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Sharma V, Chaudhary AA, Bawari S, Gupta S, Mishra R, Khan SUD, Ali MAM, Shahid M, Srivastava S, Verma D, Gupta A, Kumar S, Kumar S. Unraveling cancer progression pathways and phytochemical therapeutic strategies for its management. Front Pharmacol 2024; 15:1414790. [PMID: 39246660 PMCID: PMC11377287 DOI: 10.3389/fphar.2024.1414790] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Accepted: 05/09/2024] [Indexed: 09/10/2024] Open
Abstract
Cancer prevention is currently envisioned as a molecular-based approach to prevent carcinogenesis in pre-cancerous stages, i.e., dysplasia and carcinoma in situ. Cancer is the second-leading cause of mortality worldwide, and a more than 61% increase is expected by 2040. A detailed exploration of cancer progression pathways, including the NF-kβ signaling pathway, Wnt-B catenin signaling pathway, JAK-STAT pathway, TNF-α-mediated pathway, MAPK/mTOR pathway, and apoptotic and angiogenic pathways and effector molecules involved in cancer development, has been discussed in the manuscript. Critical evaluation of these effector molecules through molecular approaches using phytomolecules can intersect cancer formation and its metastasis. Manipulation of effector molecules like NF-kβ, SOCS, β-catenin, BAX, BAK, VEGF, STAT, Bcl2, p53, caspases, and CDKs has played an important role in inhibiting tumor growth and its spread. Plant-derived secondary metabolites obtained from natural sources have been extensively studied for their cancer-preventing potential in the last few decades. Eugenol, anethole, capsaicin, sanguinarine, EGCG, 6-gingerol, and resveratrol are some examples of such interesting lead molecules and are mentioned in the manuscript. This work is an attempt to put forward a comprehensive approach to understanding cancer progression pathways and their management using effector herbal molecules. The role of different plant metabolites and their chronic toxicity profiling in modulating cancer development pathways has also been highlighted.
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Affiliation(s)
- Vikas Sharma
- Metro College of Health Sciences and Research, Greater Noida, India
- School of Pharmacy, Sharda University, Greater Noida, India
| | - Anis Ahmad Chaudhary
- Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh, Saudi Arabia
| | - Sweta Bawari
- Amity Institute of Pharmacy, Amity University, Noida, India
| | - Saurabh Gupta
- Department of Biotechnology, GLA University, Mathura, India
| | - Richa Mishra
- Department of Computer Engineering, Parul University, Vadodara, India
| | - Salah-Ud-Din Khan
- Department of Biochemistry, College of Medicine, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh, Saudi Arabia
| | - Mohamed A M Ali
- Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University, Riyadh, Saudi Arabia
- Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Mohammad Shahid
- Department of Basic Medical Sciences, College of Medicine, Prince Sattam bin Abdulaziz University, Al-Kharj, Saudi Arabia
| | | | - Devvrat Verma
- Department of Biotechnology, Graphic Era (Deemed to be University), Dehradun, Uttarakhand, India
| | - Arti Gupta
- Lloyd School of Pharmacy, Greater Noida, India
| | - Sanjay Kumar
- Biological and Bio-computational Laboratory, Department of Life Science, Sharda School of Basic Sciences and Research, Sharda University, Greater Noida, India
| | - Sandeep Kumar
- School of Pharmacy, Sharda University, Greater Noida, India
- DST-FIST Laboratory, Department of Life Sciences, School of Basic Sciences and Research, Sharda University, Greater Noida, India
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2
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Das R, Mehta DK, Dhanawat M. Medicinal Plants in Cancer Treatment: Contribution of Nuclear Factor-Kappa B (NF-kB) Inhibitors. Mini Rev Med Chem 2022; 22:1938-1962. [PMID: 35260052 DOI: 10.2174/1389557522666220307170126] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 11/23/2021] [Accepted: 12/14/2021] [Indexed: 01/17/2023]
Abstract
Nuclear factor-kappa B (NF-κB) is one of the principal inducible proteins that is a predominant transcription factor known to control the gene expression in mammals and plays a pivotal role in regulating cell signalling in the body under certain physiological and pathological conditions. In cancer cells, such as colon, breast, pancreatic, ovarian, melanoma, and lymphoma, the NF-κB pathway has been reported to be active. In cellular proliferation, promoting angiogenesis, invasion, metastasis of tumour cells and blocking apoptosis, the constitutive activity of NF-κB signalling has been reported. Therefore, immense attention has been given to developing drugs targeting NF-κB signalling pathways to treat many types of tumours. They are a desirable therapeutic target for drugs, and many studies concentrated on recognizing compounds. They may be able to reverse or standstill the growth and spread of tumours that selectively interfere with this pathway. Recently, numerous substances derived from plants have been evaluated as possible inhibitors of the NF-κB pathway. These include various compounds, such as flavonoids, lignans, diterpenes, sesquiterpenes, polyphenols, etc. A study supported by folk medicine demonstrated that plant-derived compounds could suppress NF-κB signalling. Taking this into account, the present review revealed the anticancer potential of naturally occurring compounds which have been verified both by inhibiting the NF-κB signalling and suppressing growth and spread of cancer and highlighting their mechanism of NF-κB inhibition.
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Affiliation(s)
- Rina Das
- M.M.College of Pharmacy, Maharishi Markandeshwar (Deemed to be) University, Mullana, Ambala, HR, India
| | - Dinesh Kumar Mehta
- M.M.College of Pharmacy, Maharishi Markandeshwar (Deemed to be) University, Mullana, Ambala, HR, India
| | - Meenakshi Dhanawat
- M.M.College of Pharmacy, Maharishi Markandeshwar (Deemed to be) University, Mullana, Ambala, HR, India
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3
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Alarcón-Sánchez BR, Pérez-Carreón JI, Villa-Treviño S, Arellanes-Robledo J. Molecular alterations that precede the establishment of the hallmarks of cancer: An approach on the prevention of hepatocarcinogenesis. Biochem Pharmacol 2021; 194:114818. [PMID: 34757033 DOI: 10.1016/j.bcp.2021.114818] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 10/25/2021] [Accepted: 10/27/2021] [Indexed: 02/07/2023]
Abstract
Chronic liver injury promotes the molecular alterations that precede the establishment of cancer. Usually, several decades of chronic insults are needed to develop the most common primary liver tumor known as hepatocellular carcinoma. As other cancer types, liver cancer cells are governed by a common set of rules collectively called the hallmarks of cancer. Although those rules have provided a conceptual framework for understanding the complex pathophysiology of established tumors, therapeutic options are still ineffective in advanced stages. Thus, the molecular alterations that precede the establishment of cancer remain an attractive target for therapeutic interventions. Here, we first summarize the chemopreventive interventions targeting the early liver carcinogenesis stages. After an integrative analysis on the plethora of molecular alterations regulated by anticancer agents, we then underline and discuss that two critical processes namely oxidative stress and genetic alterations, play the role of 'dirty work laborer' in the initial cell damage and drive the transformation of preneoplastic into neoplastic cells, respectively; besides, the activation of cellular senescence works as a key mechanism in attempting to prevent the onset and establishment of liver cancer. Whereas the detrimental effects of the binomial made up of oxidative stress and genetic alterations are either eliminated or reduced, senescence activation is promoted by anticancer agents. We argue that collectively, oxidative stress, genetic alterations, and senescence are key events that influence the fate of initiated cells and the establishment of the hallmarks of cancer.
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Affiliation(s)
- Brisa Rodope Alarcón-Sánchez
- Laboratory of Liver Diseases, National Institute of Genomic Medicine - INMEGEN, CDMX, Mexico; Departament of Cell Biology, Center for Research and Advanced Studies of the National Polytechnic Institute - CINVESTAV-IPN, CDMX, Mexico
| | | | - Saúl Villa-Treviño
- Departament of Cell Biology, Center for Research and Advanced Studies of the National Polytechnic Institute - CINVESTAV-IPN, CDMX, Mexico
| | - Jaime Arellanes-Robledo
- Laboratory of Liver Diseases, National Institute of Genomic Medicine - INMEGEN, CDMX, Mexico; Directorate of Cátedras, National Council of Science and Technology - CONACYT, CDMX, Mexico.
