, Biological Mission of Galicia, CSIC, 36143 Pontevedra, Spain
| | - P. Velasco
- Group of Genetics, Breeding and Biochemistry of Brassicas, Biological Mission of Galicia, CSIC, 36143 Pontevedra, Spain
| | - M. Freire-Garabal
- Screening of New Libraries Laboratory, School of Medicine and Dentistry, University of Santiago de Compostela, 15782 A Coru�a, Spain
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29
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Lee CF, Chiang NN, Lu YH, Huang YS, Yang JS, Tsai SC, Lu CC, Chen FA. Benzyl isothiocyanate (BITC) triggers mitochondria-mediated apoptotic machinery in human cisplatin-resistant oral cancer CAR cells. Biomedicine (Taipei) 2018; 8:15. [PMID: 30141402 PMCID: PMC6108226 DOI: 10.1051/bmdcn/2018080315] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2018] [Accepted: 04/12/2018] [Indexed: 01/23/2023] Open
Abstract
Benzyl isothiocyanate (BITC), a component of dietary food, possesses a powerful anticancer activity. Previous studies have shown that BITC produces a large number of intracellular reactive oxygen species (ROS) and increases intracellular Ca2+ release from endoplasmic reticulum (ER), leading to the activation of the apoptotic mechanism in tumor cells. However, there is not much known regarding the inhibitory effect of BITC on cisplatin-resistant oral cancer cells. The purpose of this study was to examine the anticancer effect and molecular mechanism of BITC on human cisplatin-resistant oral cancer CAR cells. Our results demonstrated that BITC significantly reduced cell viability of CAR cells in a concentration- and time-dependent manner. BITC was found to cause apoptotic cell shrinkage and DNA fragmentation by morphologic observation and TUNEL/DAPI staining. Pretreatment of cells with a specific inhibitor of pan-caspase significantly reduced cell death caused by BITC. Colorimetric assay analyses also showed that the activities of caspase-3 and caspase-9 were elevated in BITC-treated CAR cells. An increase in ROS production and loss of mitochondria membrane potential (ΔΨm) occurred due to BITC exposure and was observed via flow cytometric analysis. Western blotting analyses demonstrated that the protein levels of Bax, Bad, cytochrome c, and cleaved caspase-3 were up-regulated, while those of Bcl-2, Bcl-xL and pro-caspase-9 were down-regulated in CAR cells after BITC challenge. In sum, the mitochondria-dependent pathway might contribute to BITC-induced apoptosis in human cisplatin-resistant oral cancer CAR cells.
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Affiliation(s)
- Chiu-Fang Lee
- Department of Pharmacy, Kaohsiung Veterans General Hospital Pingtung Branch, Pingtung 912, Taiwan
| | - Ni-Na Chiang
- Department of Pharmacy, Kaohsiung Veterans General Hospital Pingtung Branch, Pingtung 912, Taiwan
| | - Yao-Hua Lu
- Department of Pharmacy and Master Program, Tajen University, Pingtung 907, Taiwan
| | - Yu-Syuan Huang
- Department of Pharmacy and Master Program, Tajen University, Pingtung 907, Taiwan
| | - Jai-Sing Yang
- Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 404, Taiwan
| | - Shih-Chang Tsai
- Department of Biological Science and Technology, China Medical University, Taichung 404, Taiwan
| | - Chi-Cheng Lu
- Department of Pharmacy, Buddhist Tzu Chi General Hospital, Hualien 970, Taiwan - Department of Sport Performance, National Taiwan University of Sport, Taichung 404, Taiwan
| | - Fu-An Chen
- Department of Pharmacy and Master Program, Tajen University, Pingtung 907, Taiwan
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30
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Su J, Su L, Li D, Shuai O, Zhang Y, Liang H, Jiao C, Xu Z, Lai Y, Xie Y. Antitumor Activity of Extract From the Sporoderm-Breaking Spore of Ganoderma lucidum: Restoration on Exhausted Cytotoxic T Cell With Gut Microbiota Remodeling. Front Immunol 2018; 9:1765. [PMID: 30108589 PMCID: PMC6079217 DOI: 10.3389/fimmu.2018.01765] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2017] [Accepted: 07/17/2018] [Indexed: 12/23/2022] Open
Abstract
As breast cancer is the leading cause of cancer-related deaths in women population worldwide, ongoing endeavor has been made for alternative regimens with improved efficacy but fewer adverse effects. Recently, active components from the spores of Ganoderma lucidum have attracted much attention for their versatile biological activities owing to the advance in sporoderm-breaking technology. Here, anticancer potential of an extract derived from the sporoderm-breaking spores of G. lucidum (ESG) was explored in a 4T1-breast cancer xenograft mice model. Results showed that ESG was able to suppress 4T1 tumor growth in vivo rather than in vitro. Flowcytometry analysis revealed that ESG could significantly increase both cytotoxic T cell (Tc) population and the ratio of Tc to helper T cell (Th) in peripheral blood of the tumor-bearing mouse; similar promotion on Tc was also found in tumor-infiltrating lymphocyte. Moreover, ESG evidently downregulated the two immune checkpoints, programmed cell death protein-1 (PD-1, in the spleen) and cytotoxic T lymphocyte antigen-4 (CTLA-4, in the tumor), suggesting that ESG could effectively restore the T cell paradigm by recovering the exhaustion status via suppressing the co-inhibitory checkpoints. By 16S rRNA gene sequence analysis on the fecal microbiota, it was found that ESG would remodeling the overall structure of the samples from tumor-bearing mice toward that of the normal counterparts, including 18 genera in 5 phyla, together with regulations on several genes that are responsible for signaling pathways involved in metabolism, cellular processes, and environmental information processing. Collectively, this study demonstrated that ESG would serve as a natural anticancer adjuvant via a restoration on the exhausted Tc, highlighting important clinical implications for the treatment of breast cancer.
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Affiliation(s)
- Jiyan Su
- State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Guangdong Institute of Microbiology, Guangzhou, China
| | - Lu Su
- School of Pharmacy and Chemistry, Dali University, Dali, China.,Guangdong Yuewei Edible Fungi Technology Co. Ltd., Guangzhou, China
| | - Dan Li
- Guangdong Yuewei Edible Fungi Technology Co. Ltd., Guangzhou, China.,School of Pharmaceutical Science, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Ou Shuai
- Guangdong Yuewei Edible Fungi Technology Co. Ltd., Guangzhou, China
| | - Yifan Zhang
- State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Guangdong Institute of Microbiology, Guangzhou, China
| | - Huijia Liang
- Guangdong Yuewei Edible Fungi Technology Co. Ltd., Guangzhou, China
| | - Chunwei Jiao
- Guangdong Yuewei Edible Fungi Technology Co. Ltd., Guangzhou, China
| | - Zhanchi Xu
- School of Pharmaceutical Science, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yong Lai
- School of Pharmacy and Chemistry, Dali University, Dali, China
| | - Yizhen Xie
- State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Guangdong Institute of Microbiology, Guangzhou, China.,Guangdong Yuewei Edible Fungi Technology Co. Ltd., Guangzhou, China
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31
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Bell L, Oloyede OO, Lignou S, Wagstaff C, Methven L. Taste and Flavor Perceptions of Glucosinolates, Isothiocyanates, and Related Compounds. Mol Nutr Food Res 2018; 62:e1700990. [PMID: 29578640 DOI: 10.1002/mnfr.201700990] [Citation(s) in RCA: 105] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2017] [Revised: 02/05/2018] [Indexed: 11/07/2022]
Abstract
Brassicaceae plants are renowned for their taste, aroma and trigeminal characteristics; predominantly bitter taste, sulfurous aroma, and pungency. Compounds responsible for these sensations include the glucosinolates (GSLs) and their hydrolysis products, particularly isothiocyanates (ITCs), but also sulfur-containing volatile compounds. This article reviews the relative importance of taste and flavor perceptions resulting from such compounds; collating evidence from papers where findings are based on sensory analytical correlations, and those that have extracted specific compounds prior to sensory evaluation. Where specific GSLs impart bitterness and many ITCs impart pungency, this is clearly not true for all GSLs and ITCs. Designing crop improvement strategies for sensory traits based on total GSL content would be flawed, as it does not consider the relative differences in sensory characteristics of different GSLs and ITCs, nor the contribution from other GSL hydrolysis products. In addition, some Brassicaceae plants are consumed raw, whilst others are cooked; this affects not only the hydrolysis of GSLs, but also the generation and release of sulfides. Therefore, in breeding new plant varieties, it is prudent to consider the individual GSLs, the typical cooking conditions the plant is subjected to, enzyme stability, and resultant composition of both GSL hydrolysis products (including ITCs) and sulfides.
