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Islam F, Khan J, Zehravi M, Das R, Haque MA, Banu A, Parwaiz S, Nainu F, Nafady MH, Shahriar SMS, Hossain MJ, Muzammil K, Emran TB. Synergistic effects of carotenoids: Therapeutic benefits on human health. Process Biochem 2024; 136:254-272. [DOI: 10.1016/j.procbio.2023.11.033] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2025]
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Jomova K, Raptova R, Alomar SY, Alwasel SH, Nepovimova E, Kuca K, Valko M. Reactive oxygen species, toxicity, oxidative stress, and antioxidants: chronic diseases and aging. Arch Toxicol 2023; 97:2499-2574. [PMID: 37597078 PMCID: PMC10475008 DOI: 10.1007/s00204-023-03562-9] [Citation(s) in RCA: 665] [Impact Index Per Article: 332.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2023] [Accepted: 07/24/2023] [Indexed: 08/21/2023]
Abstract
A physiological level of oxygen/nitrogen free radicals and non-radical reactive species (collectively known as ROS/RNS) is termed oxidative eustress or "good stress" and is characterized by low to mild levels of oxidants involved in the regulation of various biochemical transformations such as carboxylation, hydroxylation, peroxidation, or modulation of signal transduction pathways such as Nuclear factor-κB (NF-κB), Mitogen-activated protein kinase (MAPK) cascade, phosphoinositide-3-kinase, nuclear factor erythroid 2-related factor 2 (Nrf2) and other processes. Increased levels of ROS/RNS, generated from both endogenous (mitochondria, NADPH oxidases) and/or exogenous sources (radiation, certain drugs, foods, cigarette smoking, pollution) result in a harmful condition termed oxidative stress ("bad stress"). Although it is widely accepted, that many chronic diseases are multifactorial in origin, they share oxidative stress as a common denominator. Here we review the importance of oxidative stress and the mechanisms through which oxidative stress contributes to the pathological states of an organism. Attention is focused on the chemistry of ROS and RNS (e.g. superoxide radical, hydrogen peroxide, hydroxyl radicals, peroxyl radicals, nitric oxide, peroxynitrite), and their role in oxidative damage of DNA, proteins, and membrane lipids. Quantitative and qualitative assessment of oxidative stress biomarkers is also discussed. Oxidative stress contributes to the pathology of cancer, cardiovascular diseases, diabetes, neurological disorders (Alzheimer's and Parkinson's diseases, Down syndrome), psychiatric diseases (depression, schizophrenia, bipolar disorder), renal disease, lung disease (chronic pulmonary obstruction, lung cancer), and aging. The concerted action of antioxidants to ameliorate the harmful effect of oxidative stress is achieved by antioxidant enzymes (Superoxide dismutases-SODs, catalase, glutathione peroxidase-GPx), and small molecular weight antioxidants (vitamins C and E, flavonoids, carotenoids, melatonin, ergothioneine, and others). Perhaps one of the most effective low molecular weight antioxidants is vitamin E, the first line of defense against the peroxidation of lipids. A promising approach appears to be the use of certain antioxidants (e.g. flavonoids), showing weak prooxidant properties that may boost cellular antioxidant systems and thus act as preventive anticancer agents. Redox metal-based enzyme mimetic compounds as potential pharmaceutical interventions and sirtuins as promising therapeutic targets for age-related diseases and anti-aging strategies are discussed.
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Affiliation(s)
- Klaudia Jomova
- Department of Chemistry, Faculty of Natural Sciences, Constantine the Philosopher University in Nitra, Nitra, 949 74, Slovakia
| | - Renata Raptova
- Faculty of Chemical and Food Technology, Slovak University of Technology, Bratislava, 812 37, Slovakia
| | - Suliman Y Alomar
- Zoology Department, College of Science, King Saud University, 11451, Riyadh, Saudi Arabia
| | - Saleh H Alwasel
- Zoology Department, College of Science, King Saud University, 11451, Riyadh, Saudi Arabia
| | - Eugenie Nepovimova
- Department of Chemistry, Faculty of Sciences, University of Hradec Kralove, 50005, Hradec Kralove, Czech Republic
| | - Kamil Kuca
- Department of Chemistry, Faculty of Sciences, University of Hradec Kralove, 50005, Hradec Kralove, Czech Republic
| | - Marian Valko
- Faculty of Chemical and Food Technology, Slovak University of Technology, Bratislava, 812 37, Slovakia.
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The Anti-Cancer Activity of Lycopene: A Systematic Review of Human and Animal Studies. Nutrients 2022; 14:nu14235152. [PMID: 36501182 PMCID: PMC9741066 DOI: 10.3390/nu14235152] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 11/25/2022] [Accepted: 11/29/2022] [Indexed: 12/10/2022] Open
Abstract
Lycopene is a nutraceutical with health-promoting and anti-cancer activities, but due to a lack of evidence, there are no recommendations regarding its use and dosage. This review aimed to evaluate the benefits of lycopene supplementation in cancer prevention and treatment based on the results of in vivo studies. We identified 72 human and animal studies that were then analysed for endpoints such as cancer incidence, improvement in treatment outcomes, and the mechanisms of lycopene action. We concluded that the results of most of the reviewed in vivo studies confirmed the anti-cancer activities of lycopene. Most of the studies concerned prostate cancer, reflecting the number of in vitro studies. The reported mechanisms of lycopene action in vivo included regulation of oxidative and inflammatory processes, induction of apoptosis, and inhibition of cell division, angiogenesis, and metastasis formation. The predominance of particular mechanisms seemed to depend on tumour organ localisation and the local storage capacity of lycopene. Finally, there is a need to look for predictive factors to identify a population that may benefit from lycopene supplementation. The potential candidates appear to be race, single nucleotide polymorphisms in carotene-cleaving enzymes, some genetic abbreviations, and insulin-like growth factor-dependent and inflammatory diseases.