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4
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Mandlik DS, Mandlik SK. An Overview of Hepatocellular Carcinoma with Emphasis on Dietary Products and Herbal Remedies. Nutr Cancer 2021; 74:1549-1567. [PMID: 34396860 DOI: 10.1080/01635581.2021.1965630] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
The most common principal malignant tumor that accounts for ∼80% of cases of liver cancer across the world is hepatocellular carcinoma (HCC). It is a multifacetedillness that is caused by several risk factors and often progresses in the context of underlying cirrhosis. It is tremendously difficult and essential for the screening of novel therapeutic medications to establish HCC preclinical models that are equivalent to clinical diseases settings, i.e., representing the tumor microenvironment of HCC. In the progress of HCC, numerous molecular cascades have been supposed to play a part. Sorafenib is the only drug permitted by the US Food and Drug Administration for the treatment of HCC. Yet because of the increasing resistance to the drug and its toxicity, clinical treatment methods are not completely adequate. Newer treatment therapy options are essential for the management of HCC in patients. Natural compounds can be afforded by the patients with improved results with less toxicity and fewer side effects, among different methods of liver cancer treatment. The treatment and management of HCC with natural drugs and their phytoconstituents are connected to several paths that can prevent the occurrence and progress of HCC in several ways. The present review summarizes the etiology of HCC, molecular pathways, newer therapeutic approaches, natural dietary products, herbal plants and phytoconstituents for HCC treatment.
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Affiliation(s)
- Deepa S Mandlik
- Poona College of Pharmacy, Bharati Vidyapeeth, Deemed to be University, Pune, India
| | - Satish K Mandlik
- Poona College of Pharmacy, Bharati Vidyapeeth, Deemed to be University, Pune, India
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5
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Olgierd B, Kamila Ż, Anna B, Emilia M. The Pluripotent Activities of Caffeic Acid Phenethyl Ester. Molecules 2021; 26:molecules26051335. [PMID: 33801469 PMCID: PMC7958844 DOI: 10.3390/molecules26051335] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 02/24/2021] [Accepted: 02/26/2021] [Indexed: 12/14/2022] Open
Abstract
Caffeic acid phenethyl ester (CAPE) is a strong antioxidant extracted from honey bee-hive propolis. The mentioned compound, a well-known NF-κB inhibitor, has been used in traditional medicine as a potent anti-inflammatory agent. CAPE has a broad spectrum of biological properties including anti-viral, anti-bacterial, anti-cancer, immunomodulatory, and wound-healing activities. This review characterizes published data about CAPE biological properties and potential therapeutic applications, that can be used in various diseases.
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Affiliation(s)
- Batoryna Olgierd
- Department of Community Pharmacy, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia in Katowice, 40-055 Katowice, Poland;
- Correspondence: or ; Tel.: +48-602-689-347
| | - Żyła Kamila
- Department of Community Pharmacy, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia in Katowice, 40-055 Katowice, Poland;
| | - Banyś Anna
- Department of Pharmaceutical Technology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia in Katowice, 40-055 Katowice, Poland;
| | - Morawiec Emilia
- Department of Microbiology, Faculty of Medicine in Zabrze, University of Technology in Katowice, 40-555 Katowice, Poland;
- GynCentrum, Laboratory of Molecular Biology and Virology, 40-851 Katowice, Poland
- Department of Histology, Cytophysiology and Embryology in Zabrze, Faculty of Medicine in Zabrze, University of Technology in Katowice, 40-555 Katowice, Poland
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6
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Godina-Nava JJ, Torres-Vega G, López-Riquelme GO, López-Sandoval E, Samana AR, García Velasco F, Hernández-Aguilar C, Domínguez-Pacheco A. Quantum mechanical model for the anticarcinogenic effect of extremely-low-frequency electromagnetic fields on early chemical hepatocarcinogenesis. Phys Rev E 2017; 95:022416. [PMID: 28297882 DOI: 10.1103/physreve.95.022416] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2016] [Indexed: 11/07/2022]
Abstract
Using the conventional Haberkorn approach, it is evaluated the recombination of the radical pair (RP) singlet spin state to study theoretically the cytoprotective effect of an extremely-low-frequency electromagnetic field (ELF-EMF) on early stages of hepatic cancer chemically induced in rats. The proposal is that ELF-EMF modulates the interconversion rate of singlet and triplet spin states of the RP populations modifying the products from the metabolization of carcinogens. Previously, we found that the daily treatment with ELF-EMF 120 Hz inhibited the number and area of preneoplastic lesions in chemical carcinogenesis. The singlet spin population is evaluated diagonalizing the spin density matrix through the Lanczos method in a radical pair mechanism (RPM). Using four values of the interchange energy, we have studied the variations over the singlet population. The low magnetic field effect as a test of the influence over the enzymatic chemical reaction is evaluated calculating the quantum yield. Through a bootstrap technique the range is found for the singlet decay rate for the process. Applying the quantum measurements concept, we addressed the impact toward hepatic cells. The result contributes to improving our understanding of the chemical carcinogenesis process affected by charged particles that damage the DNA.
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Affiliation(s)
| | - Gabino Torres-Vega
- Departamento de Física CINVESTAV-IPN, Ap. Postal 14-740, CdMex, C.P. 07000, Mexico
| | | | - Eduardo López-Sandoval
- Departamento de Ciências Exatas e Tecnológicas, Universidade Estadual de Santa Cruz, Campus Soane Nazaré de Andrade, Rodovia Jorge Amado, Km 16, Bairro Salobrinho, 45662-900 Ilhéus, BA, Brazil
| | - Arturo Rodolfo Samana
- Departamento de Ciências Exatas e Tecnológicas, Universidade Estadual de Santa Cruz, Campus Soane Nazaré de Andrade, Rodovia Jorge Amado, Km 16, Bairro Salobrinho, 45662-900 Ilhéus, BA, Brazil
| | - Fermín García Velasco
- Departamento de Ciências Exatas e Tecnológicas, Universidade Estadual de Santa Cruz, Campus Soane Nazaré de Andrade, Rodovia Jorge Amado, Km 16, Bairro Salobrinho, 45662-900 Ilhéus, BA, Brazil
| | - Claudia Hernández-Aguilar
- National Polytechnic Institute, Sepi-ESIME, Zacatenco, Professional Unit Adolfo López Mateos, Col. Lindavista, Cd Mex, C.P. 07738, Mexico
| | - Arturo Domínguez-Pacheco
- National Polytechnic Institute, Sepi-ESIME, Zacatenco, Professional Unit Adolfo López Mateos, Col. Lindavista, Cd Mex, C.P. 07738, Mexico
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7
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Sánchez-Rodríguez R, Torres-Mena JE, Quintanar-Jurado V, Chagoya-Hazas V, Rojas Del Castillo E, Del Pozo Yauner L, Villa-Treviño S, Pérez-Carreón JI. Ptgr1 expression is regulated by NRF2 in rat hepatocarcinogenesis and promotes cell proliferation and resistance to oxidative stress. Free Radic Biol Med 2017; 102:87-99. [PMID: 27867096 DOI: 10.1016/j.freeradbiomed.2016.11.027] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2016] [Revised: 10/24/2016] [Accepted: 11/14/2016] [Indexed: 02/07/2023]
Abstract
Prostaglandin reductase-1 (Ptgr1) is an alkenal/one oxidoreductase that is involved in the catabolism of eicosanoids and lipid peroxidation such as 4-hydroxynonenal (4-HNE). Recently, we reported that Ptgr1 is overexpressed in human clinical and experimentally induced samples of hepatocellular carcinoma (HCC). However, how the expression of this gene is regulated and its role in carcinogenesis are not yet known. Here, we studied parameters associated with antioxidant responses and the mechanisms underlying the induction of Ptgr1 expression by the activation of Nuclear Factor (erythroid-derived-2)-like-2 (NRF2). For these experiments, we used two protocols of induced hepatocarcinogenesis in rats. Furthermore, we determined the effect of PTGR1 on cell proliferation and resistance to oxidative stress in cell cultures of the epithelial liver cell line, C9. Ptgr1 was overexpressed during the early phase in altered hepatocyte foci, and this high level of expression was maintained in persistent nodules until tumors developed. Ptgr1 expression was regulated by NRF2, which bound to an antioxidant response element at -653bp in the rat Ptgr1 gene. The activation of NRF2 induced the activation of an antioxidant response that included effects on proteins such as glutamate-cysteine ligase, catalytic subunit, NAD(P)H dehydrogenase quinone-1 (NQO1) and glutathione-S-transferase-P (GSTP1). These effects may have produced a reduced status that was associated with a high proliferation rate in experimental tumors. Indeed, when Ptgr1 was stably expressed, we observed a reduction in the time required for proliferation and a protective effect against hydrogen peroxide- and 4-HNE-induced cell death. These data were consistent with data showing colocalization between PTGR1 and 4-HNE protein adducts in liver nodules. These findings suggest that Ptgr1 and antioxidant responses act as a metabolic adaptation and could contribute to proliferation and cell-death evasion in liver tumor cells. Furthermore, these data indicate that Ptgr1 could be used to design early diagnostic tools or targeted therapies for HCC.