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Affiliation(s)
- Luke Bell
- Department of Food and Nutritional Sciences, University of Reading, Whiteknights, Reading, RG6 6AP, Berkshire, UK
| | - Omobolanle O Oloyede
- Department of Food and Nutritional Sciences, University of Reading, Whiteknights, Reading, RG6 6AP, Berkshire, UK
| | - Stella Lignou
- Department of Food and Nutritional Sciences, University of Reading, Whiteknights, Reading, RG6 6AP, Berkshire, UK
| | - Carol Wagstaff
- Department of Food and Nutritional Sciences, University of Reading, Whiteknights, Reading, RG6 6AP, Berkshire, UK
| | - Lisa Methven
- Department of Food and Nutritional Sciences, University of Reading, Whiteknights, Reading, RG6 6AP, Berkshire, UK
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32
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Wang Y, Xu H, Lu Z, Yu X, Lv C, Tian Y, Sui D. Pseudo-Ginsenoside Rh2 induces A549 cells apoptosis via the Ras/Raf/ERK/p53 pathway. Exp Ther Med 2018; 15:4916-4924. [PMID: 29805515 PMCID: PMC5958631 DOI: 10.3892/etm.2018.6067] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2017] [Accepted: 02/22/2018] [Indexed: 12/18/2022] Open
Abstract
Ginsenoside Rh2, a major effective constituent of ginseng, has been suggested to have a pro-apoptotic effect in a variety of cancer cells. Pseudo-Ginsenside-Rh2 (pseudo-G-Rh2) is a novel derivative of ginsenoside Rh2. The aim of the present study was to evaluate the effect of pseudo-G-Rh2 on the apoptosis of lung adenocarcinoma A549 cells. The cytotoxicity of pseudo-G-Rh2 on A549 cells was evaluated using an MTT assay. Apoptosis was detected using DAPI staining and flow cytometry. The expression of apoptosis associated proteins was identified by western blot analysis. The results demonstrated that pseudo-G-Rh2 inhibits the proliferation of A549 cells in a dose-dependent manner. DAPI staining revealed topical morphological changes in apoptotic bodies following pseudo-G-Rh2 treatment. Flow cytometric analysis revealed that the percentage of Annexin V-fluorescein isothiocyanate-positive cells, which are apoptotic, increased with pseudo-G-Rh2 treatment in a dose-dependent manner. Furthermore, treatment with pseudo-G-Rh2 increased the level of reactive oxygen species in A549 cells as well as the activation of caspase-9, caspase-3 and poly ADP-ribose polymerase. Pseudo-G-Rh2 treatment was observed to induce mitochondrial membrane potential loss. Furthermore, the results of western blotting revealed that B-cell lymphoma 2 (Bcl-2) expression was significantly decreased while Bcl-2-associated X protein expression was significantly upregulated in A549 cells with pseudo-G-Rh2 treatment. Pseudo-G-Rh2-induced apoptosis was accompanied by sustained phosphorylation of Ras, Raf, extracellular signal-regulated kinase (ERK) and p53. In conclusion, the results of the present study suggest that pseudo-G-Rh2 induces mitochondrial apoptosis in A549 cells and is responsible for excessive activation of the Ras/Raf/ERK/p53 pathway.
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Affiliation(s)
- Yuchen Wang
- Department of Pharmacology, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China.,School of Pharmaceutical Sciences, Changchun University of Chinese Medicine, Changchun, Jilin 130117, P.R. China
| | - Huali Xu
- Department of Pharmacology, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Zeyuan Lu
- Department of Pharmacology, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Xiaofeng Yu
- Department of Pharmacology, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Chen Lv
- Department of Pharmacology, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Yuan Tian
- Department of Pharmacology, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Dayun Sui
- Department of Pharmacology, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China
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33
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Qin G, Li P, Xue Z. Effect of allyl isothiocyanate on the viability and apoptosis of the human cervical cancer HeLa cell line in vitro. Oncol Lett 2018; 15:8756-8760. [PMID: 29805614 DOI: 10.3892/ol.2018.8428] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2016] [Accepted: 09/01/2017] [Indexed: 11/06/2022] Open
Abstract
The present study aimed to investigate the effect of allyl isothiocyanate (AITC) on the viability and apoptosis of the human cervical cancer HeLa cell line in vitro, and to explore the potential underlying mechanisms of this. HeLa cells were treated with varying concentrations of AITC for different durations. The cell viability was then measured using a Cell Counting kit-8 assay and the apoptosis rate of the cells was detected using flow cytometry. Additionally, the B cell lymphoma-2 (Bcl-2) and Bcl-2-associated X protein (Bax) mRNA expression levels were determined by reverse transcription-quantitative polymerase chain reaction, while the Bax and Bcl-2 protein expression levels in cells were detected by western blot analysis. AITC was revealed to inhibit the viability of HeLa cells. AITC was revealed to induce the apoptosis of HeLa cells, as the apoptosis rate increased gradually with an increase in the dose. As the concentration of AITC increased, the Bax mRNA expression level increased, whilst the Bcl-2 mRNA expression level decreased. Furthermore, the Bax protein expression intensity increased whilst Bcl-2 protein expression intensity decreased, thereby resulting in a decrease in the ratio of Bcl-2/Bax proteins. AITC may inhibit cell viability by inducing the apoptosis of HeLa cells and this may be accounted for by the imbalance in the Bcl-2/Bax expression ratio.