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Song X, Luo Y, Ma L, Hu X, Simal-Gandara J, Wang LS, Bajpai VK, Xiao J, Chen F. Recent trends and advances in the epidemiology, synergism, and delivery system of lycopene as an anti-cancer agent. Semin Cancer Biol 2021; 73:331-346. [PMID: 33794344 DOI: 10.1016/j.semcancer.2021.03.028] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 03/20/2021] [Accepted: 03/22/2021] [Indexed: 02/07/2023]
Abstract
Dietary interventions are key nutritional strategies to prevent, improve, and prolong the survival of cancer patients. Lycopene, one of the strongest natural antioxidants, and its biologically active metabolites, have shown significant potential to prevent a variety of cancers, including prostate, breast, and stomach cancers, making it a promising anti-cancer agent. We review the potential regulatory mechanisms and epidemiological evidences of lycopene and its metabolites to delay the progression of cancers at different developmental stages. Recent studies have revealed that lycopene and its metabolites mediate multiple molecular mechanisms in cancer treatment such as redox homeostasis, selective anti-proliferation, apoptosis, anti-angiogenesis, tumour microenvironment regulation, and anti-metastasis and anti-invasion. Gut microbes and cholesterol metabolism are also the potential regulation targets of lycopene and its metabolites. As a dietary supplement, the synergistic interaction of lycopene with other drugs and nutrients is highlighted especially due to its binding activity with other nutrients in the diet found central to the fight against cancer. Furthermore, the application of several of novel lycopene delivery carriers are on the rise including nanoemulsions, nanostructured liposomes, and polymer nanoparticles for cancer prevention as discussed in this review with future needed development. Moreover, the synergistic mechanism between lycopene and other nutrients or drugs and novel delivery systems of lycopene should now be deeply investigated to improve its clinical application in cancer intervention in the future.
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Affiliation(s)
- Xunyu Song
- College of Food Science and Nutritional Engineering, National Engineering Research Centre for Fruit and Vegetable Processing, Key Laboratory of Fruits and Vegetables Processing, Ministry of Agriculture, Engineering Research Centre for Fruits and Vegetables Processing, Ministry of Education, China Agricultural University, Beijing 100083, China
| | - Yinghua Luo
- College of Food Science and Nutritional Engineering, National Engineering Research Centre for Fruit and Vegetable Processing, Key Laboratory of Fruits and Vegetables Processing, Ministry of Agriculture, Engineering Research Centre for Fruits and Vegetables Processing, Ministry of Education, China Agricultural University, Beijing 100083, China
| | - Lingjun Ma
- College of Food Science and Nutritional Engineering, National Engineering Research Centre for Fruit and Vegetable Processing, Key Laboratory of Fruits and Vegetables Processing, Ministry of Agriculture, Engineering Research Centre for Fruits and Vegetables Processing, Ministry of Education, China Agricultural University, Beijing 100083, China
| | - Xiaosong Hu
- College of Food Science and Nutritional Engineering, National Engineering Research Centre for Fruit and Vegetable Processing, Key Laboratory of Fruits and Vegetables Processing, Ministry of Agriculture, Engineering Research Centre for Fruits and Vegetables Processing, Ministry of Education, China Agricultural University, Beijing 100083, China
| | - Jesus Simal-Gandara
- Nutrition and Bromatology Group, Department of Analytical Chemistry and Food Science, Faculty of Food Science and Technology, University of Vigo - Ourense Campus, E-32004 Ourense, Spain
| | - Li-Shu Wang
- Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Vivek K Bajpai
- Department of Energy and Materials Engineering, Dongguk University, 30 Pildong-ro 1-gil, Seoul 04620, Republic of Korea
| | - Jianbo Xiao
- Nutrition and Bromatology Group, Department of Analytical Chemistry and Food Science, Faculty of Food Science and Technology, University of Vigo - Ourense Campus, E-32004 Ourense, Spain.
| | - Fang Chen
- College of Food Science and Nutritional Engineering, National Engineering Research Centre for Fruit and Vegetable Processing, Key Laboratory of Fruits and Vegetables Processing, Ministry of Agriculture, Engineering Research Centre for Fruits and Vegetables Processing, Ministry of Education, China Agricultural University, Beijing 100083, China.
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Tao A, Wang X, Li C. Effect of Lycopene on Oral Squamous Cell Carcinoma Cell Growth by Inhibiting IGF1 Pathway. Cancer Manag Res 2021; 13:723-732. [PMID: 33531840 PMCID: PMC7847369 DOI: 10.2147/cmar.s283927] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Accepted: 01/05/2021] [Indexed: 12/23/2022] Open
Abstract
Purpose Lycopene has produced robust clinical effects and shows a promising chemopreventive in the oral cancer and precancerous lesions. However, much is still unknown about its mechanisms of the carotenoid in protecting against oral squamous cell carcinoma (OSCC). Insulin-like growth factor 1 (IGF1) pathway serves as a key regulatory signal pathway in the tumor microenvironment, which may be associated with the angiogenesis, tumorigenicity, and cancer proliferation. The current study was focused on elucidating the potential pathway played for lycopene to exert its function in treating with OSCC. Materials and Methods Firstly, we explored the dose- and time-response of CAL-27 and WSU-HN6 cells to lycopene. Both cells were incubated with various concentrations of lycopene (0.25, 0.5, 1, 2 µM). The inhibiting rate of cell proliferation was assessed using MTT assay. To observe the regulating effect of lycopene on OSCC, cell migration, apoptosis and tumor formation were detected in vitro and in vivo. The potential signaling pathways of OSCC cells treated with lycopene were analyzed by Affymetrix microarrays. And then, we investigated the changing of IGF1 signaling pathway, on the protein levels of tumor tissue after lycopene. Results Cell proliferation was inhibited by lycopene in a dose- and time-dependent manner. The optimum inhibition efficiencies for OSCC cells were also found. Further, the results also demonstrated that pre-treatment of OSCC with lycopene drastically induced cell apoptosis suppresses cell migration and tumor growth. Mechanistically, ingenuity pathway analysis further revealed that IGF1 pathway participate in killing effects on OSCC after treatment of lycopene. Lycopene may inhibit the pathway by regulating protein expression of IGF1, IGF binding protein (BP) 1, IGFBP3, transcription factor Jun/AP-1 (JUN), and forkhead box O1 (FOXO1). Conclusion These observations indicate that lycopene regulates OSCC cell growth by inhibiting IGF1 pathway, which may be a promising agent for the treatment of OSCC.