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Affiliation(s)
| | - Julia Esperanza Torres-Mena
- Instituto Nacional de Medicina Genómica, Mexico; Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del IPN, Mexico
| | | | | | | | | | - Saul Villa-Treviño
- Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del IPN, Mexico
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8
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Kim HG, Han EH, Im JH, Lee EJ, Jin SW, Jeong HG. Caffeic acid phenethyl ester inhibits 3-MC-induced CYP1A1 expression through induction of hypoxia-inducible factor-1α. Biochem Biophys Res Commun 2015; 465:562-8. [PMID: 26296470 DOI: 10.1016/j.bbrc.2015.08.060] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2015] [Accepted: 08/13/2015] [Indexed: 01/25/2023]
Abstract
Caffeic acid phenethyl ester (CAPE), a natural component of propolis, is reported to have anticarcinogenic properties, although its precise chemopreventive mechanism remains unclear. In this study, we examined the effects of CAPE on 3-methylcholanthrene (3-MC)-induced CYP1A1 expression and activities. CAPE reduced the formation of the benzo[a]pyrene-DNA adduct. Moreover, CAPE inhibited 3-MC-induced CYP1A1 activity, mRNA expression, protein level, and promoter activity. CAPE treatment also decreased 3-MC-inducible xenobiotic-response element (XRE)-linked luciferase, aryl hydrocarbons receptor (AhR) transactivation and nuclear localization. CAPE induced hypoxia inducible factor-1α (HIF-1α) protein level and HIF-1α responsible element (HRE) transcriptional activity. CAPE-mediated HIF-1α reduced 3-MC-inducible CYP1A1 protein expression. Taken together, CAPE decreases 3-MC-mediated CYP1A1 expression, and this inhibitory response is associated with inhibition of AhR and HIF-1α induction.
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Affiliation(s)
- Hyung Gyun Kim
- Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon, South Korea
| | - Eun Hee Han
- Division of Life Science, Korea Basic Science Institute, Daejeon, South Korea
| | - Ji Hye Im
- Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon, South Korea
| | - Eun Ji Lee
- Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon, South Korea
| | - Sun Woo Jin
- Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon, South Korea
| | - Hye Gwang Jeong
- Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon, South Korea.
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Caffeic Acid phenethyl ester is a potential therapeutic agent for oral cancer. Int J Mol Sci 2015; 16:10748-66. [PMID: 25984601 PMCID: PMC4463674 DOI: 10.3390/ijms160510748] [Citation(s) in RCA: 75] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2015] [Revised: 04/07/2015] [Accepted: 05/06/2015] [Indexed: 12/15/2022] Open
Abstract
Head and neck cancers, which affect 650,000 people and cause 350,000 deaths per year, is the sixth leading cancer by cancer incidence and eighth by cancer-related death worldwide. Oral cancer is the most common type of head and neck cancer. More than 90% of oral cancers are oral and oropharyngeal squamous cell carcinoma (OSCC). The overall five-year survival rate of OSCC patients is approximately 63%, which is due to the low response rate to current therapeutic drugs. In this review we discuss the possibility of using caffeic acid phenethyl ester (CAPE) as an alternative treatment for oral cancer. CAPE is a strong antioxidant extracted from honeybee hive propolis. Recent studies indicate that CAPE treatment can effectively suppress the proliferation, survival, and metastasis of oral cancer cells. CAPE treatment inhibits Akt signaling, cell cycle regulatory proteins, NF-κB function, as well as activity of matrix metalloproteinase (MMPs), epidermal growth factor receptor (EGFR), and Cyclooxygenase-2 (COX-2). Therefore, CAPE treatment induces cell cycle arrest and apoptosis in oral cancer cells. According to the evidence that aberrations in the EGFR/phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling, NF-κB function, COX-2 activity, and MMPs activity are frequently found in oral cancers, and that the phosphorylation of Akt, EGFR, and COX-2 correlates to oral cancer patient survival and clinical progression, we believe that CAPE treatment will be useful for treatment of advanced oral cancer patients.
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Armutcu F, Akyol S, Ustunsoy S, Turan FF. Therapeutic potential of caffeic acid phenethyl ester and its anti-inflammatory and immunomodulatory effects (Review). Exp Ther Med 2015; 9:1582-1588. [PMID: 26136862 DOI: 10.3892/etm.2015.2346] [Citation(s) in RCA: 113] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2014] [Accepted: 03/03/2015] [Indexed: 12/15/2022] Open
Abstract
Caffeic acid phenethyl ester (CAPE), a naturally occurring compound isolated from propolis extract, has been reported to have a number of biological and pharmacological properties, exerting antioxidant, anti-inflammatory, anticarcinogenic, antibacterial and immunomodulatory effects. Recent in vivo and in vitro study findings have provided novel insights into the molecular mechanisms involved in the anti-inflammatory and immunomodulatory activities of this natural compound. CAPE has been reported to have anti-inflammatory properties involving the inhibition of certain enzyme activities, such as xanthine oxidase, cyclooxygenase and nuclear factor-κB (NF-κB) activation. Since inflammation and immune mechanisms play a crucial role in the onset of several inflammatory diseases, the inhibition of NF-κB represents a rationale for the development of novel and safe anti-inflammatory agents. The primary goal of the present review is to highlight the anti-inflammatory and immunomodulatory activities of CAPE, and critically evaluate its potential therapeutic effects.
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Affiliation(s)
- Ferah Armutcu
- Department of Biochemistry, Cerrahpasa Medical Faculty, Istanbul University, Istanbul 34098, Turkey
| | - Sumeyya Akyol
- Department of Medical Biology, Medical Faculty, Turgut Ozal University, Ankara 06010, Turkey
| | - Seyfettin Ustunsoy
- Department of Biochemistry, Medical Faculty, Fatih University, Istanbul 34500, Turkey
| | - Fatime Filiz Turan
- Department of Biochemistry, Medical Faculty, Fatih University, Istanbul 34500, Turkey
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11
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Vásquez-Garzón VR, Beltrán-Ramírez O, Salcido-Neyoy ME, Cervante-Anaya N, Villa-Treviño S. Analysis of gene expression profiles as a tool to uncover tumor markers of liver cancer progression in a rat model. Biomed Rep 2014; 3:167-172. [PMID: 25798242 DOI: 10.3892/br.2014.411] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2014] [Accepted: 12/10/2014] [Indexed: 11/05/2022] Open
Abstract
Establishing a transcriptomic profile of human hepatocellular liver cancer (HCC) progression is a complex undertaking. A rat model of HCC was employed to develop a transcriptomic profile. Using three interventions, preneoplastic lesions appeared after 30 days and they progressed to HCC by 9 months. Preneoplastic and cancer lesions were characterized for transcriptomic analysis, and RNA from total liver homogenates was obtained at 1, 7, 11 and 16 days after the initiation treatment. RNA from dissected persistent preneoplastic lesions, adjacent tissue or cancer tissue was used for 30 days, and 5, 9, 12 and 18 months. The GeneChip® Rat Exon 1.0 ST arrays, Partek software and an Affymetrix console were employed for these analyses. LGALS3BP was differentially expressed at each time point, from the initial period, through the preneoplastic evolution period and until the end of cancer progression period. Twelve differentially expressed genes common to the preneoplastic evolution and to the cancer progression period were detected, which included ABCC3. Validation of the microarrays was confirmed by reverse transcription-quantitative polymerase chain reaction of six genes, including LGALS3BP and ABCC3. Of note, the proteins of these two genes are associated with the multidrug response complex, and evasion of immune surveillance and negative regulation of T cell proliferation. This model is useful for identifying candidate genes, and to validate them with regards to determining their relevance in rat HCC progression.