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Affiliation(s)
- Guangyi Qin
- Department of Obstetrics and Gynecology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, P.R. China
| | - Ping Li
- Department of Obstetrics and Gynecology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, P.R. China
| | - Zhuowei Xue
- Department of Obstetrics and Gynecology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, P.R. China
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34
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Tang YH, Yue ZS, Zheng WJ, Shen HF, Zeng LR, Hu ZQ, Xiong ZF. 4-Phenylbutyric acid presents therapeutic effect on osteoarthritis via inhibiting cell apoptosis and inflammatory response induced by endoplasmic reticulum stress. Biotechnol Appl Biochem 2018; 65:540-546. [PMID: 29327364 DOI: 10.1002/bab.1642] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2017] [Accepted: 01/06/2018] [Indexed: 12/28/2022]
Abstract
Osteoarthritis (OA) is a common bone and joint disease with a wild range of risk factors, which is associated with endoplasmic reticulum (ER) stress. The aim of our study was to discuss the possible mechanism of ER stress associated with OA in vivo and explore novel therapeutic method against OA. OA-induced damages in cartilage tissues were evaluated by HE, Safranin O/fast green, and TUNEL staining. The inflammatory factors concentration and the expression of FAP, MMP2, MMP9, Bax, Bcl-2, CHOP, and GRP78 were evaluated by ELISA, real-time PCR, and Western blot analyses. As results, 4-phenylbutyric acid (4-PBA)-treated OA cartilage tissues presented alleviated tissue damage with less apoptotic cells and cytokine production in comparison with advanced-OA tissues. Downregulation of Bax/Bcl-2, CHOP, GRP78, inflammatory factors, and reactive oxygen species generation, and the increase of MMP level detected after 4-PBA treatment indicated an inhibitory effect of 4-PBA on cell apoptosis, inflammatory response, and ER stress in OA. In conclusion, we indicate that ER stress causes cell apoptosis and inflammatory response, resulting in the tissue damage within OA. At the same time, 4-PBA exhibited protective effect on cartilage cells against OA through the inhibition of ER stress.
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Affiliation(s)
- Yang-Hua Tang
- Department of Orthopedics, Xiaoshan Traditional Chinese Medical Hospital, Hangzhou, 311201, Zhejiang, People's Republic of China
| | - Zhen-Shuang Yue
- Department of Orthopedics, Xiaoshan Traditional Chinese Medical Hospital, Hangzhou, 311201, Zhejiang, People's Republic of China
| | - Wen-Jie Zheng
- Department of Orthopedics, Xiaoshan Traditional Chinese Medical Hospital, Hangzhou, 311201, Zhejiang, People's Republic of China
| | - Hong-Fei Shen
- Department of Orthopedics, Xiaoshan Traditional Chinese Medical Hospital, Hangzhou, 311201, Zhejiang, People's Republic of China
| | - Lin-Ru Zeng
- Department of Orthopedics, Xiaoshan Traditional Chinese Medical Hospital, Hangzhou, 311201, Zhejiang, People's Republic of China
| | - Zhong-Qing Hu
- Department of Orthopedics, Xiaoshan Traditional Chinese Medical Hospital, Hangzhou, 311201, Zhejiang, People's Republic of China
| | - Zhen-Fei Xiong
- Department of Orthopedics, Xiaoshan Traditional Chinese Medical Hospital, Hangzhou, 311201, Zhejiang, People's Republic of China
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35
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Assi M. The differential role of reactive oxygen species in early and late stages of cancer. Am J Physiol Regul Integr Comp Physiol 2017; 313:R646-R653. [DOI: 10.1152/ajpregu.00247.2017] [Citation(s) in RCA: 79] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2017] [Revised: 08/15/2017] [Accepted: 08/20/2017] [Indexed: 12/31/2022]
Abstract
The large doses of vitamins C and E and β-carotene used to reduce reactive oxygen species (ROS) production and oxidative damages in cancerous tissue have produced disappointing and contradictory results. This therapeutic conundrum was attributed to the double-faced role of ROS, notably, their ability to induce either proliferation or apoptosis of cancer cells. However, for a ROS-inhibitory approach to be effective, it must target ROS when they induce proliferation rather than apoptosis. On the basis of recent advances in redox biology, this review underlined a differential regulation of prooxidant and antioxidant system, respective to the stage of cancer. At early precancerous and neoplastic stages, antioxidant activity decreases and ROS appear to promote cancer initiation via inducing oxidative damage and base pair substitution mutations in prooncogenes and tumor suppressor genes, such as RAS and TP53, respectively. Whereas in late stages of cancer progression, tumor cells escape apoptosis by producing high levels of intracellular antioxidants, like NADPH and GSH, via the pentose phosphate pathway to buffer the excessive production of ROS and related intratumor oxidative injuries. Therefore, antioxidants should be prohibited in patients with advanced stages of cancer and/or undergoing anticancer therapies. Interestingly, the biochemical and biophysical properties of some polyphenols allow them to selectively recognize tumor cells. This characteristic was exploited to design and deliver nanoparticles coated with low doses of polyphenols and containing chemotherapeutic drugs into tumor-bearing animals. First results are encouraging, which may revolutionize the conventional use of antioxidants in cancer.
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Affiliation(s)
- Mohamad Assi
- Laboratory “Movement, Sport and Health Sciences,” University of Rennes II-Ecole Normale Superieur Rennes, France
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36
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Gründemann C, Huber R. Chemoprevention with isothiocyanates - From bench to bedside. Cancer Lett 2017; 414:26-33. [PMID: 29111351 DOI: 10.1016/j.canlet.2017.10.033] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2017] [Revised: 10/10/2017] [Accepted: 10/20/2017] [Indexed: 12/15/2022]
Abstract
Isothiocyanates (ITCs) are naturally occurring hydrolization products from glucosinolates (GLSs) in brassicaceae and in epidemiological studies their intake has been weakly to moderately inversely correlated with the risk of colorectal cancer, prostate cancer and lung cancer. Numerous preclinical studies demonstrate chemopreventive mode of actions of ITCs, mainly related to a.) detoxification (induction of phase II enzymes), b.) anti-inflammatory properties by down-regulation of NFkappaB activity, c.) cyclin-mediated cell cycle arrest and d.) epigenetic modulation by inhibition of histone deacetylase activity. First prospective clinical trials were promising in patients with risk of prostate cancer recurrence. The glutathione-S-transferase gene expression seems to play a major role in the individual susceptibility towards ITCs. Safety issues are widely unclear and should be more addressed in future studies because ITCs can, in low concentrations, compromise the function of human immune cells and might impair genome stability.
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Affiliation(s)
- Carsten Gründemann
- Center for Complementary Medicine, Institute for Infection Prevention and Hospital Epidemiology, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
| | - Roman Huber
- Center for Complementary Medicine, Institute for Infection Prevention and Hospital Epidemiology, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
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37
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Lin JF, Tsai TF, Yang SC, Lin YC, Chen HE, Chou KY, Hwang TIS. Benzyl isothiocyanate induces reactive oxygen species-initiated autophagy and apoptosis in human prostate cancer cells. Oncotarget 2017; 8:20220-20234. [PMID: 28423628 PMCID: PMC5386757 DOI: 10.18632/oncotarget.15643] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2015] [Accepted: 12/03/2016] [Indexed: 11/25/2022] Open
Abstract
Benzyl isothiocyanate (BITC) in cruciferous plants, which are part of the human diet, has been shown to induce apoptosis in various types of cancer. In this study, we show that BITC effectively suppresses the growth of cultured human prostate cancer cells (CRW-22Rv1 and PC3) by causing mitochondrial membrane potential loss, caspase 3/7 activation and DNA fragmentation. Furthermore, BITC induces ROS generation in these cells. The induction of apoptosis by BITC was significantly attenuated in the presence of N-acetylcysteine (NAC) and catalase (CAT), well-studied ROS scavengers. The induction of autophagy in BITC-treated cells were also diminished by the application of NAC or CAT. In addition, BITC-induced apoptosis and autophagy were both enhanced by the pretreatment of catalase inhibitor, 3-Amino-1,2,4-triazole (3-AT). Pretreatment with specific inhibitors of autophagy (3-methyladenine or bafilomycin A1) or apoptosis (Z-VAD-FMK) reduced BITC-induced autophagy and apoptosis, respectively, but did not abolish BITC-induced ROS generation. In conclusion, the present study provides evidences that BITC caused prostate cancer cell death was dependent on the ROS status, and clarified the mechanism underlying BITC-induced cell death, which involves the induction of ROS production, autophagy and apoptosis, and the relationship between these three important processes.