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Affiliation(s)
- Anqi Tao
- Central Laboratory, Peking University School and Hospital of Stomatology, Beijing 100081, People's Republic of China
| | - Xing Wang
- Department of Stomatology, Chinese PLA General Hospital, Beijing 100853, People's Republic of China
| | - Cuiying Li
- Central Laboratory, Peking University School and Hospital of Stomatology, Beijing 100081, People's Republic of China
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Koul A, Bansal MP, Aniqa A, Chaudhary H, Chugh NA. Lycopene enriched tomato extract suppresses chemically induced skin tumorigenesis in mice. INT J VITAM NUTR RES 2020; 90:493-513. [DOI: 10.1024/0300-9831/a000597] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Abstract. The present study revealed the effects of Lycopene enriched tomato extract (LycT) on chemically induced skin cancer in mice. Skin tumors were induced by topical application of 7,12-Dimethylbenz(a)anthracene (DMBA) [500 nmol/100 ul of acetone, twice a week for two weeks] and 12-O-tetradecanoyl phorbol-13-acetate (TPA) [1.7 nmol/100 ul of acetone, twice a week for eighteen weeks] and LycT (5 mg/kg b.w.) was administered orally. Male Balb/c mice were divided into four groups (n = 15 per group): control, DMBA/TPA, LycT and LycT + DMBA/TPA. The chemopreventive response of LycT to skin tumorigenesis was evident by inhibition in tumor incidence, number, size, burden and volume in LycT + DMBA/TPA group when compared to DMBA/TPA group. This was associated with inhibition of cell proliferation in LycT + DMBA/TPA group as observed by the decrease in epidermal morphometric parameters and mRNA and protein expression of proliferating cell nuclear antigen when compared to DMBA/TPA group (p ≤ 0.05). LycT decreased (p ≤ 0.05) the mRNA and protein expression of angiogenic genes (vascular endothelial growth factor, angiopoietin-2, basic fibroblast growth factor) in LycT + DMBA/TPA group, suggesting its anti-angiogenic effects. The increase (p ≤ 0.05) in protein expression of connexin-32 and 43 in LycT + DMBA/TPA group suggests improved inter cellular communication when compared to DMBA/TPA group. Histochemical studies demonstrated that the components of extracellular matrix (fibrous proteins and mucopolysaccharides) were also modulated during skin carcinogenesis and its chemoprevention by LycT. The decrease in cell proliferation parameters and expression of angiogenesis associated genes, modulation of ECM components and increase in expression of connexins suggest that LycT improved multiple dysregulated processes during chemoprevention of skin cancer.
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Affiliation(s)
- Ashwani Koul
- Department of Biophysics, Panjab University, Chandigarh, India
| | | | - Aniqa Aniqa
- Department of Biophysics, Panjab University, Chandigarh, India
| | - Harsh Chaudhary
- Department of Biophysics, Panjab University, Chandigarh, India
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Wang R, Lu X, Yu R. Lycopene Inhibits Epithelial-Mesenchymal Transition and Promotes Apoptosis in Oral Cancer via PI3K/AKT/m-TOR Signal Pathway. DRUG DESIGN DEVELOPMENT AND THERAPY 2020; 14:2461-2471. [PMID: 32606612 PMCID: PMC7321693 DOI: 10.2147/dddt.s251614] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Accepted: 06/10/2020] [Indexed: 12/11/2022]
Abstract
Background Oral cancer (OC) is one of the most common cancers around the world. Despite the progress in treatment, the prognosis of OC remains poor, especially for patients with advanced diseases. It urges the development of novel therapeutic options against OC. Lycopene (LYC) is an antioxidant with chemoprotective properties against cancer. However, little is known about the mechanisms underlying the protective role of LYC in OC tumorigenesis. Methods In this study, we investigated the anti-cancer effect of LYC on the progression of OC in vitro and in vivo and explored the underlying mechanisms involved in this process. Results LYC inhibited OC cell proliferation, migration, invasion, apoptosis, and xenograft tumor growth in a dose-dependent manner. Furthermore, we found that LYC might inhibit epithelial-mesenchymal transition and induce apoptosis in OC cells by deactivating the PI3K/AKT/m-TOR signaling through increasing the levels of E-cadherin and Bax and downregulating N-cadherin, p-PI3K, p-AKT, p-m-TOR, and bcl-2. Conclusion We reported for the first time that LYC exhibited anti-cancer effects on OC development both in vitro and in vivo via regulating EMT process and apoptosis. These findings provide support for the potential clinical use of LYC in OC treatment.
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Affiliation(s)
- Ran Wang
- Department of Stomatology, Beijing Shijitan Hospital, Capital Medical University, Beijing, People's Republic of China
| | - Xinxing Lu
- Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, People's Republic of China
| | - Riyue Yu
- Department of Stomatology, Beijing Shijitan Hospital, Capital Medical University, Beijing, People's Republic of China
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Liang X, Ma C, Yan X, Liu X, Liu F. Advances in research on bioactivity, metabolism, stability and delivery systems of lycopene. Trends Food Sci Technol 2019. [DOI: 10.1016/j.tifs.2019.08.019] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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Yao AJ, Chen JH, Xu Y, Zhang ZW, Zou ZQ, Yang HT, Hua QH, Zhao JS, Kang JX, Zhang XH. Endogenous n-3 polyunsaturated fatty acids prevent azoxymethane-induced colon tumorigenesis in mice fed a high-fat diet. J Funct Foods 2018. [DOI: 10.1016/j.jff.2018.07.042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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Sahin K, Yenice E, Tuzcu M, Orhan C, Mizrak C, Ozercan IH, Sahin N, Yilmaz B, Bilir B, Ozpolat B, Kucuk O. Lycopene Protects Against Spontaneous Ovarian Cancer Formation in Laying Hens. J Cancer Prev 2018; 23:25-36. [PMID: 29629346 PMCID: PMC5886492 DOI: 10.15430/jcp.2018.23.1.25] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2018] [Revised: 03/09/2018] [Accepted: 03/09/2018] [Indexed: 12/16/2022] Open
Abstract
Background Dietary intake of lycopene has been associated with a reduced risk of ovarian cancer, suggesting its chemopreventive potential against ovarian carcinogenesis. Lycopene's molecular mechanisms of action in ovarian cancer have not been fully understood. Therefore, in the present study, we investigated the effects of lycopene on the ovarian cancer formation using the laying hen model, a biologically relevant animal model of spontaneous ovarian carcinogenesis due to high incidence rates similar to humans. Methods In this study, a total of 150 laying hens at age of 102 weeks were randomized into groups of 50: a control group (0 mg of lycopene per kg of diet) and two treatment groups (200 mg or 400 mg of lycopene per kg of diet, or ~26 and 52 mg/d/hen, respectively). At the end of 12 months, blood, ovarian tissues and tumors were collected. Results We observed that lycopene supplementation significantly reduced the overall ovarian tumor incidence (P < 0.01) as well as the number and the size of the tumors (P < 0.004 and P < 0.005, respectively). Lycopene also significantly decreased the rate of adenocarcinoma, including serous and mucinous subtypes (P < 0.006). Moreover, we also found that the serum level of oxidative stress marker malondialdehyde was significantly lower in lycopene-fed hens compared to control birds (P < 0.001). Molecular analysis of the ovarian tumors revealed that lycopene reduced the expression of NF-κB while increasing the expression of nuclear factor erythroid 2 and its major target protein, heme oxygenase 1. In addition, lycopene supplementation decreased the expression of STAT3 by inducing the protein inhibitor of activated STAT3 expression in the ovarian tissues. Conclusions Taken together, our findings strongly support the potential of lycopene in the chemoprevention of ovarian cancer through antioxidant and anti-inflammatory mechanisms.