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Affiliation(s)
- Verónica R Vásquez-Garzón
- Department of Cell Biology, Center for Research and Advanced Studies (CINVESTAV-IPN), México, DF 07360, México
| | | | - Martha E Salcido-Neyoy
- National Cancer Institute, Colonia Sección XVI Delegación Tlalpan, México, DF 14080, México
| | - Nancy Cervante-Anaya
- Department of Cell Biology, Center for Research and Advanced Studies (CINVESTAV-IPN), México, DF 07360, México
| | - Saúl Villa-Treviño
- Department of Cell Biology, Center for Research and Advanced Studies (CINVESTAV-IPN), México, DF 07360, México
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12
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Sánchez-Rodríguez R, Torres-Mena JE, De-la-Luz-Cruz M, Bernal-Ramos GA, Villa-Treviño S, Chagoya-Hazas V, Landero-López L, García-Román R, Rouimi P, Del-Pozo-Yauner L, Meléndez-Zajgla J, Pérez-Carreón JI. Increased expression of prostaglandin reductase 1 in hepatocellular carcinomas from clinical cases and experimental tumors in rats. Int J Biochem Cell Biol 2014; 53:186-94. [PMID: 24853774 DOI: 10.1016/j.biocel.2014.05.017] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2014] [Revised: 05/03/2014] [Accepted: 05/07/2014] [Indexed: 01/05/2023]
Abstract
To identify novel tumor-associated proteins, we analyzed the protein expression patterns from experimental hepatocellular carcinoma (HCC) that were induced using hepatocarcinogenesis models in rats. Rats were subjected to two previously described protocols of hepatocarcinogenesis using diethylnitrosamine as a carcinogen: the alternative Solt-Farber (aS&F) protocol, which induces HCC within 9 months, and Schiffer's model, which induces cirrhosis and multifocal HCC within 18 weeks. The patterns of protein expression from tumors and normal liver tissue were examined by SDS-PAGE and the bands identified at 33-34 kDa were analyzed by mass spectrometry. The prostaglandin reductase 1 (PTGR1) showed the highest number of peptides, with a confidence of level >99%. The increased expression of PTGR1 in tumors was confirmed in these two models by Western blotting and by increase in alkenal/one oxidoreductase activity (25-fold higher than normal liver). In addition, the gene expression level of Ptgr1, as measured by qRT-PCR, was increased during cancer development in a time-dependent manner (200-fold higher than normal liver). Furthermore, PTGR1 was detected in the cytoplasm of neoplastic cells in rat tumors and in 12 human HCC cases by immunohistochemistry. These analyses were performed by comparing the expression of PTGR1 to that of two well-known markers of hepatocarcinoma, Glutathione S-transferase pi 1 (GSTP1) in rats and glypican-3 in humans. The increased expression and activity of PTGR1 in liver carcinogenesis encourage further research aimed at understanding the metabolic role of PTGR1 in HCC and its potential application for human cancer diagnosis and treatment.
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Affiliation(s)
| | - Julia Esperanza Torres-Mena
- Instituto Nacional de Medicina Genómica, México D.F., Mexico; Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del IPN, México D.F., Mexico
| | | | | | - Saúl Villa-Treviño
- Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del IPN, México D.F., Mexico
| | - Victoria Chagoya-Hazas
- Instituto de Fisiología Celular. Universidad Nacional Autónoma de México, México D.F., Mexico
| | - Luis Landero-López
- Centro de Especialidades Médicas del Estado de Veracruz "Dr. Rafael Lucio", Xalapa Veracruz, México D.F., Mexico
| | | | - Patrick Rouimi
- Institut National de la Recherche Agronomique (INRA), UMR 1331 TOXALIM (Research Centre in Food Toxicology), Toulouse, France
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Scolastici C, de Conti A, Cardozo MT, Ong TP, Purgatto E, Horst MA, Heidor R, Furtado KS, Bassoli BK, Moreno FS. β-ionone inhibits persistent preneoplastic lesions during the early promotion phase of rat hepatocarcinogenesis: TGF-α, NF-κB, and p53 as cellular targets. Nutr Cancer 2013; 66:234-41. [PMID: 24364727 DOI: 10.1080/01635581.2014.863364] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Dietary isoprenic derivatives such as β-ionone (βI) are a promising class of chemopreventive agents. In this study, cellular aspects of βI protective activities during early hepatocarcinogenesis were evaluated. Male Wistar rats were submitted to "resistant hepatocyte" model and then received daily 16 mg/100 g body weight (b.w.) of βI (βI group) or only 0.25 mL/100 g b.w. of corn oil (vehicle, control group [CO]) during 4 wk, specifically during early promotion phase. Compared to controls, βI inhibited (P < 0.05) the development of persistent preneoplastic lesions (pPNL), considered to be potential hepatocellular carcinoma (HCC) progression sites, and increased remodeling PNL (rPNL) (P < 0.05) that tend to regress to a normal phenotype. Increased βI hepatic levels (P < 0.05), in the βI group, were associated with its chemopreventive actions. Compared to control rats, βI reduced the frequency of both pPNL and rPNL positive for tumor growth factor (TGF)-α (P < 0.05), reduced the frequency of pPNL stained for p65 (nuclear factor-kappaB; NF-κB) (P < 0.05), and reduced the frequency of pPNL positive for cytoplasmic p53 (P < 0.05). Our data demonstrated that βI targets TGF-α, NF-κB, and p53 in initial phases of hepatocarcinogenesis and specifically inhibits PNL with increased probability to progress to HCC. This isoprenoid may represent a chemopreventive agent of choice for HCC control.
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Affiliation(s)
- Clarissa Scolastici
- a Laboratory of Diet, Nutrition and Cancer, Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences , University of São Paulo , São Paulo , Brazil
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Park MH, Kang DW, Jung Y, Choi KY, Min DS. Caffeic acid phenethyl ester downregulates phospholipase D1 via direct binding and inhibition of NFκB transactivation. Biochem Biophys Res Commun 2013; 442:1-7. [PMID: 24103753 DOI: 10.1016/j.bbrc.2013.09.105] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2013] [Accepted: 09/20/2013] [Indexed: 11/26/2022]
Abstract
Upregulation of phospholipase D (PLD) is functionally linked with oncogenic signals and tumorigenesis. Caffeic acid phenethyl ester (CAPE) is an active compound of propolis extract that exhibits anti-proliferative, anti-inflammatory, anti-oxidant, and antineoplastic properties. In this study, we demonstrated that CAPE suppressed the expression of PLD1 at the transcriptional level via inhibition of binding of NFκB to PLD1 promoter. Moreover, CAPE, but not its analogs, bound to a Cys837 residue of PLD1 and inhibited enzymatic activity of PLD. CAPE also decreased activation of matrix metalloproteinases-2 induced by phosphatidic acid, a product of PLD activity. Ultimately, CAPE-induced downregulation of PLD1 suppressed invasion and proliferation of glioma cells. Taken together, the results of this study indicate that CAPE might contribute to anti-neoplastic effect by targeting PLD1.
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Affiliation(s)
- Mi Hee Park
- Department of Molecular Biology, Pusan National University, Busan 609-735, Republic of Korea
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The effect of caffeic acid phenethyl ester analogues in a modified resistant hepatocyte model. Anticancer Drugs 2013; 24:394-405. [PMID: 23388162 DOI: 10.1097/cad.0b013e32835e9743] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
We present a study of the chemoprotective effects of two caffeic acid phenethyl ester (CAPE)-related structures: LQM717 and LQM706. The modified resistant hepatocyte model in rats was used to study the chemoprevention of these CAPE analogues, which are inexpensive and easily obtained. In the liver cancer model used, we detected extensive necrosis and lipid peroxidation after 24 h, many altered hepatic foci, putatively preneoplastic lesions with γ-glutamyl transpeptidase staining after 30 days, and liver tumors at 12 months. We tested the effect of the CAPE analogues on necrosis, lipid peroxidation, proliferation, p65 activation, altered hepatic foci, and tumors. Both compounds exerted protective effects on lipid peroxidation, necrosis, cell proliferation, p65 activation, and preneoplastic lesions. Rats under a carcinogenic protocol showed a 52, 71.74, and 51.6% decrease in the number of preneoplastic nodules when pretreated with CAPE, LQM706, and LQM717, respectively. At 12 months after carcinogenic treatment, eight of eight rats developed liver cancer, whereas in the group of rats that received pretreatment with CAPE, LQM706, or LQM717, 62.5, 83.3, or 42.85%, respectively, had tumors. In conclusion, LQM717 has the potential to enhance chemoprotection activity much better than CAPE by markedly reducing the formation of liver cancers in this model, and this is a compound that is easy to obtain.