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Affiliation(s)
- Ji-Fan Lin
- Central Laboratory, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, 111, Taiwan
| | - Te-Fu Tsai
- Division of Urology, Department of Surgery, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, 111, Taiwan.,Division of Urology, School of Medicine, Fu-Jen Catholic University, New Taipei, 242, Taiwan
| | - Shan-Che Yang
- Central Laboratory, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, 111, Taiwan
| | - Yi-Chia Lin
- Division of Urology, Department of Surgery, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, 111, Taiwan
| | - Hung-En Chen
- Division of Urology, Department of Surgery, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, 111, Taiwan
| | - Kuang-Yu Chou
- Division of Urology, Department of Surgery, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, 111, Taiwan.,Division of Urology, School of Medicine, Fu-Jen Catholic University, New Taipei, 242, Taiwan
| | - Thomas I-Sheng Hwang
- Division of Urology, Department of Surgery, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, 111, Taiwan.,Division of Urology, School of Medicine, Fu-Jen Catholic University, New Taipei, 242, Taiwan.,Department of Urology, Taipei Medical University, Taipei, 111, Taiwan
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38
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Pereira LP, Silva P, Duarte M, Rodrigues L, Duarte CMM, Albuquerque C, Serra AT. Targeting Colorectal Cancer Proliferation, Stemness and Metastatic Potential Using Brassicaceae Extracts Enriched in Isothiocyanates: A 3D Cell Model-Based Study. Nutrients 2017; 9:nu9040368. [PMID: 28394276 PMCID: PMC5409707 DOI: 10.3390/nu9040368] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2017] [Revised: 03/23/2017] [Accepted: 04/01/2017] [Indexed: 01/28/2023] Open
Abstract
Colorectal cancer (CRC) recurrence is often attributable to circulating tumor cells and/or cancer stem cells (CSCs) that resist to conventional therapies and foster tumor progression. Isothiocyanates (ITCs) derived from Brassicaceae vegetables have demonstrated anticancer effects in CRC, however little is known about their effect in CSCs and tumor initiation properties. Here we examined the effect of ITCs-enriched Brassicaceae extracts derived from watercress and broccoli in cell proliferation, CSC phenotype and metastasis using a previously developed three-dimensional HT29 cell model with CSC-like traits. Both extracts were phytochemically characterized and their antiproliferative effect in HT29 monolayers was explored. Next, we performed cell proliferation assays and flow cytometry analysis in HT29 spheroids treated with watercress and broccoli extracts and respective main ITCs, phenethyl isothiocyanate (PEITC) and sulforaphane (SFN). Soft agar assays and relative quantitative expression analysis of stemness markers and Wnt/β-catenin signaling players were performed to evaluate the effect of these phytochemicals in stemness and metastasis. Our results showed that both Brassicaceae extracts and ITCs exert antiproliferative effects in HT29 spheroids, arresting cell cycle at G₂/M, possibly due to ITC-induced DNA damage. Colony formation and expression of LGR5 and CD133 cancer stemness markers were significantly reduced. Only watercress extract and PEITC decreased ALDH1 activity in a dose-dependent manner, as well as β-catenin expression. Our research provides new insights on CRC therapy using ITC-enriched Brassicaceae extracts, specially watercress extract, to target CSCs and circulating tumor cells by impairing cell proliferation, ALDH1-mediated chemo-resistance, anoikis evasion, self-renewal and metastatic potential.
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Affiliation(s)
- Lucília P Pereira
- iBET, Instituto de Biologia Experimental e Tecnológica, Apartado 12, 2780-901 Oeiras, Portugal.
- Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa (ITQB NOVA), 2780-157 Oeiras, Portugal.
| | - Patrícia Silva
- Unidade de Investigação em Patobiologia Molecular (UIPM), Instituto Português de Oncologia de Lisboa Francisco Gentil, E.P.E (IPOLFG, EPE), 1099-023 Lisboa, Portugal.
| | - Marlene Duarte
- Unidade de Investigação em Patobiologia Molecular (UIPM), Instituto Português de Oncologia de Lisboa Francisco Gentil, E.P.E (IPOLFG, EPE), 1099-023 Lisboa, Portugal.
| | - Liliana Rodrigues
- iBET, Instituto de Biologia Experimental e Tecnológica, Apartado 12, 2780-901 Oeiras, Portugal.
- Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa (ITQB NOVA), 2780-157 Oeiras, Portugal.
| | - Catarina M M Duarte
- iBET, Instituto de Biologia Experimental e Tecnológica, Apartado 12, 2780-901 Oeiras, Portugal.
- Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa (ITQB NOVA), 2780-157 Oeiras, Portugal.
| | - Cristina Albuquerque
- Unidade de Investigação em Patobiologia Molecular (UIPM), Instituto Português de Oncologia de Lisboa Francisco Gentil, E.P.E (IPOLFG, EPE), 1099-023 Lisboa, Portugal.
| | - Ana Teresa Serra
- iBET, Instituto de Biologia Experimental e Tecnológica, Apartado 12, 2780-901 Oeiras, Portugal.
- Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa (ITQB NOVA), 2780-157 Oeiras, Portugal.
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39
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Wang H, Xu K. [Advances in Research of Antitumor Mechanisms of Isothiocyanates]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2017; 20:213-218. [PMID: 28302225 PMCID: PMC5973296 DOI: 10.3779/j.issn.1009-3419.2017.03.11] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Isothiocyanates (ITCs) are naturally occurring small molecules that are generated by the enzymic hydrolysis of glucosinolate in cruciferous vegetables. Numerous studies showed that ITCs inhibit the growth of tumors by the mechanisms including inducing cell cycle arrest, promoting apoptosis and producing reactive oxygen species in vitro and in vivo. Recent studies showed that ITCs also inhibit metastasis of cancer cells, induce endoplasmic reticulum stress and autophagy. This review summarizes the antitumor mechanisms of ITCs.
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Affiliation(s)
- Huimin Wang
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Ke Xu
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin 300052, China
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40
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Zhu M, Li W, Dong X, Chen Y, Lu Y, Lin B, Guo J, Li M. Benzyl-isothiocyanate Induces Apoptosis and Inhibits Migration and Invasion of Hepatocellular Carcinoma Cells in vitro. J Cancer 2017; 8:240-248. [PMID: 28243328 PMCID: PMC5327373 DOI: 10.7150/jca.16402] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2016] [Accepted: 10/29/2016] [Indexed: 12/11/2022] Open
Abstract
Despite consideration of benzyl isothiocyanate(BITC) is applied to prevention and therapeutic of cancer, the role of BITC in inducing apoptosis, and inhibiting migration and invasion of hepatocellular carcinoma(HCC) cells is still unclear. In this study, we aim to explore the effects of BITC on the growth, migration and invasion of HCC cells in vitro. When human HCC cell lines, Bel 7402 and HLE, were treated with an optimal concentration of BITC for 48 hours, the results indicated that BITC inhibits growth and promotes apoptosis of HCC cells; BITC has a significant inhibitory effect on the migration and invasion of HCC cells. BITC stimulated expression of caspase-3/8 and PARP-1, and suppressed expression of survivin, MMP2/9 and CXCR4. BITC also inhibited the enzymatic activities of MMP2 and MMP9. Altogether, BITC was able to induce apoptosis and suppress the invasive and migratory abilities of Bel 7402 and HLE cells. The role mechanism of BITC might involve an up-regulating the expression of apoptosis-related proteins and down-regulating the expression of metastasis-related proteins. BITC may be applied as a novel chemotherapy for HCC patients.