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Affiliation(s)
- Kazim Sahin
- Department of Animal Nutrition, Faculty of Veterinary Science, Firat University, Elazig, Turkey
| | | | - Mehmet Tuzcu
- Division of Biology, Faculty of Science, Firat University, Elazig, Turkey
| | - Cemal Orhan
- Department of Animal Nutrition, Faculty of Veterinary Science, Firat University, Elazig, Turkey
| | | | - Ibrahim H Ozercan
- Department of Pathology, Faculty of Medicine, Firat University, Elazig, Turkey
| | - Nurhan Sahin
- Department of Animal Nutrition, Faculty of Veterinary Science, Firat University, Elazig, Turkey
| | - Bahiddin Yilmaz
- Winship Cancer Institute of Emory University, Atlanta, GA, USA
| | - Birdal Bilir
- Winship Cancer Institute of Emory University, Atlanta, GA, USA
| | - Bulent Ozpolat
- Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Omer Kucuk
- Winship Cancer Institute of Emory University, Atlanta, GA, USA
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Desai SJ, Prickril B, Rasooly A. Mechanisms of Phytonutrient Modulation of Cyclooxygenase-2 (COX-2) and Inflammation Related to Cancer. Nutr Cancer 2018; 70:350-375. [PMID: 29578814 DOI: 10.1080/01635581.2018.1446091] [Citation(s) in RCA: 153] [Impact Index Per Article: 21.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The link between chronic inflammation and cancer involves cytokines and mediators of inflammatory pathways. Cyclooxygenase-2 (COX-2), a key enzyme in fatty acid metabolism, is upregulated during both inflammation and cancer. COX-2 is induced by pro-inflammatory cytokines at the site of inflammation and enhanced COX-2-induced synthesis of prostaglandins stimulates cancer cell proliferation, promotes angiogenesis, inhibits apoptosis, and increases metastatic potential. As a result, COX-2 inhibitors are a subject of intense research interest toward potential clinical applications. Epidemiological studies highlight the potential benefits of diets rich in phytonutrients for cancer prevention. Plants contain numerous phytonutrient secondary metabolites shown to modulate COX-2. Studies have shown that these metabolites, some of which are used in traditional medicine, can reduce inflammation and carcinogenesis. This review describes the molecular mechanisms by which phytonutrients modulate inflammation, including studies of carotenoids, phenolic compounds, and fatty acids targeting various inflammation-related molecules and pathways associated with cancer. Examples of pathways include those of COX-2, mitogen-activated protein kinase kinase kinase, mitogen-activated protein kinase, pro-inflammatory cytokines, and transcription factors like nuclear factor kappa B. Such phytonutrient modulation of COX-2 and inflammation continue to be explored for applications in the prevention and treatment of cancer.
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Affiliation(s)
- Shreena J Desai
- a Office of Cancer Complementary and Alternative Medicine , National Cancer Institute , Rockville , Maryland , USA
| | - Ben Prickril
- a Office of Cancer Complementary and Alternative Medicine , National Cancer Institute , Rockville , Maryland , USA
| | - Avraham Rasooly
- a Office of Cancer Complementary and Alternative Medicine , National Cancer Institute , Rockville , Maryland , USA
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Apo-10'-lycopenoic acid inhibits cancer cell migration and angiogenesis and induces peroxisome proliferator-activated receptor γ. J Nutr Biochem 2018; 56:26-34. [PMID: 29454996 DOI: 10.1016/j.jnutbio.2018.01.003] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2017] [Revised: 12/21/2017] [Accepted: 01/11/2018] [Indexed: 12/13/2022]
Abstract
SCOPE We have previously shown that apo-10'-lycopenoic acid (ALA), a derivative of lycopene through cleavage by carotene-9',10'-oxygenase, inhibits tumor progression and metastasis in both liver and lung cancer animal models. The underlying mechanism remains unknown. We hypothesized that ALA inhibits cancer cell motility and angiogenesis by up-regulating peroxisome proliferator-activated receptor γ (PPARγ) which is involved in controlling angiogenesis, tumor progression and metastasis. METHODS AND RESULTS ALA treatment, in dose-dependent manner, was effective at inhibiting migration and invasion of liver and lung cancer cells (HuH7 and A549) in both Transwell and wound-healing models, as well as suppressing actin remodeling and ruffling/lamellipodia formation in HuH7 and immortalized lung BEAS-2B cells. ALA treatment resulted in suppression of angiogenesis in both tube formation and aortic ring assays and inhibition of matrix metalloproteinase-2 expression and activation in both HuH7 and A549 cells. Additionally, ALA dose-dependently increased the mRNA expression and protein levels of PPARγ in human THLE-2 liver cells. CONCLUSION ALA inhibits cancer cell motility and angiogenesis and induces PPARγ expression, which could be one of the potential mechanisms for ALA protecting against tumor progression.
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Bansal M, Singh N, Pal S, Dev I, Ansari KM. Chemopreventive Role of Dietary Phytochemicals in Colorectal Cancer. ADVANCES IN MOLECULAR TOXICOLOGY 2018. [DOI: 10.1016/b978-0-444-64199-1.00004-x] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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Mouhid L, Corzo-Martínez M, Torres C, Vázquez L, Reglero G, Fornari T, Ramírez de Molina A. Improving In Vivo Efficacy of Bioactive Molecules: An Overview of Potentially Antitumor Phytochemicals and Currently Available Lipid-Based Delivery Systems. JOURNAL OF ONCOLOGY 2017; 2017:7351976. [PMID: 28555156 PMCID: PMC5438845 DOI: 10.1155/2017/7351976] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/29/2016] [Accepted: 03/06/2017] [Indexed: 02/07/2023]
Abstract
Cancer is among the leading causes of morbidity and mortality worldwide. Many of the chemotherapeutic agents used in cancer treatment exhibit cell toxicity and display teratogenic effect on nontumor cells. Therefore, the search for alternative compounds which are effective against tumor cells but reduce toxicity against nontumor ones is of great importance in the progress or development of cancer treatments. In this sense, scientific knowledge about relevant aspects of nutrition intimately involved in the development and progression of cancer progresses rapidly. Phytochemicals, considered as bioactive ingredients present in plant products, have shown promising effects as potential therapeutic/preventive agents on cancer in several in vitro and in vivo assays. However, despite their bioactive properties, phytochemicals are still not commonly used in clinical practice due to several reasons, mainly attributed to their poor bioavailability. In this sense, new formulation strategies are proposed as carriers to improve their bioefficacy, highlighting the use of lipid-based delivery systems. Here, we review the potential antitumoral activity of the bioactive compounds derived from plants and the current studies carried out in animal and human models. Furthermore, their association with lipids as a formulation strategy to enhance their efficacy in vivo is also reported. The development of high effective bioactive supplements for cancer treatment based on the improvement of their bioavailability goes through this association.