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Abduljawad SH, El-Refaei MF, El-Nashar NN. Protective and anti-angiopathy effects of caffeic acid phenethyl ester against induced type 1 diabetes in vivo. Int Immunopharmacol 2013; 17:408-14. [PMID: 23831012 DOI: 10.1016/j.intimp.2013.06.019] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2013] [Revised: 06/17/2013] [Accepted: 06/18/2013] [Indexed: 12/17/2022]
Abstract
OBJECTIVE This study aims at investigating the anti-diabetic effects of caffeic acid phenethyl ester (CAPE) against induced immunoregulated diabetes in vivo. METHODS Swiss mice were administered cyclosporine (CsA) 20mg/kg/day, s.c. for 10 days and simultaneously received multiple low doses of streptozotocin (MLDSTZ) 40mg/kg/day, i.p. for 5 consecutive days. RESULTS Our results showed that administering CAPE (5μM/kg i.p./every 2 days) to diabetic mice led to a time-dependent decrease in blood glucose levels to 137.1±7.2 from 229.1±12.6mg/dl and induced a significant increase in serum insulin levels by 93.8% compared with untreated ones. An in vivo anti-inflammatory effect of CAPE treated diabetic mice was observed, based on a significant decrease in IL-1β and IFN-γ (P<0.01) levels and a highly significant reduction in NO (P<0.001). An anti-angiogenic effect of CAPE was observed, as determined by a significant serum matrix metalloproteinase (MMP-9) reduction, angiopoietin (Ang-2) reduction and activation of endostatin serum level in the CAPE treated diabetic mice. Furthermore, histopathological examination showed that destroyed pancreatic islets were regenerated and became free of cell infiltration after treatment. CONCLUSION CAPE has a significant anti-diabetic effect on mice in vivo. This anti-diabetic effect may be related to its anti-inflammatory and angiostatic effects. It also reduced angiogenic factors which may shift the equilibrium to the angiostatic effect of CAPE. These findings provide the validity of CAPE as anti-diabetic agent in the special model of CsA/STZ and could be relevant in the future for human diabetes.
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Affiliation(s)
- Soha H Abduljawad
- Food Sciences Dept, Taibah University, Al Madinah Al-Munawarah, Saudi Arabia
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El-Amir YO, Hassanein KMA. Protective effect of curcumin on N-nitrosodiethylamine and carbon tetrachloride-induced hepatocarcinogenesis in Sprague–Dawley rats. COMPARATIVE CLINICAL PATHOLOGY 2013; 22:631-636. [DOI: 10.1007/s00580-012-1457-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Akyol S, Ozturk G, Ginis Z, Armutcu F, Yigitoglu MR, Akyol O. In Vivo and In Vitro Antıneoplastic Actions of Caffeic Acid Phenethyl Ester (CAPE): Therapeutic Perspectives. Nutr Cancer 2013; 65:515-26. [DOI: 10.1080/01635581.2013.776693] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
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Lin HP, Lin CY, Liu CC, Su LC, Huo C, Kuo YY, Tseng JC, Hsu JM, Chen CK, Chuu CP. Caffeic Acid phenethyl ester as a potential treatment for advanced prostate cancer targeting akt signaling. Int J Mol Sci 2013; 14:5264-83. [PMID: 23466879 PMCID: PMC3634405 DOI: 10.3390/ijms14035264] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2013] [Revised: 02/19/2013] [Accepted: 02/28/2013] [Indexed: 12/20/2022] Open
Abstract
Prostate cancer is the fifth most common cancer overall in the world. Androgen ablation therapy is the primary treatment for metastatic prostate cancer. However, most prostate cancer patients receiving the androgen ablation therapy ultimately develop recurrent castration-resistant tumors within 1–3 years after treatment. The median overall survival time is 1–2 years after tumor relapse. Chemotherapy shows little effect on prolonging survival for patients with metastatic hormone-refractory prostate cancer. More than 80% of prostate tumors acquire mutation or deletion of tumor suppressor phosphatase and tensin homolog (PTEN), a negative regulator of PI3K/Akt signaling, indicating that inhibition of PI3K/Akt might be a potential therapy for advanced prostate tumors. Caffeic acid phenethyl ester (CAPE) is a strong antioxidant extracted from honeybee hive propolis. CAPE is a well-known NF-κB inhibitor. CAPE has been used in folk medicine as a potent anti-inflammatory agent. Recent studies indicate that CAPE treatment suppresses tumor growth and Akt signaling in human prostate cancer cells. We discuss the potential of using CAPE as a treatment for patients with advanced prostate cancer targeting Akt signaling pathway in this review article.
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Affiliation(s)
- Hui-Ping Lin
- Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli 35053, Taiwan; E-Mails: (H.-P.L.); (C.-Y.L.); (L.-C.S.); (C.H.); (Y.-Y.K.); (J.-C.T.)
- Translational Center for Glandular Malignancies, National Health Research Institutes, Miaoli 35053, Taiwan
| | - Ching-Yu Lin
- Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli 35053, Taiwan; E-Mails: (H.-P.L.); (C.-Y.L.); (L.-C.S.); (C.H.); (Y.-Y.K.); (J.-C.T.)
- Translational Center for Glandular Malignancies, National Health Research Institutes, Miaoli 35053, Taiwan
- National Institute of Cancer Research, National Health Research Institutes, Miaoli 35053, Taiwan
| | - Chun-Chieh Liu
- Division of Cardiology, Department of Internal Medicine, Mackay Memorial Hospital, Taipei City 10449, Taiwan; E-Mail:
- Mackay Medical College, New Taipei City 25245, Taiwan
- Mackay Medicine, Nursing and Management College, New Taipei City 25245, Taiwan
| | - Liang-Cheng Su
- Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli 35053, Taiwan; E-Mails: (H.-P.L.); (C.-Y.L.); (L.-C.S.); (C.H.); (Y.-Y.K.); (J.-C.T.)
- Translational Center for Glandular Malignancies, National Health Research Institutes, Miaoli 35053, Taiwan
| | - Chieh Huo
- Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli 35053, Taiwan; E-Mails: (H.-P.L.); (C.-Y.L.); (L.-C.S.); (C.H.); (Y.-Y.K.); (J.-C.T.)
- Translational Center for Glandular Malignancies, National Health Research Institutes, Miaoli 35053, Taiwan
- Department of Life Sciences, National Central University, Taoyuan City 32001, Taiwan
| | - Ying-Yu Kuo
- Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli 35053, Taiwan; E-Mails: (H.-P.L.); (C.-Y.L.); (L.-C.S.); (C.H.); (Y.-Y.K.); (J.-C.T.)
- Translational Center for Glandular Malignancies, National Health Research Institutes, Miaoli 35053, Taiwan
| | - Jen-Chih Tseng
- Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli 35053, Taiwan; E-Mails: (H.-P.L.); (C.-Y.L.); (L.-C.S.); (C.H.); (Y.-Y.K.); (J.-C.T.)
- Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu City 30013, Taiwan
| | - Jong-Ming Hsu
- Department of Urology, Mackay Memorial Hospital, Taipei City 10449, Taiwan; E-Mail:
| | - Chi-Kuan Chen
- Department of Pathology, Mackay Memorial Hospital, Taipei City 10449, Taiwan; E-Mail:
| | - Chih-Pin Chuu
- Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli 35053, Taiwan; E-Mails: (H.-P.L.); (C.-Y.L.); (L.-C.S.); (C.H.); (Y.-Y.K.); (J.-C.T.)