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Affiliation(s)
- Mingyue Zhu
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou 571199, Hainan Province, PR. China
- Key Laboratory of Molecular Biology, Hainan Medical College, Haikou 571199, Hainan Province, PR. China
| | - Wei Li
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou 571199, Hainan Province, PR. China
- Key Laboratory of Molecular Biology, Hainan Medical College, Haikou 571199, Hainan Province, PR. China
| | - Xu Dong
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou 571199, Hainan Province, PR. China
- Key Laboratory of Molecular Biology, Hainan Medical College, Haikou 571199, Hainan Province, PR. China
| | - Yi Chen
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou 571199, Hainan Province, PR. China
- Key Laboratory of Molecular Biology, Hainan Medical College, Haikou 571199, Hainan Province, PR. China
| | - Yan Lu
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou 571199, Hainan Province, PR. China
- Key Laboratory of Molecular Biology, Hainan Medical College, Haikou 571199, Hainan Province, PR. China
| | - Bo Lin
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou 571199, Hainan Province, PR. China
- Key Laboratory of Molecular Biology, Hainan Medical College, Haikou 571199, Hainan Province, PR. China
| | - Junli Guo
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou 571199, Hainan Province, PR. China
| | - Mengsen Li
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou 571199, Hainan Province, PR. China
- Key Laboratory of Molecular Biology, Hainan Medical College, Haikou 571199, Hainan Province, PR. China
- Institution of Tumor, Hainan Medical College, Haikou 570102, Hainan Province, PR. China
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Hsu YC, Chiang JH, Yu CS, Hsia TC, Wu RSC, Lien JC, Lai KC, Yu FS, Chung JG. Antitumor effects of deguelin on H460 human lung cancer cells in vitro and in vivo: Roles of apoptotic cell death and H460 tumor xenografts model. ENVIRONMENTAL TOXICOLOGY 2017; 32:84-98. [PMID: 26592500 DOI: 10.1002/tox.22214] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/04/2015] [Revised: 10/16/2015] [Accepted: 10/18/2015] [Indexed: 06/05/2023]
Abstract
Deguelin, a naturally occurring rotenoid of the flavonoid family, is known to be an Akt inhibitor, to have chemopreventive activities and anti-tumor effect on several cancers. In this study, investigation to elucidate the effect of deguelin on apoptotic pathways in human lung cancer cells and on the anti-tumor effect in lung cancer xenograft nu/nu mice was performed. In vitro studies, found that deguelin induced cell morphological changes, and decreased the percentage of viability through the induction of apoptosis in H460 lung cancer cells. Deguelin triggered apoptosis in H460 cells was also confirmed by DAPI staining, DNA gel electrophoresis, and Annexin V-FITC staining and these effects are dose-dependent manners. It was also found that deguelin promoted the Ca2+ production and activation of caspase-3 but decreased the level of ΔΨm in H460 cells. Western blots indicated that the protein levels of cytochrome c, AIF, and pro-apoptotic Bax and Bak protein were increased, but the anti-apoptotic Bcl-2 and Bcl-x were decreased that may have led to apoptosis in H460 cells after exposure to deguelin. It was also confirmed by confocal laser microscope examination that deguelin promoted the release of AIF from mitochondria to cytosol. In vivo studies, found that in immunodeficient nu/nu mice bearing H460 tumor xenografts showed that the deguelin significantly suppressed tumor growth. Deguelin might be a potential therapeutic agent for the treatment of lung cancer in the future. This finding might fully support a critical event for deguelin via induction of apoptotic cell death and H460 tumor xenografts model against human lung cancer. © 2015 Wiley Periodicals, Inc. Environ Toxicol 32: 84-98, 2017.
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Affiliation(s)
- Yu-Chieh Hsu
- Department of Biological Science and Technology, China Medical University, Taichung, 404, Taiwan
| | - Jo-Hua Chiang
- Department of Nursing, Chung-Jen Junior College of Nursing, Health Sciences and Management, Chiayi County, 62241, Taiwan
| | - Chun-Shu Yu
- School of Pharmacy, China Medical University, Taichung, 404, Taiwan
| | - Te-Chun Hsia
- Graduate Institute of Chinese Medicine, China Medical University, Taichung, 404, Taiwan
- Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Rick Sai-Chuen Wu
- Department of Anesthesiology, China Medical University Hospital, Taichung, 404, Taiwan
| | - Jin-Cherng Lien
- School of Pharmacy, China Medical University, Taichung, 404, Taiwan
| | - Kuang-Chi Lai
- School of Medicine, China Medical University Hospital, Taichung, 404, Taiwan
- Department of Surgery, China Medical University Beigang Hospital, Yunlin, 651, Taiwan
| | - Fu-Shun Yu
- School of Dentist, China Medical University, Taichung, 404, Taiwan
| | - Jing-Gung Chung
- Department of Biological Science and Technology, China Medical University, Taichung, 404, Taiwan
- Department of Biotechnology, Asia University, Taichung, 413, Taiwan
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Chou YC, Chang MY, Wang MJ, Liu HC, Chang SJ, Harnod T, Hung CH, Lee HT, Shen CC, Chung JG. Phenethyl isothiocyanate alters the gene expression and the levels of protein associated with cell cycle regulation in human glioblastoma GBM 8401 cells. ENVIRONMENTAL TOXICOLOGY 2017; 32:176-187. [PMID: 26678675 DOI: 10.1002/tox.22224] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/29/2015] [Revised: 11/12/2015] [Accepted: 11/25/2015] [Indexed: 06/05/2023]
Abstract
Glioblastoma is the most common and aggressive primary brain malignancy. Phenethyl isothiocyanate (PEITC), a member of the isothiocyanate family, can induce apoptosis in many human cancer cells. Our previous study disclosed that PEITC induces apoptosis through the extrinsic pathway, dysfunction of mitochondria, reactive oxygen species (ROS)-induced endoplasmic reticulum (ER) stress, and intrinsic (mitochondrial) pathway in human brain glioblastoma multiforme (GBM) 8401 cells. To the best of our knowledge, we first investigated the effects of PEITC on the genetic levels of GBM 8401 cells in vitro. PEITC may induce G0/G1 cell-cycle arrest through affecting the proteins such as cdk2, cyclin E, and p21 in GBM 8401 cells. Many genes associated with cell-cycle regulation of GBM 8401 cells were changed after PEITC treatment: 48 genes were upregulated and 118 were downregulated. The cell-division cycle protein 20 (CDC20), Budding uninhibited by benzimidazole 1 homolog beta (BUB1B), and cyclin B1 were downregulated, and clusterin was upregulated in GBM 8401 cells treated with PEITC. These changes of gene expression can provide the effects of PEITC on the genetic levels and potential biomarkers for glioblastoma. © 2015 Wiley Periodicals, Inc. Environ Toxicol 32: 176-187, 2017.