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Affiliation(s)
- Lamia Mouhid
- Molecular Oncology and Nutritional Genomics of Cancer, IMDEA Food Institute, CEI UAM+CSIC, Madrid, Spain
| | - Marta Corzo-Martínez
- Department of Production and Characterization of Novel Foods, Institute of Food Science Research (CIAL), Campus of International Excellence (CEI) UAM+CSIC, 28049 Madrid, Spain
| | - Carlos Torres
- Department of Production and Characterization of Novel Foods, Institute of Food Science Research (CIAL), Campus of International Excellence (CEI) UAM+CSIC, 28049 Madrid, Spain
| | - Luis Vázquez
- Department of Production and Characterization of Novel Foods, Institute of Food Science Research (CIAL), Campus of International Excellence (CEI) UAM+CSIC, 28049 Madrid, Spain
| | - Guillermo Reglero
- Molecular Oncology and Nutritional Genomics of Cancer, IMDEA Food Institute, CEI UAM+CSIC, Madrid, Spain
- Department of Production and Characterization of Novel Foods, Institute of Food Science Research (CIAL), Campus of International Excellence (CEI) UAM+CSIC, 28049 Madrid, Spain
| | - Tiziana Fornari
- Department of Production and Characterization of Novel Foods, Institute of Food Science Research (CIAL), Campus of International Excellence (CEI) UAM+CSIC, 28049 Madrid, Spain
| | - Ana Ramírez de Molina
- Molecular Oncology and Nutritional Genomics of Cancer, IMDEA Food Institute, CEI UAM+CSIC, Madrid, Spain
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The regulatory effects of fish oil and chitosan on hepatic lipogenic signals in high-fat diet-induced obese rats. J Food Drug Anal 2017; 25:919-930. [PMID: 28987369 PMCID: PMC9328862 DOI: 10.1016/j.jfda.2016.11.015] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2016] [Revised: 11/15/2016] [Accepted: 11/22/2016] [Indexed: 12/20/2022] Open
Abstract
The present study investigated the regulatory effects of fish oil and chitosan on the signals of hepatic lipid metabolism and the postulated mechanism in high-fat diet-induced obese rats. Diet supplementation of chitosan and fish oil efficiently suppressed the increased weights in body and livers of high-fat diet-fed rats. Supplementation of chitosan and fish oil significantly decreased the activities of hepatic lipid biosynthesis-related enzymes and efficiently regulated plasma lipoprotein homeostasis. Both chitosan and fish oil significantly ameliorated the alterations in the protein expressions of hepatic lipogenic transcription factors (LXRα and PPARα), and could also significantly regulate the downstream hepatic lipogenic genes (FAS, HMGCR, CYP7A1, FATP, FABP, AOX, and ABCA) expressions in high-fat diet-fed rats. These results suggest that both fish oil and chitosan exerts downregulative effects on hepatic lipid metabolism in high-fat diet-induced obese rats via the LXRα inhibition and PPARα activation, which further affect the expressions of hepatic lipogenesis-associated genes.
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Li XN, Lin J, Xia J, Qin L, Zhu SY, Li JL. Lycopene mitigates atrazine-induced cardiac inflammation via blocking the NF-κB pathway and NO production. J Funct Foods 2017. [DOI: 10.1016/j.jff.2016.12.029] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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Yarla NS, Bishayee A, Sethi G, Reddanna P, Kalle AM, Dhananjaya BL, Dowluru KSVGK, Chintala R, Duddukuri GR. Targeting arachidonic acid pathway by natural products for cancer prevention and therapy. Semin Cancer Biol 2016; 40-41:48-81. [PMID: 26853158 DOI: 10.1016/j.semcancer.2016.02.001] [Citation(s) in RCA: 250] [Impact Index Per Article: 27.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2015] [Revised: 01/23/2016] [Accepted: 02/01/2016] [Indexed: 12/16/2022]
Abstract
Arachidonic acid (AA) pathway, a metabolic process, plays a key role in carcinogenesis. Hence, AA pathway metabolic enzymes phospholipase A2s (PLA2s), cyclooxygenases (COXs) and lipoxygenases (LOXs) and their metabolic products, such as prostaglandins and leukotrienes, have been considered novel preventive and therapeutic targets in cancer. Bioactive natural products are a good source for development of novel cancer preventive and therapeutic drugs, which have been widely used in clinical practice due to their safety profiles. AA pathway inhibitory natural products have been developed as chemopreventive and therapeutic agents against several cancers. Curcumin, resveratrol, apigenin, anthocyans, berberine, ellagic acid, eugenol, fisetin, ursolic acid, [6]-gingerol, guggulsteone, lycopene and genistein are well known cancer chemopreventive agents which act by targeting multiple pathways, including COX-2. Nordihydroguaiaretic acid and baicalein can be chemopreventive molecules against various cancers by inhibiting LOXs. Several PLA2s inhibitory natural products have been identified with chemopreventive and therapeutic potentials against various cancers. In this review, we critically discuss the possible utility of natural products as preventive and therapeutic agents against various oncologic diseases, including prostate, pancreatic, lung, skin, gastric, oral, blood, head and neck, colorectal, liver, cervical and breast cancers, by targeting AA pathway. Further, the current status of clinical studies evaluating AA pathway inhibitory natural products in cancer is reviewed. In addition, various emerging issues, including bioavailability, toxicity and explorability of combination therapy, for the development of AA pathway inhibitory natural products as chemopreventive and therapeutic agents against human malignancy are also discussed.
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Affiliation(s)
- Nagendra Sastry Yarla
- Department of Biochemisty/Bionformatics, Institute of Science, GITAM University, Rushikonda, Visakhapatnam 530 045, Adhra Pradesh, India
| | - Anupam Bishayee
- Department of Pharmaceutical Sciences, College of Pharmacy, Larkin Health Sciences Institute, 18301 N. Miami Avenue, Miami, FL 33169, USA.