- Translational Center for Glandular Malignancies, National Health Research Institutes, Miaoli 35053, Taiwan
- Graduate Program for Aging, China Medical University, Taichung City 40402, Taiwan
- Ph.D. Program in Tissue Engineering and Regenerative Medicine, National Chung Hsing University, Taichung City 40227, Taiwan
- Author to whom correspondence should be addressed; E-Mail: ; Tel.: +886-3724-6166 (ext. 37300); Fax: +886-3758-7408
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Akçam M, Artan R, Yilmaz A, Ozdem S, Gelen T, Nazıroğlu M. Caffeic acid phenethyl ester modulates aflatoxin B1-induced hepatotoxicity in rats. Cell Biochem Funct 2013; 31:692-7. [DOI: 10.1002/cbf.2957] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2012] [Revised: 12/07/2012] [Accepted: 01/02/2013] [Indexed: 01/22/2023]
Affiliation(s)
- Mustafa Akçam
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, Medical Faculty; Suleyman Demirel University; Isparta Turkey
| | - Reha Artan
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, Medical Faculty; Akdeniz University; Antalya Turkey
| | - Aygen Yilmaz
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, Medical Faculty; Akdeniz University; Antalya Turkey
| | - Sebahat Ozdem
- Department of Biochemistry, Medical Faculty; Akdeniz University; Antalya Turkey
| | - Tekinalp Gelen
- Department of Pathology, Medical Faculty; Akdeniz University; Antalya Turkey
| | - Mustafa Nazıroğlu
- Neuroscience Research Center; Suleyman Demirel University; Isparta Turkey
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Vásquez-Garzón VR, Macias-Pérez JR, Jiménez-García MN, Villegas V, Fattel-Fazenta S, Villa-Treviño S. The chemopreventive capacity of quercetin to induce programmed cell death in hepatocarcinogenesis. Toxicol Pathol 2012. [PMID: 23197198 DOI: 10.1177/0192623312467522] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
In this study of chemoprevention in the rat modified resistant hepatocyte model, preneoplastic cells were diminished by >60% with quercetin pretreatment compared with those rats treated with N-Diethylnitrosamine (DEN) to induce liver cancer. This decrease occurred associated with an abolished DEN-induced lipid peroxidation as well as activation of caspase 9 and increased caspase 3, as determined by increased expression of cleaved caspase 3 and 9, but not cleaved caspase 8 and increased fragmentation of Poly (ADP-ribose) polymerase (PARP) inducing apoptosis of presumed genetically injured cells, when quercetin was administered before the initiation agent.
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Bezerra RMN, Veiga LF, Caetano AC, Rosalen PL, Amaral MEC, Palanch AC, de Alencar SM. Caffeic acid phenethyl ester reduces the activation of the nuclear factor κB pathway by high-fat diet-induced obesity in mice. Metabolism 2012; 61:1606-14. [PMID: 22575582 DOI: 10.1016/j.metabol.2012.04.006] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2011] [Revised: 04/04/2012] [Accepted: 04/04/2012] [Indexed: 12/14/2022]
Abstract
OBJECTIVE The aim of this study was to investigate the effect of CAPE on the insulin signaling and inflammatory pathway in the liver of mice with high fat diet induced obesity. MATERIAL/METHODS Swiss mice were fed with standard chow or high-fat diet for 12-week. After the eighth week, animals in the HFD group with serum glucose levels higher than 200 mg/dL were divided into two groups, HFD and HFD receiving 30 mg/kg of CAPE for 4 weeks. After 12 weeks, the blood samples could be collected and liver tissue extracted for hormonal and biochemical measurements, and insulin signaling and inflammatory pathway analyzes. RESULTS The high-fat diet group exhibited more weight gain, glucose intolerance, and hepatic steatosis compared with standard diet group. The CAPE treatment showed improvement in glucose sensitivity characterized by an area under glucose curve similar to the control group in an oral glucose tolerance test Furthermore, CAPE treatment promoted amelioration in hepatic steatosis compared with the high-fat diet group. The increase in glucose sensitivity was associated with the improvement in insulin-stimulated phosphorylation of the insulin receptor substrate-2, followed by an increase in Akt phosphorylation. In addition, it was observed that CAPE reduced the induction of the inflammatory pathway, c-jun-N- terminal kinase, the nuclear factor kappa B, and cyclooxygenase-2 expression, respectively. CONCLUSIONS Overall, these findings indicate that CAPE exhibited anti-inflammatory activity that partly restores normal metabolism, reduces the molecular changes observed in obesity and insulin resistance, and therefore has a potential as a therapeutic agent in obesity.
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Stagos D, Amoutzias GD, Matakos A, Spyrou A, Tsatsakis AM, Kouretas D. Chemoprevention of liver cancer by plant polyphenols. Food Chem Toxicol 2012; 50:2155-70. [DOI: 10.1016/j.fct.2012.04.002] [Citation(s) in RCA: 126] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2011] [Revised: 03/31/2012] [Accepted: 04/02/2012] [Indexed: 02/07/2023]
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Beltrán-Ramírez O, Pérez RM, Sierra-Santoyo A, Villa-Treviño S. Cancer Prevention Mediated by Caffeic Acid Phenethyl Ester Involves Cyp2b1/2 Modulation in Hepatocarcinogenesis. Toxicol Pathol 2012; 40:466-72. [DOI: 10.1177/0192623311431947] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
- Olga Beltrán-Ramírez
- Dirección de Investigación, Hospital Juárez de México, México City, Distrito Federal, México
| | - Roberto Macías Pérez
- Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV), San Pedro Zacatenco, México
| | - Adolfo Sierra-Santoyo
- Departamento de Toxicología, Centro de Investigación y de Estudios Avanzados del IPN (CINVESTAV). San Pedro Zacatenco, México
| | - Saúl Villa-Treviño
- Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV), San Pedro Zacatenco, México
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Lin HP, Su LC, Lin CY, Chiech H, Chuu CP. Anticancer Effect of Caffeic Acid Phenethyl Ester. ACTA ACUST UNITED AC 2012. [DOI: 10.5567/pharmacologia.2012.26.30] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
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An approach to the study of gene expression in hepatocarcinogenesis initiation. Transl Oncol 2011; 3:142-8. [PMID: 20360939 DOI: 10.1593/tlo.09298] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2009] [Revised: 11/23/2009] [Accepted: 11/25/2009] [Indexed: 01/09/2023] Open
Abstract
In carcinogenesis, determination of gene and protein expression profiles is important for prevention and treatment. Caffeic acid phenethyl ester (CAPE) in a single dose administered before carcinogenic initiation induced by diethylnitrosamine (DEN) prevents the appearance of preneoplastic lesions. On the basis of this approach, the main purpose of this work was to compare the gene expression profiles induced by DEN or a previously administered single dose of CAPE. Using a modified hepatocarcinogenesis-resistant hepatocyte model, male Fischer-344 rats were administered with one intraperitoneal dose of CAPE (20 mg/kg) 12 hours before DEN administration (200 mg/kg). Livers were removed and processed for microarray analysis and reverse transcription-polymerase chain reaction 12 hours after CAPE dosing and 24 hours after DEN administration with or without CAPE. CAPE alone did not alter the expression profile. DEN treatment modified the expression of 665 genes, and CAPE plus DEN induced changes in 1371 genes. DEN treatment increased the expression of genes associated with oxidative stress such as glutathione reductase, genes involved in cell cycle regulation including p53, and modified cytochrome P450. CAPE plus DEN diminished the expression of cytochrome involved in DEN bioactivation such as CYP2B1 as well as the expression of regulators of oxidative stress such as glutathione reductase, GST-kappa and GST-theta, and cell cycle regulators such as p53. Using CAPE as a tool, we uncovered new approaches for studying the altered expression of reactive genes and identifying proteins that will help to propose well-sustained and concrete hypothesis of DEN mechanism of hepatocarcinogenesis initiation.