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Affiliation(s)
- Yu-Cheng Chou
- Division of Neurosurgical Oncology, Neurological Institute, Taichung Veterans General Hospital, Taichung, 407, Taiwan
- Institute of Medical Sciences, Tzu Chi University, Hualien, 970, Taiwan
- National Defense Medical Center, Taipei, 114, Taiwan
- Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, 404, Taiwan
| | - Meng-Ya Chang
- Institute of Medical Sciences, Tzu Chi University, Hualien, 970, Taiwan
| | - Mei-Jen Wang
- Institute of Medical Sciences, Tzu Chi University, Hualien, 970, Taiwan
- Department of Medical Research, Buddhist Tzu Chi General Hospital, Hualien, 970, Taiwan
| | - Hsin-Chung Liu
- Departments of Biological Science and Technology, China Medical University, Taichung, 404, Taiwan
| | - Shu-Jen Chang
- School of Pharmacy, China Medical University, Taichung, 404, Taiwan
| | - Tomor Harnod
- Department of Neurosurgery, Buddhist Tzu Chi General Hospital and College of Medicine, Tzu Chi University, Hualien, 970, Taiwan
| | - Chih-Huang Hung
- Institute of Medical Sciences, Tzu Chi University, Hualien, 970, Taiwan
| | - Hsu-Tung Lee
- Division of Neurosurgical Oncology, Neurological Institute, Taichung Veterans General Hospital, Taichung, 407, Taiwan
- Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, 114, Taiwan
| | - Chiung-Chyi Shen
- Division of Minimally Invasive Skull Base Neurosurgery, Neurological Institute, Taichung Veterans General Hospital, Taichung, 407, Taiwan
| | - Jing-Gung Chung
- Departments of Biological Science and Technology, China Medical University, Taichung, 404, Taiwan
- Department of Biotechnology, Asia University, Taichung, 413, Taiwan, Republic of China
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Kasiappan R, Jutooru I, Karki K, Hedrick E, Safe S. Benzyl Isothiocyanate (BITC) Induces Reactive Oxygen Species-dependent Repression of STAT3 Protein by Down-regulation of Specificity Proteins in Pancreatic Cancer. J Biol Chem 2016; 291:27122-27133. [PMID: 27875298 PMCID: PMC5207142 DOI: 10.1074/jbc.m116.746339] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Revised: 11/08/2016] [Indexed: 01/05/2023] Open
Abstract
The antineoplastic agent benzyl isothiocyanate (BITC) acts by targeting multiple pro-oncogenic pathways/genes, including signal transducer and activator of transcription 3 (STAT3); however, the mechanism of action is not well known. As reported previously, BITC induced reactive oxygen species (ROS) in Panc1, MiaPaCa2, and L3.6pL pancreatic cancer cells. This was accompanied by induction of apoptosis and inhibition of cell growth and migration, and these responses were attenuated in cells cotreated with BITC plus glutathione (GSH). BITC also decreased expression of specificity proteins (Sp) Sp1, Sp3, and Sp4 transcription factors (TFs) and several pro-oncogenic Sp-regulated genes, including STAT3 and phospho-STAT3 (pSTAT3), and GSH attenuated these responses. Knockdown of Sp TFs by RNA interference also decreased STAT3/pSTAT3 expression. BITC-induced ROS activated a cascade of events that included down-regulation of c-Myc, and it was also demonstrated that c-Myc knockdown decreased expression of Sp TFs and STAT3 These results demonstrate that in pancreatic cancer cells, STAT3 is an Sp-regulated gene that can be targeted by BITC and other ROS inducers, thereby identifying a novel therapeutic approach for targeting STAT3.
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Affiliation(s)
- Ravi Kasiappan
- From the Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas 77843-4466
| | - Indira Jutooru
- From the Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas 77843-4466
| | - Keshav Karki
- From the Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas 77843-4466
| | - Erik Hedrick
- From the Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas 77843-4466
| | - Stephen Safe
- From the Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas 77843-4466
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Shang HS, Shih YL, Lu TJ, Lee CH, Hsueh SC, Chou YC, Lu HF, Liao NC, Chung JG. Benzyl isothiocyanate (BITC) induces apoptosis of GBM 8401 human brain glioblastoma multiforms cells via activation of caspase-8/Bid and the reactive oxygen species-dependent mitochondrial pathway. ENVIRONMENTAL TOXICOLOGY 2016; 31:1751-1760. [PMID: 28675694 DOI: 10.1002/tox.22177] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/12/2015] [Revised: 07/15/2015] [Accepted: 07/16/2015] [Indexed: 06/07/2023]
Abstract
Benzyl isothiocyanate (BITC) is one of member of the isothiocyanate family which has been shown to induce cancer cell apoptosis in many human cancer cells. In the present study, we investigated the effects of BITC on the growth of GBM 8401 human brain glioblastoma multiforms cells. Results indicated that BITC-induced cell morphological changes decreased in the percentage of viable GBM8401 cells and these effects are dose-dependent manners. Results from flow cytometric assay indicated that BITC induced sub-G1 phase and induction of apoptosis of GBM 8401 cells. Furthermore, results also showed that BITC promoted the production of reactive oxygen species (ROS) and Ca2+ release, but decreased the mitochondrial membrane potential (ΔΨm ) and promoted caspase-8, -9, and -3 activates. After cells were pretreated with Z-IETD-FMK, Z-LEHD-FMK, and Z-DEVD-FMK (caspase-8, -9, and -3 inhibitors, respectively) led to decrease in the activities of caspase-8, -9, and -3 and increased the percentage of viable GBM 8401 cells that indicated which BITC induced cell apoptosis through caspase-dependent pathways. Western blotting indicated that BITC induced Fas, Fas-L, FADD, caspase-8, caspase -3, and pro-apoptotic protein (Bax, Bid, and Bak), but inhibited the ant-apoptotic proteins (Bcl-2 and Bcl-x) in GBM 8401 cells. Furthermore, BITC increased the release of cytochrome c, AIF, and Endo G from mitochondria that led to cell apoptosis. Results also showed that BITC increased GADD153, GRP 78, XBP-1, and ATF-6β, IRE-1α, IRE-1β, Calpain 1 and 2 in GBM 8401 cells, which is associated with ER stress. Based on these observations, we may suggest that BITC-induced apoptosis might be through Fas receptor, ROS induced ER stress, caspase-3, and mitochondrial signaling pathways. Taken together, these molecular alterations and signaling pathways offer an insight into BITC-caused growth inhibition and induced apoptotic cell death of GBM 8401 cells. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1751-1760, 2016.