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore; School of Biomedical Sciences, Curtin Health Innovation Research Institute, Biosciences Research Precinct, Curtin University, Western Australia 6009, Australia
| | - Pallu Reddanna
- Department of Animal Biology, School of Life Sciences, University of Hyderabad, Gachibowli, Hyderabad 500 046, Telagana, India
| | - Arunasree M Kalle
- Department of Animal Biology, School of Life Sciences, University of Hyderabad, Gachibowli, Hyderabad 500 046, Telagana, India; Department of Environmental Health Sciences, Laboratory of Human Environmental Epigenomes, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA
| | - Bhadrapura Lakkappa Dhananjaya
- Toxinology/Toxicology and Drug Discovery Unit, Center for Emerging Technologies, Jain Global Campus, Jain University, Kanakapura Taluk, Ramanagara 562 112, Karnataka, India
| | - Kaladhar S V G K Dowluru
- Department of Biochemisty/Bionformatics, Institute of Science, GITAM University, Rushikonda, Visakhapatnam 530 045, Adhra Pradesh, India; Department of Microbiology and Bioinformatics, Bilaspur University, Bilaspur 495 001, Chhattisgarh, India
| | - Ramakrishna Chintala
- Department of Environmental Sciences, Institute of Science, GITAM University, Rushikonda, Visakhapatnam 530 045, Adhra Pradesh, India
| | - Govinda Rao Duddukuri
- Department of Biochemisty/Bionformatics, Institute of Science, GITAM University, Rushikonda, Visakhapatnam 530 045, Adhra Pradesh, India.
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Huang RFS, Wei YJ, Inbaraj BS, Chen BH. Inhibition of colon cancer cell growth by nanoemulsion carrying gold nanoparticles and lycopene. Int J Nanomedicine 2015; 10:2823-2846. [PMID: 25914533 PMCID: PMC4399598 DOI: 10.2147/ijn.s79107] [Citation(s) in RCA: 30] [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] [Indexed: 12/22/2022] Open
Abstract
Lycopene (LP), an important functional compound in tomatoes, and gold nanoparticles (AN), have received considerable attention as potential candidates for cancer therapy. However, the extreme instability and poor bioavailability of LP limits its in vivo application. This study intends to develop a nanoemulsion system incorporating both LP and AN, and to study the possible synergistic effects on the inhibition of the HT-29 colon cancer cell line. LP-nanogold nanoemulsion containing Tween 80 as an emulsifier was prepared, followed by characterization using transmission electron microscopy (TEM), dynamic light scattering (DLS) analysis, ultraviolet spectroscopy, and zeta potential analysis. The particle size as determined by TEM and DLS was 21.3±3.7 nm and 25.0±4.2 nm for nanoemulsion and 4.7±1.1 nm and 3.3±0.6 nm for AN, while the zeta potential of nanoemulsion and AN was -32.2±1.8 mV and -48.5±2.7 mV, respectively. Compared with the control treatment, both the combo (AN 10 ppm plus LP 12 μM) and nanoemulsion (AN 0.16 ppm plus LP 0.4 μM) treatments resulted in a five- and 15-fold rise in early apoptotic cells of HT-29, respectively. Also, the nanoemulsion significantly reduced the expressions of procaspases 8, 3, and 9, as well as PARP-1 and Bcl-2, while Bax expression was enhanced. A fivefold decline in the migration capability of HT-29 cells was observed for this nanoemulsion when compared to control, with the invasion-associated markers being significantly reversed through the upregulation of the epithelial marker E-cadherin and downregulation of Akt, nuclear factor kappa B, pro-matrix metalloproteinase (MMP)-2, and active MMP-9 expressions. The TEM images revealed that numerous nanoemulsion-filled vacuoles invaded cytosol and converged into the mitochondria, resulting in an abnormally elongated morphology with reduced cristae and matrix contents, demonstrating a possible passive targeting effect. The nanoemulsion containing vacuoles were engulfed and internalized by the nuclear membrane envelop for subsequent invasion into the nucleoli. Taken together, LP-nanogold nanoemulsion could provide synergistic effects at AN and LP doses 250 and 120 times lower than that in the combo treatment, respectively, demonstrating the potential of nanoemulsion developed in this study for a possible application in colon cancer therapy.
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Affiliation(s)
- Rwei-Fen S Huang
- Graduate Institute of Nutrition and Food Science, Fu Jen University, Taipei, Taiwan
- Department of Nutritional Science, Fu Jen University, Taipei, Taiwan
| | - Yi-Jun Wei
- Graduate Institute of Nutrition and Food Science, Fu Jen University, Taipei, Taiwan
- Department of Nutritional Science, Fu Jen University, Taipei, Taiwan
| | | | - Bing-Huei Chen
- Graduate Institute of Nutrition and Food Science, Fu Jen University, Taipei, Taiwan
- Department of Food Science, Fu Jen University, Taipei, Taiwan
- Graduate Institute of Medicine, Fu Jen University, Taipei, Taiwan
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Woo JK, Kang JH, Jang YS, Ro S, Cho JM, Kim HM, Lee SJ, Oh SH. Evaluation of preventive and therapeutic activity of novel non-steroidal anti-inflammatory drug, CG100649, in colon cancer: Increased expression of TNF-related apoptosis-inducing ligand receptors enhance the apoptotic response to combination treatment with TRAIL. Oncol Rep 2015; 33:1947-55. [PMID: 25672292 DOI: 10.3892/or.2015.3793] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2014] [Accepted: 01/23/2015] [Indexed: 11/05/2022] Open
Abstract
Non-steroidal anti-inflammatory drugs (NSAIDs) have been suggested as the potential new class of preventive or therapeutic antitumor agents. The aim of the present study was to evaluate the antitumor activity of the novel NSAID, CG100649. CG100649 is a novel NSAID dual inhibitor for COX-2 and carbonic anhydrase (CA)-I/-II. In the present study, we investigated the alternative mechanism by which CG100649 mediated suppression of the colon cancer growth and development. The anchorage‑dependent and -independent clonogenic assay showed that CG100649 inhibited the clonogenicity of human colon cancer cells. The flow cytometric analysis showed that CG100649 induced the G2/M cell cycle arrest in colon cancer cells. Animal studies showed that CG100649 inhibited the tumor growth in colon cancer xenograft in nude mice. Furthermore, quantitative PCR and FACS analysis demonstrated that CG100649 upregulated the expression of TNF-related apoptosis-inducing ligand (TRAIL) receptors (DR4 and DR5) but decreased the expression of decoy receptors (DcR1 and DcR2) in colon cancer cells. The results showed that CG100649 treatment sensitized TRAIL‑mediated growth suppression and apoptotic cell death. The combination treatment resulted in significant repression of the intestinal polyp formation in APCmin/+ mice. Our data clearly demonstrated that CG100649 contains preventive and therapeutic activity for colon cancer. The present study may be useful for identification of the potential benefit of the NSAID CG100649, for the achievement of a better treatment response in colon cancer.