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Khan MS, Devaraj H, Devaraj N. Chrysin abrogates early hepatocarcinogenesis and induces apoptosis in N-nitrosodiethylamine-induced preneoplastic nodules in rats. Toxicol Appl Pharmacol 2011; 251:85-94. [PMID: 21167192 DOI: 10.1016/j.taap.2010.12.004] [Citation(s) in RCA: 67] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2010] [Revised: 12/06/2010] [Accepted: 12/07/2010] [Indexed: 01/14/2023]
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Colakoglu N, Kus I, Kukner A, Pekmez H, Ozan E, Sarsilmaz M. Protective Effects of CAPE on Liver Injury Induced by CCL4: An Electron Microscopy Study. Ultrastruct Pathol 2011; 35:26-30. [DOI: 10.3109/01913123.2010.527036] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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Lee Y, Shin DH, Kim JH, Hong S, Choi D, Kim YJ, Kwak MK, Jung Y. Caffeic acid phenethyl ester-mediated Nrf2 activation and IkappaB kinase inhibition are involved in NFkappaB inhibitory effect: structural analysis for NFkappaB inhibition. Eur J Pharmacol 2010; 643:21-8. [PMID: 20599928 DOI: 10.1016/j.ejphar.2010.06.016] [Citation(s) in RCA: 115] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2010] [Revised: 05/28/2010] [Accepted: 06/10/2010] [Indexed: 12/30/2022]
Abstract
Caffeic acid phenethyl ester (CAPE) is an active component of propolis from honeybee. We investigated potential molecular mechanisms underlying CAPE-mediated nuclear factor kappa beta (NFkappaB) inhibition and analyzed structure of CAPE for its biological effect. CAPE attenuated expression of NFkappaB dependent luciferase stimulated with TNF-alpha or LPS and suppressed LPS-mediated induction of iNOS, a target gene product of NFkappaB. In HCT116 cells, CAPE interfered with TNF-alpha dependent IkappaBalpha degradation and subsequent nuclear accumulation of p65, which occurred by direct inhibition of inhibitory protein kappaB kinase (IKK). CAPE increased the expression of Nrf2-dependent luciferase and heme oxygenase-1, a target gene of Nrf2, and elevated the nuclear level of Nrf2 protein, indicating that CAPE activated the Nrf2 pathway. In HCT116 cells with stable expression of Nrf2 shRNA, CAPE elicited a reduced inhibitory effect on TNF-alpha-activated NFsmall ka, CyrillicB compared to scramble RNA expressing control cells. On the other hand, the NFkappaB inhibitory effect of CAPE was diminished by removal or modification of the Michael reaction acceptor, catechol or phenethyl moiety in CAPE. These data suggest that CAPE inhibits TNF-alpha-dependent NFkappaB activation via direct inhibition of IKK as well as activation of Nrf2 pathway, in which the functional groups in CAPE may be involved.
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Affiliation(s)
- Youna Lee
- College of Pharmacy, Pusan National University, Busan 609-735, Republic of Korea
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Anti-proliferative effect of extremely low frequency electromagnetic field on preneoplastic lesions formation in the rat liver. BMC Cancer 2010; 10:159. [PMID: 20416104 PMCID: PMC2873390 DOI: 10.1186/1471-2407-10-159] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2009] [Accepted: 04/24/2010] [Indexed: 12/22/2022] Open
Abstract
Background Recently, extremely low frequency electromagnetic fields (ELF-EMF) have been studied with great interest due to their possible effects on human health. In this study, we evaluated the effect of 4.5 mT - 120 Hz ELF-EMF on the development of preneoplastic lesions in experimental hepatocarcinogenesis. Methods Male Fischer-344 rats were subjected to the modified resistant hepatocyte model and were exposed to 4.5 mT - 120 Hz ELF-EMF. The effects of the ELF-EMF on hepatocarcinogenesis, apoptosis, proliferation and cell cycle progression were evaluated by histochemical, TUNEL assay, caspase 3 levels, immunohistochemical and western blot analyses. Results The application of the ELF-EMF resulted in a decrease of more than 50% of the number and the area of γ-glutamyl transpeptidase-positive preneoplastic lesions (P = 0.01 and P = 0.03, respectively) and glutathione S-transferase placental expression (P = 0.01). The number of TUNEL-positive cells and the cleaved caspase 3 levels were unaffected; however, the proliferating cell nuclear antigen, Ki-67, and cyclin D1 expression decreased significantly (P ≤ 0.03), as compared to the sham-exposure group. Conclusion The application of 4.5 mT - 120 Hz ELF-EMF inhibits preneoplastic lesions chemically induced in the rat liver through the reduction of cell proliferation, without altering the apoptosis process.
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Toyoda T, Tsukamoto T, Takasu S, Shi L, Hirano N, Ban H, Kumagai T, Tatematsu M. Anti-inflammatory effects of caffeic acid phenethyl ester (CAPE), a nuclear factor-kappaB inhibitor, on Helicobacter pylori-induced gastritis in Mongolian gerbils. Int J Cancer 2009; 125:1786-95. [PMID: 19610061 DOI: 10.1002/ijc.24586] [Citation(s) in RCA: 76] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Nuclear factor-kappaB (NF-kappaB) plays a major role in host inflammatory responses and carcinogenesis and as such is an important drug target for adjuvant therapy. In this study, we examined the effect of caffeic acid phenethyl ester (CAPE), an NF-kappaB inhibitor, on Helicobacter pylori (H. pylori)-induced NF-kappaB activation in cell culture and chronic gastritis in Mongolian gerbils. In AGS gastric cancer cells, CAPE significantly inhibited H. pylori-stimulated NF-kappaB activation and mRNA expression of several inflammatory factors in a dose-dependent manner, and prevented degradation of IkappaB-alpha and phosphorylation of p65 subunit. To evaluate the effects of CAPE on H. pylori-induced gastritis, specific pathogen-free male, 6-week-old Mongolian gerbils were intragastrically inoculated with H. pylori, fed diets containing CAPE (0-0.1%) and sacrificed after 12 weeks. Infiltration of neutrophils and mononuclear cells and expression of NF-kappaB p50 subunit and phospho-IkappaB-alpha were significantly suppressed by 0.1% CAPE treatment in the antrum of H. pylori-infected gerbils. Labeling indices for 5'-bromo-2'-deoxyuridine both in the antrum and corpus and lengths of isolated pyloric glands were also markedly reduced at the highest dose, suggesting a preventive effect of CAPE on epithelial proliferation. Furthermore, in the pyloric mucosa, mRNA expression of inflammatory mediators including tumor necrosis factor-alpha, interferon-gamma, interleukin (IL)-2, IL-6, KC (IL-8 homologue), and inducible nitric oxide synthase was significantly reduced. These results suggest that CAPE has inhibitory effects on H. pylori-induced gastritis in Mongolian gerbils through the suppression of NF-kappaB activation, and may thus have potential for prevention and therapy of H. pylori-associated gastric disorders.
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Affiliation(s)
- Takeshi Toyoda
- Division of Oncological Pathology, Aichi Cancer Center Research Institute, Chikusa-ku, Nagoya 464-8681, Japan
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García-Román R, Salazar-González D, Rosas S, Arellanes-Robledo J, Beltrán-Ramírez O, Fattel-Fazenda S, Villa-Treviño S. The differential NF-kB modulation by S-adenosyl-L-methionine, N-acetylcysteine and quercetin on the promotion stage of chemical hepatocarcinogenesis. Free Radic Res 2009; 42:331-43. [DOI: 10.1080/10715760802005169] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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Lee ES, Lee JO, Lee SK, Kim JH, Jung JH, Keum B, Park SH, Kim HS. Caffeic acid phenethyl ester accumulates beta-catenin through GSK-3beta and participates in proliferation through mTOR in C2C12 cells. Life Sci 2009; 84:755-9. [PMID: 19303025 DOI: 10.1016/j.lfs.2009.03.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2008] [Revised: 03/03/2009] [Accepted: 03/06/2009] [Indexed: 12/11/2022]
Abstract
AIM The aim of this study is to characterize the roles of caffeic acid phenethyl ester (CAPE) in the skeletal muscle cells. MAIN METHODS We performed immunoblotting assay using various phosphorylation specific antibodies. KEY FINDINGS We found that CAPE induces rapid and transient phosphorylation of glycogen synthase kinase (GSK)-3beta in a phosphoinositide 3-kinase (PI3K)-dependent manner. CAPE also decreases phosphorylation of beta-catenin, ultimately leading to beta-catenin accumulation. In addition, we demonstrated that CAPE activated the mammalian target of rapamycin (mTOR)-p70 S6 ribosomal kinase (S6K) and also stimulated extracellular signal-regulated kinase (ERK). The inhibition of mTOR blocked CAPE-induced ERK phosphorylation. SIGNIFICANCE Our results suggest that CAPE may act through beta-catenin accumulation via stimulation of GSK-3beta and may also participate in cellular proliferation through the mTOR-ERK pathway.