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Affiliation(s)
- Hung-Sheng Shang
- Department of Pathology, Division of Clinical Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China
| | - Yung-Luen Shih
- Department of School of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan, Republic of China
- Department of Pathology and Laboratory Medicine, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan, Republic of China
- School of Medical Laboratory Science and Biotechnology, Taipei Medical University, Taipei, Taiwan, Republic of China
| | - Tai-Jung Lu
- Jen-The Junior College of Medicine, Nursing and Management, Miaoli County, Taiwan, Republic of China
| | - Ching-Hsiao Lee
- Jen-The Junior College of Medicine, Nursing and Management, Miaoli County, Taiwan, Republic of China
| | - Shu-Ching Hsueh
- Department of Clinical Pathology, Cheng Hsin General Hospital, Taipei, Taiwan, Republic of China
| | - Yu-Cheng Chou
- Division of Neurosurgical Oncology, Neurological Institute, Taichung Veterans General Hospital, Taichung, Taiwan, Republic of China
- Institute of Medical Sciences, Tzu Chi University, Hualien, Taiwan, Republic of China
| | - Hsu-Feng Lu
- Department of Clinical Pathology, Cheng Hsin General Hospital, Taipei, Taiwan, Republic of China
- Department of Restaurant, Hotel and Institutional Management, Fu-Jen Catholic University, New Taipei City, Taiwan, Republic of China
| | - Nien-Chieh Liao
- Department of Clinical Pathology, Cheng Hsin General Hospital, Taipei, Taiwan, Republic of China
| | - Jing-Gung Chung
- Department of Biological Science and Technology, China Medical University, Taichung, Taiwan, Republic of China
- Department of Biotechnology, Asia University, Taichung, Taiwan, Republic of China
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45
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Jiang Z, Liu X, Chang K, Liu X, Xiong J. Allyl Isothiocyanate Inhibits the Proliferation of Renal Carcinoma Cell Line GRC-1 by Inducing an Imbalance Between Bcl2 and Bax. Med Sci Monit 2016; 22:4283-4288. [PMID: 27834342 PMCID: PMC5115214 DOI: 10.12659/msm.897315] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Background Because of the insensitivity of renal cell carcinoma (RCC) to both chemotherapy and radiotherapy, surgery remains the primary approach for anticancer treatment. However, patients who do not receive timely diagnoses may not be suitable for surgery, especially in the late phase of tumor development. Thus, the discovery of novel effective treatment is of great importance. Allyl isothiocyanate (AITC) can inhibit the proliferation and induce apoptosis in many cancer cells. In this paper, we report on an in vitro study to determine the effect of AITC on proliferation and apoptosis of RCC line GRC-1. Material/Methods CCK8 assay was used to detect cell proliferation under gradient concentrations of AITC. Flow cytometry was employed to evaluate cell apoptosis. Real-time fluorescent polymerase chain reaction quantified mRNA levels of Bax and Bcl-2 genes. Western blotting was further employed for protein expression assay. Results AITC inhibited GRC-1 cell proliferation and induced cell apoptosis in a dose-dependent manner; it also elevated Bax while suppressing Bcl-2 gene expression at both mRNA and protein levels. In general, increasing concentration of AITC decreased Bcl-2/Bax ratio. Conclusions The inhibitory effect of AITC on GRC-1 cells is exerted via cell apoptosis, in which the imbalance of Bcl-2/Bax plays a significant role.
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Affiliation(s)
- Zhongyong Jiang
- Department of Clinical Laboratory, Chengdu Military General Hospital, Chengdu, Sichuan, China (mainland)
| | - Xi Liu
- Medical Department, Chengdu Military General Hospital, Chengdu, Sichuan, China (mainland)
| | - Kai Chang
- Department of Clinical Laboratory, Chengdu Military General Hospital, Chengdu, Sichuan, China (mainland)
| | - Xia Liu
- Department of Clinical Laboratory, Chengdu Military General Hospital, Chengdu, Sichuan, China (mainland)
| | - Jie Xiong
- Department of Clinical Laboratory, Chengdu Military General Hospital, Chengdu, Sichuan, China (mainland)
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Safe S, Kasiappan R. Natural Products as Mechanism-based Anticancer Agents: Sp Transcription Factors as Targets. Phytother Res 2016; 30:1723-1732. [PMID: 27384261 DOI: 10.1002/ptr.5669] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2016] [Revised: 05/16/2016] [Accepted: 06/01/2016] [Indexed: 08/29/2023]
Abstract
Naturally occurring anticancer agents and their derivatives act on multiple pathways to inhibit carcinogenesis and their inhibition of migration, invasion, growth, survival, and metastasis is associated with downregulation of genes associated with these responses. Several phytochemical-derived anticancer drugs including curcumin, betulinic acid, phenethylisothiocyanate and celastrol, and many others induce reactive oxygen species, and their effects on gene regulation show some overlap in various cancer cell lines. We hypothesize that reactive oxygen species-inducing anticancer agents and many other natural products target a common pathway in cancer cells, which initially involves downregulation of specificity protein 1 (Sp1), Sp3, and Sp4, which are highly expressed in tumors/cell lines derived from solid tumors. This hypothesis is supported by several published reports showing that a large number of phytochemical-derived anticancer agents downregulate Sp1, Sp3, Sp4, and pro-oncogenic Sp-regulated genes involved in cell growth (cyclin D1 and growth factor receptors), survival (bcl-2 and survivin), angiogenesis and migration (MMP-9, vascular endothelial growth factor and its receptors), and inflammation (NF-kB). The contribution of this pathway to the anticancer activity of drugs such as curcumin, celastrol, betulinic acid, and phenethylisothiocyanate must be determined in order to optimize clinical applications of drug combinations containing these compounds. Copyright © 2016 John Wiley & Sons, Ltd.
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Affiliation(s)
- Stephen Safe
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX, 77843-4466, USA.
| | - Ravi Kasiappan
- Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX, 77843-4466, USA
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47
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Benzyl isothiocyanate promotes apoptosis of oral cancer cells via an acute redox stress-mediated DNA damage response. Food Chem Toxicol 2016; 97:336-345. [DOI: 10.1016/j.fct.2016.09.028] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2016] [Revised: 09/19/2016] [Accepted: 09/26/2016] [Indexed: 11/24/2022]
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48
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Lin CC, Lee MH, Lin JH, Lin ML, Chueh FS, Yu CC, Lin JP, Chou YC, Hsu SC, Chung JG. Crude extract of Rheum palmatum L. Induces cell cycle arrest S phase and apoptosis through mitochondrial-dependent pathways in U-2 OS human osteosarcoma cells. ENVIRONMENTAL TOXICOLOGY 2016; 31:957-969. [PMID: 25689151 DOI: 10.1002/tox.22105] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/25/2014] [Revised: 12/19/2014] [Accepted: 12/21/2014] [Indexed: 06/04/2023]
Abstract
Cancer is the second cause of death in children. Osteosarcoma is the most common primary malignancy of solid bone cancer primarily affecting adolescents and young adults. In the Chinese population, the crude extract of Rheum palmatum L. (CERP) has been used for treating different diseases, including SARS, rheumatoid arthritis, coxsackievirus B3, and human colon cancer cell, pancreatic cancer. There are no reports on CERP and human osteosarcoma cells. The present study examined effects of CERP on cytotoxicity including cell cycle distribution and cell death (apoptosis) in U-2 OS human osteosarcoma cells. CERP significantly induced S phase arrest in U-2 OS cells in a dose-dependent. CERP produced DNA damage and DNA condensation. Other effects of CERP were stimulation of ROS and Ca(2+) , mitochondria impairment, and activation of caspase-3, -8, and -9. CERP increased the levels of Bax, Bak, Bad, cyclin B, Fas, PARP, GRP78, GADD153, AIF, Endo G, Calpain-2, p21, and p27, but decreased the levels of Bcl-2, BCL-X, XIAP, Akt, CDC25A, CDK2, Cyclin A, and Cyclin E of U-2 OS cells. It was also observed that CERP promoted the expression of AIF, Endo G, GADD153, and cytochrome c. These results indicate that CERP has anticancer effects in vitro and provide the foundation for in vivo studies of animal models of osteosarcoma. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 957-969, 2016.