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Affiliation(s)
- Jong Kyu Woo
- College of Pharmacy, Gachon Institute of Pharmaceutical Science, Gachon University, Incheon 406-840, Republic of Korea
| | - Ju-Hee Kang
- Research Institute, National Cancer Center, Goyang-si, Gyeonggi-do 410-769, Republic of Korea
| | - Yeong-Su Jang
- College of Pharmacy, Gachon Institute of Pharmaceutical Science, Gachon University, Incheon 406-840, Republic of Korea
| | - Seonggu Ro
- Crystal Genomics, Seongnam-si, Gyeonggi-do 463-400, Republic of Korea
| | - Joong Myung Cho
- Crystal Genomics, Seongnam-si, Gyeonggi-do 463-400, Republic of Korea
| | - Hwan-Mook Kim
- College of Pharmacy, Gachon Institute of Pharmaceutical Science, Gachon University, Incheon 406-840, Republic of Korea
| | - Sang-Jin Lee
- Crystal Genomics, Seongnam-si, Gyeonggi-do 463-400, Republic of Korea
| | - Seung Hyun Oh
- College of Pharmacy, Gachon Institute of Pharmaceutical Science, Gachon University, Incheon 406-840, Republic of Korea
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Lv JC, Wang G, Pan SH, Bai XW, Sun B. Lycopene protects pancreatic acinar cells against severe acute pancreatitis by abating the oxidative stress through JNK pathway. Free Radic Res 2014; 49:151-63. [PMID: 25410533 DOI: 10.3109/10715762.2014.988150] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
This study investigated the anti-oxidative and anti-inflammatory effects of lycopene on severe acute pancreatitis (SAP) in both in vivo and in vitro models. Utilizing a rat model, we found that lycopene administration protected against SAP, as indicated by the decreased levels of serum amylase and C-reactive protein. Pathological changes were alleviated by pretreatment with lycopene. The serum levels of tumor necrosis factor-α, interleukin-6, macrophage inflammatory protein-1α, and monocyte chemotactic protein-1 were decreased by lycopene. The decreased reactive oxygen species (ROS) content in the pancreatic tissues of the lycopene-treated group were indirectly evaluated by measuring the levels of myeloperoxidase, lipid peroxidase, and superoxide dismutase. Lycopene protected acinar cells against necrosis and apoptosis by relieving the mitochondrial and endoplasmic stress caused by ROS which was shown in electron microscopy and immunohistochemistry staining of active nuclear factor-κB p65. The protective effect was also observed in a simulated SAP model in a rat acinar cell line. ROS and apoptotic staining were compared between groups. Lycopene exerts protective effects against SAP in rats that may be related to its anti-inflammatory property through inhibiting the expression of damage-associated molecular patterns, and anti-oxidative property which can thus maintain cellular homeostasis and prevent the phosphorylation of JNK pathway.
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Affiliation(s)
- J C Lv
- Department of Pancreatic and Biliary Surgery, the First Affiliated Hospital of Harbin Medical University , Harbin, Heilongjiang , P. R. China
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Verma S, Kesh K, Ganguly N, Jana S, Swarnakar S. Matrix metalloproteinases and gastrointestinal cancers: Impacts of dietary antioxidants. World J Biol Chem 2014; 5:355-376. [PMID: 25225603 PMCID: PMC4160529 DOI: 10.4331/wjbc.v5.i3.355] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2014] [Revised: 05/07/2014] [Accepted: 06/11/2014] [Indexed: 02/05/2023] Open
Abstract
The process of carcinogenesis is tightly regulated by antioxidant enzymes and matrix degrading enzymes, namely, matrix metalloproteinases (MMPs). Degradation of extracellular matrix (ECM) proteins like collagen, proteoglycan, laminin, elastin and fibronectin is considered to be the prerequisite for tumor invasion and metastasis. MMPs can degrade essentially all of the ECM components and, most MMPs also substantially contribute to angiogenesis, differentiation, proliferation and apoptosis. Hence, MMPs are important regulators of tumor growth both at the primary site and in distant metastases; thus the enzymes are considered as important targets for cancer therapy. The implications of MMPs in cancers are no longer mysterious; however, the mechanism of action is yet to be explained. Herein, our major interest is to clarify how MMPs are tied up with gastrointestinal cancers. Gastrointestinal cancer is a variety of cancer types, including the cancers of gastrointestinal tract and organs, i.e., esophagus, stomach, biliary system, pancreas, small intestine, large intestine, rectum and anus. The activity of MMPs is regulated by its endogenous inhibitor tissue inhibitor of metalloproteinase (TIMP) which bind MMPs with a 1:1 stoichiometry. In addition, RECK (reversion including cysteine-rich protein with kazal motifs) is a membrane bound glycoprotein that inhibits MMP-2, -9 and -14. Moreover, α2-macroglobulin mediates the uptake of several MMPs thereby inhibit their activity. Cancerous conditions increase intrinsic reactive oxygen species (ROS) through mitochondrial dysfunction leading to altered protease/anti-protease balance. ROS, an index of oxidative stress is also involved in tumorigenesis by activation of different MAP kinase pathways including MMP induction. Oxidative stress is involved in cancer by changing the activity and expression of regulatory proteins especially MMPs. Epidemiological studies have shown that high intake of fruits that rich in antioxidants is associated with a lower cancer incidence. Evidence indicates that some antioxidants inhibit the growth of malignant cells by inducing apoptosis and inhibiting the activity of MMPs. This review is discussed in six subchapters, as follows.
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Chiang EPI, Tsai SY, Kuo YH, Pai MH, Chiu HL, Rodriguez RL, Tang FY. Caffeic acid derivatives inhibit the growth of colon cancer: involvement of the PI3-K/Akt and AMPK signaling pathways. PLoS One 2014; 9:e99631. [PMID: 24960186 PMCID: PMC4069067 DOI: 10.1371/journal.pone.0099631] [Citation(s) in RCA: 75] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2013] [Accepted: 05/16/2014] [Indexed: 12/27/2022] Open
Abstract
Background The aberrant regulation of phosphatidylinositide 3-kinases (PI3-K)/Akt, AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (m-TOR) signaling pathways in cancer has prompted significant interest in the suppression of these pathways to treat cancer. Caffeic acid (CA) has been reported to possess important anti-inflammatory actions. However, the molecular mechanisms by which CA derivatives including caffeic acid phenethyl ester (CAPE) and caffeic acid phenylpropyl ester (CAPPE), exert inhibitory effects on the proliferation of human colorectal cancer (CRC) cells have yet to be elucidated. Methodology/Principal Findings CAPE and CAPPE were evaluated for their ability to modulate these signaling pathways and suppress the proliferation of CRC cells both in vitro and in vivo. Anti-cancer effects of these CA derivatives were measured by using proliferation assays, cell cycle analysis, western blotting assay, reporter gene assay and immunohistochemical (IHC) staining assays both in vitro and in vivo. This study demonstrates that CAPE and CAPPE exhibit a dose-dependent inhibition of proliferation and survival of CRC cells through the induction of G0/G1 cell cycle arrest and augmentation of apoptotic pathways. Consumption of CAPE and CAPPE significantly inhibited the growth of colorectal tumors in a mouse xenograft model. The mechanisms of action included a modulation of PI3-K/Akt, AMPK and m-TOR signaling cascades both in vitro and in vivo. In conclusion, the results demonstrate novel anti-cancer mechanisms of CA derivatives against the growth of human CRC cells. Conclusions CA derivatives are potent anti-cancer agents that augment AMPK activation and promote apoptosis in human CRC cells. The structure of CA derivatives can be used for the rational design of novel inhibitors that target human CRC cells.
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Affiliation(s)
- En-Pei Isabel Chiang
- Department of Food Science and Biotechnology, National Chung Hsing University, Taichung, Taiwan, Republic of China
- NCHU-UCD Plant and Food Biotechnology Program and Agricultural Biotechnology Center, National Chung Hsing University, Taichung, Taiwan, Republic of China
| | - Shu-Yao Tsai
- Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan, Republic of China
| | - Yueh-Hsiung Kuo
- Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, China Medical University, Taichung, Taiwan, Republic of China
- Department of Biotechnology, Asia University, Taichung, Taiwan, Republic of China
| | - Man-Hui Pai
- Department of Anatomy, Taipei Medical University, Taipei, Taiwan, Republic of China
| | - Hsi-Lin Chiu
- Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, China Medical University, Taichung, Taiwan, Republic of China
- Department of Biotechnology, Asia University, Taichung, Taiwan, Republic of China
| | - Raymond L. Rodriguez
- Department of Molecular and Cellular Biology, University of California Davis, Davis, California, United States of America
| | - Feng-Yao Tang
- Biomedical Science Laboratory, Department of Nutrition, China Medical University, Taichung, Taiwan, Republic of China
- * E-mail:
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Trejo-Solís C, Pedraza-Chaverrí J, Torres-Ramos M, Jiménez-Farfán D, Cruz Salgado A, Serrano-García N, Osorio-Rico L, Sotelo J. Multiple molecular and cellular mechanisms of action of lycopene in cancer inhibition. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2013; 2013:705121. [PMID: 23970935 PMCID: PMC3736525 DOI: 10.1155/2013/705121] [Citation(s) in RCA: 80] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/25/2013] [Revised: 06/05/2013] [Accepted: 06/19/2013] [Indexed: 12/15/2022]
Abstract
Epidemiological studies suggest that including fruits, vegetables, and whole grains in regular dietary intake might prevent and reverse cellular carcinogenesis, reducing the incidence of primary tumours. Bioactive components present in food can simultaneously modulate more than one carcinogenic process, including cancer metabolism, hormonal balance, transcriptional activity, cell-cycle control, apoptosis, inflammation, angiogenesis and metastasis. Some studies have shown an inverse correlation between a diet rich in fruits, vegetables, and carotenoids and a low incidence of different types of cancer. Lycopene, the predominant carotenoid found in tomatoes, exhibits a high antioxidant capacity and has been shown to prevent cancer, as evidenced by clinical trials and studies in cell culture and animal models. In vitro studies have shown that lycopene treatment can selectively arrest cell growth and induce apoptosis in cancer cells without affecting normal cells. In vivo studies have revealed that lycopene treatment inhibits tumour growth in the liver, lung, prostate, breast, and colon. Clinical studies have shown that lycopene protects against prostate cancer. One of the main challenges in cancer prevention is the integration of new molecular findings into clinical practice. Thus, the identification of molecular biomarkers associated with lycopene levels is essential for improving our understanding of the mechanisms underlying its antineoplastic activity.
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Affiliation(s)
- Cristina Trejo-Solís
- Departamentos de Neuroinmunología, Instituto Nacional de Neurología y Neurocirugía (INNN), C.P. 14269, Mexico City, DF, Mexico
| | - Jose Pedraza-Chaverrí
- Neurobiología Molecular y Celular INNN-UNAM, Instituto Nacional de Neurología y Neurocirugía (INNN), C.P. 14269, Mexico City, DF, Mexico
- Facultad de Química, Universidad Nacional Autónoma de México (UNAM), C.P. 04510, Mexico City, DF, Mexico
| | - Mónica Torres-Ramos
- Unidad Periferica de NeuroCiencias INNN-UNAM, Instituto Nacional de Neurología y Neurocirugía (INNN), C.P. 14269, Mexico City, DF, Mexico
| | - Dolores Jiménez-Farfán
- Facultad de Odontología, Universidad Nacional Autónoma de México (UNAM), C.P. 04510, Mexico City, DF, Mexico
| | - Arturo Cruz Salgado
- Facultad de Odontología, Universidad Nacional Autónoma de México (UNAM), C.P. 04510, Mexico City, DF, Mexico
| | - Norma Serrano-García
- Neurobiología Molecular y Celular INNN-UNAM, Instituto Nacional de Neurología y Neurocirugía (INNN), C.P. 14269, Mexico City, DF, Mexico
- Facultad de Química, Universidad Nacional Autónoma de México (UNAM), C.P. 04510, Mexico City, DF, Mexico
| | - Laura Osorio-Rico
- Neuroquimica, Instituto Nacional de Neurología y Neurocirugía (INNN), C.P. 14269, Mexico City, DF, Mexico
| | - Julio Sotelo
- Departamentos de Neuroinmunología, Instituto Nacional de Neurología y Neurocirugía (INNN), C.P. 14269, Mexico City, DF, Mexico
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