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Affiliation(s)
- Chin-Chung Lin
- Department of Chinese Medicine, Feng-Yuan Hospital, Ministry of Health and Welfare, Executive Yuan, Taichung, 420, Taiwan
- General Education Center, Central Taiwan University of Science and Technology, Taichung, 406, Taiwan
| | - Ming-Huei Lee
- General Education Center, Central Taiwan University of Science and Technology, Taichung, 406, Taiwan
- Department of Urology, Feng-Yuan Hospital, Ministry of Health and Welfare, Executive Yuan, Taichung, 420, Taiwan
| | - Ju-Hwa Lin
- Department of Biological Science and Technology, China Medical University, Taichung, 404, Taiwan
| | - Meng-Liang Lin
- Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung, Taiwan
| | - Fu-Shin Chueh
- Department of Health and Nutrition Biotechnology, Asia University, Taichung, 413, Taiwan
| | - Chien-Chih Yu
- School of Pharmacy, China Medical University, Taichung, 404, Taiwan
| | - Jing-Pin Lin
- School of Chinese Medicine, China Medical University, Taichung, 404, Taiwan
| | - Yu-Cheng Chou
- Division of Neurosurgical Oncology, Neurological Institute, Taichung Veterans General Hospital, Taichung, 407, Taiwan
- Institute of Medical Sciences, Tzu Chi University, Hualien, 970, Taiwan
| | - Shu-Chun Hsu
- Department of Biological Science and Technology, China Medical University, Taichung, 404, Taiwan
| | - Jing-Gung Chung
- Department of Biological Science and Technology, China Medical University, Taichung, 404, Taiwan
- Department of Biotechnology, Asia University, Taichung, 413, Taiwan
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Shiue YW, Lu CC, Hsiao YP, Liao CL, Lin JP, Lai KC, Yu CC, Huang YP, Ho HC, Chung JG. Casticin Induced Apoptosis in A375.S2 Human Melanoma Cells through the Inhibition of NF-[Formula: see text]B and Mitochondria-Dependent Pathways In Vitro and Inhibited Human Melanoma Xenografts in a Mouse Model In Vivo. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2016; 44:637-61. [PMID: 27109154 DOI: 10.1142/s0192415x1650035x] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Casticin, a polymethoxyflavone occurring in natural plants, has been shown to have anticancer activities. In the present study, we aims to investigate the anti-skin cancer activity of casticin on melanoma cells in vitro and the antitumor effect of casticin on human melanoma xenografts in nu/nu mice in vivo. A flow cytometric assay was performed to detect expression of viable cells, cell cycles, reactive oxygen species production, levels of [Formula: see text] and caspase activity. A Western blotting assay and confocal laser microscope examination were performed to detect expression of protein levels. In the in vitro studies, we found that casticin induced morphological cell changes and DNA condensation and damage, decreased the total viable cells, and induced G2/M phase arrest. Casticin promoted reactive oxygen species (ROS) production, decreased the level of [Formula: see text], and promoted caspase-3 activities in A375.S2 cells. The induced G2/M phase arrest indicated by the Western blotting assay showed that casticin promoted the expression of p53, p21 and CHK-1 proteins and inhibited the protein levels of Cdc25c, CDK-1, Cyclin A and B. The casticin-induced apoptosis indicated that casticin promoted pro-apoptotic proteins but inhibited anti-apoptotic proteins. These findings also were confirmed by the fact that casticin promoted the release of AIF and Endo G from mitochondria to cytosol. An electrophoretic mobility shift assay (EMSA) assay showed that casticin inhibited the NF-[Formula: see text]B binding DNA and that these effects were time-dependent. In the in vivo studies, results from immuno-deficient nu/nu mice bearing the A375.S2 tumor xenograft indicated that casticin significantly suppressed tumor growth based on tumor size and weight decreases. Early G2/M arrest and mitochondria-dependent signaling contributed to the apoptotic A375.S2 cell demise induced by casticin. In in vivo experiments, A375.S2 also efficaciously suppressed tumor volume in a xenotransplantation model. Therefore, casticin might be a potential therapeutic agent for the treatment of skin cancer in the future.
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Affiliation(s)
- Yin-Wen Shiue
- * Department of Biological Science and Technology, China Medical University Taichung 404, Taiwan
| | - Chi-Cheng Lu
- † School of Nutrition and Health Sciences, Taipei Medical University, Taipei 11031, Taiwan
| | - Yu-Ping Hsiao
- ‡ Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan.,§ Department of Dermatology, Chung Shan Medical University Hospital Taichung 402, Taiwan
| | - Ching-Lung Liao
- ¶ Graduate Institute of Chinese Medicine, China Medical University, Taichung 404, Taiwan
| | - Jing-Pin Lin
- ∥ School of Chinese Medicine, China Medical University, Taichung 404, Taiwan
| | - Kuang-Chi Lai
- ** School of Medicine, China Medical University, Taichung 404, Taiwan.,†† Department of Surgery, China Medical University Beigang Hospital, Yunlin 651, Taiwan
| | - Chien-Chih Yu
- ‡‡ School of Pharmacy, China Medical University, Taichung 404, Taiwan
| | - Yi-Ping Huang
- §§ Department of Physiology, China Medical University, Taichung 404, Taiwan
| | - Heng-Chien Ho
- ** School of Medicine, China Medical University, Taichung 404, Taiwan
| | - Jing-Gung Chung
- * Department of Biological Science and Technology, China Medical University Taichung 404, Taiwan.,¶¶ Department of Biotechnology, Asia University, Taichung 413, Taiwan
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Cazzaniga A, Maier JAM, Castiglioni S. Prednisolone inhibits SaOS2 osteosarcoma cell proliferation by activating inducible nitric oxide synthase. World J Transl Med 2016; 5:53-58. [DOI: 10.5528/wjtm.v5.i1.53] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2015] [Revised: 12/14/2015] [Accepted: 01/31/2016] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effect of prednisolone, a synthetic glucocorticoid used in inflammatory diseases, on the growth of cultured osteosarcoma cells.
METHODS: Two osteosarcoma cell lines with different degree of differentiation were used. SaOS2 show a rather mature phenotype, while U2OS are negative for almost all osteoblastic markers. The cells were exposed to different concentrations of prednisolone (1-9 μmol/L) with or without antioxidants or the inhibitor of inducible nitric oxide synthase (iNOS) l-N6-(iminoethyl)-lysine-HCl (L-NIL). Cell growth was assessed by counting viable cells. The production of nitric oxide (NO) was measured in the conditioned media by the Griess method. The production of reactive oxygen species was quantified using 2’-7’-dichlorofluorescein diacetate. Western blot with specific antibodies against NOSs was performed on cell extracts.
RESULTS: Prednisolone inhibited SaOS2 cell growth in a dose dependent manner. No significant effects were observed in U2OS. The inhibition of SaOS2 growth is not due to oxidative stress, because antioxidants do not rescue cell proliferation. Since high concentrations of NO inhibit bone formation, we also measured NO and found it induced in SaOS2, but not in U2OS, exposed to prednisolone, because of the upregulation of iNOS as detected by western blot. Therefore, we treated SaOS2 with prednisolone in the presence or in the absence of L-NIL. L-NIL prevented NO release induced by prednisolone at all the concentrations apart from 9 μmol/L. At the same concentrations, we found that L-NIL rescued SaOS2 growth after exposure to prednisolone. In U2OS cells, prednisolone did not induce NO production nor affected cell growth. All together, these data indicate that a link exists between increased amounts of NO and growth inhibition in response to prednisolone in SaOS2.
CONCLUSION: Prednisolone inhibited SaOS2 proliferation by increasing the release of NO through the upregulation of iNOS, while no effect was exerted on U2OS.
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