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Affiliation(s)
- Eun Soo Lee
- Department of Anatomy, Korea University College of Medicine, Seoul 136-705, Republic of Korea
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Mann CD, Neal CP, Garcea G, Manson MM, Dennison AR, Berry DP. Phytochemicals as potential chemopreventive and chemotherapeutic agents in hepatocarcinogenesis. Eur J Cancer Prev 2009; 18:13-25. [PMID: 19077560 DOI: 10.1097/cej.0b013e3282f0c090] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC) is the fifth commonest malignancy worldwide and the incidence is rising. Surgery, including transplantation resection, is currently the most effective treatment for HCC; however, recurrence rates are high and long-term survival is poor. Identifying novel chemopreventive and chemotherapeutic agents and targeting them to patients at high risk of developing HCC or following curative treatment may go some way towards improving prognosis. This review examines current knowledge regarding the chemopreventive and chemotherapeutic potential of phytochemicals in heptocarcinogenesis. Both in-vitro and animal studies demonstrate that several phytochemicals, including curcumin, resveratrol, green tea catechins, oltipraz and silibinin, possess promising chemopreventive and chemotherapeutic properties. Despite this, very few clinical trials have been performed. Problems regarding validation of biomarkers, agent delivery, side effects and patient selection are barriers that need to be overcome to determine the potential of such agents in clinical practice.
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Affiliation(s)
- Christopher D Mann
- Cancer Biomarkers and Prevention Group, Department of Cancer Studies and Molecular Medicine, Biocentre, University of Leicester, Leicester, UK.
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35
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Beltrán-Ramírez O, Alemán-Lazarini L, Salcido-Neyoy M, Hernández-García S, Fattel-Fazenda S, Arce-Popoca E, Arellanes-Robledo J, García-Román R, Vázquez-Vázquez P, Sierra-Santoyo A, Villa-Treviño S. Evidence that the Anticarcinogenic Effect of Caffeic Acid Phenethyl Ester in the Resistant Hepatocyte Model Involves Modifications of Cytochrome P450. Toxicol Sci 2008; 104:100-6. [DOI: 10.1093/toxsci/kfn071] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
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36
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Differences in Gastroprotective and Mutagenic Actions Between Polar and Apolar Extracts ofAnanas ananassoides. J Med Food 2008; 11:160-8. [DOI: 10.1089/jmf.2007.508] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
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37
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Rosales-Reyes T, de la Garza M, Arias-Castro C, Rodríguez-Mendiola M, Fattel-Fazenda S, Arce-Popoca E, Hernández-García S, Villa-Treviño S. Aqueous crude extract of Rhoeo discolor, a Mexican medicinal plant, decreases the formation of liver preneoplastic foci in rats. JOURNAL OF ETHNOPHARMACOLOGY 2008; 115:381-386. [PMID: 18063494 DOI: 10.1016/j.jep.2007.10.022] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/29/2007] [Revised: 10/04/2007] [Accepted: 10/09/2007] [Indexed: 05/25/2023]
Abstract
There are many plants in Mexico with medicinal properties, some of them used in alternative medicine to treat cancer, such is the case of Rhoeo discolor L. Hér Hance (Commelinaceae family); however, there are not scientific reports that validate their antitumoral property. The present study shows the protective effects of the Rhoeo discolor aqueous crude extract (ACE) against rat liver cancer using the resistant-hepatocyte model. The carcinogenesis protocol consisted on the initiation with N-diethylnitrosamine, followed by the promotion with 2-acetylaminofluorene and a partial hepatectomy. After 24 days, the gamma-glutamyl transpeptidase positive, corresponding to altered hepatocytes foci (AHF), were quantified. Additionally to discard a possible carcinogenic effect of ACE, it was first tested as promoting agent instead 2-acetylaminofluorene, and second, ACE was administered as initiator and promoter instead of the whole carcinogenic treatment. In summary, firstly, ACE administration reduced the number and area of preneoplastic lesions with dose below 20mg/kg body weight and secondly, ACE administration neither presented a promoting or initiator effects nor induced the development of AHF. Results of this investigation justify continuing with further studies of Rhoeo discolor components to develop chemoprevention strategies as an option in the treatment of cancer.
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Affiliation(s)
- Tábata Rosales-Reyes
- Laboratorio de Biotecnología Vegetal, Centro de Investigación y Graduados Agropecuarios del Instituto Tecnológico de Tlajomulco, Jalisco, Km 10 Carr. San Miguel Cuyutlán-Tlajomulco, Tlajomulco de Zúñiga, Jal., Mexico
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Mazzantini RP, de Conti A, Moreno FS. Persistent and remodeling hepatic preneoplastic lesions present differences in cell proliferation and apoptosis, as well as in p53, Bcl-2 and NF-κB pathways. J Cell Biochem 2008; 103:538-46. [PMID: 17546582 DOI: 10.1002/jcb.21420] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
During rat hepatocarcinogenesis preneoplastic lesions (PNL) emerge which may persist (pPNL) and be sites of progress to cancer or suffer remodeling (rPNL) tending to disappear. Cellular and molecular mechanisms involved in both phenotypes are not sufficiently elucidated. pPNL and rPNL cellular proliferation and apoptosis were evaluated in rats submitted to the resistant hepatocyte (RH) model, and an adjusted growth index (AGI) was established. p53, Bcl-2, and NF-kappaB p65 subunit expression was evaluated by immunohistochemistry in pPNL and rPNL. p65 expression and NF-kappaB activation was evaluated by Western blot assays in whole livers. A lower number of BrdU-stained hepatocyte nuclei/mm(2) and higher number of apoptotic bodies (AB) per mm(2) were observed in remodeling compared to pPNL. Cytoplasmic p53 accumulation is related to increased hepatocarcinoma malignancy. We observed that 71.3% pPNL and 25.4% rPNL (P < 0.05) presented p53 staining in the cytoplasm. Similarly, 67.7% pPNL and 23.1 % rPNL (P < 0.05) presented increased Bcl-2 staining. Thirty-two percent pPNL and 15.6% rPNL (P < 0.05) presented p65 staining. Compared to normal rats, increase (P < 0.05) of hepatic p65 expression and NF-kappaB activation in rats submitted to the RH model was observed. In agreement to previous studies hepatic pPNL and rPNL differ regarding cell proliferation and apoptosis. Moreover, persistence and remodeling involve differences in p53, Bcl-2, and NF-kappaB pathways. These data point to molecular pathways that may direct preneoplastic lesions to spontaneously regress or to progress to cancer. J. Cell. Biochem. 103: 538-546, 2008. (c) 2007 Wiley-Liss, Inc.
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Affiliation(s)
- Rogério Pietro Mazzantini
- Laboratory of Diet, Nutrition and Cancer, Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil
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39
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40
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Celli N, Dragani LK, Murzilli S, Pagliani T, Poggi A. In vitro and in vivo stability of caffeic acid phenethyl ester, a bioactive compound of propolis. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2007; 55:3398-407. [PMID: 17394337 DOI: 10.1021/jf063477o] [Citation(s) in RCA: 89] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/14/2023]
Abstract
The in vitro biochemical stability of caffeic acid phenethyl ester in rat and human plasma was investigated and compared with the stability of other caffeic acid esters (chlorogenic acid and rosmarinic acid). The incubation of the compounds in rat plasma for up to 6 h showed that caffeic acid phenethyl ester, but not the other compounds, was hydrolyzed, whereas human plasma did not affect the stability of all the assayed compounds. The products in rat plasma were caffeic acid and an unknown compound, which was identified by mass spectrometry as caffeic acid ethyl ester, produced by transesterification in the presence of ethanol used as vehicle for standard compounds. Specific inhibitors of different plasma esterases allowed the identification of a carboxylesterase as the enzyme involved in the metabolism of caffeic acid phenethyl ester. The oral administration in rats of caffeic acid phenethyl ester in the presence of both ethanol and 2-(2-ethoxyethoxy)ethanol gave rise to a dramatic increase of caffeic acid, as well as low levels of caffeic acid phenethyl ester, caffeic acid ethyl ester, and caffeic acid 2-(2-ethoxyethoxy)ethyl ester, in urine collected within 24 h after treatment. These results suggest that caffeic acid phenethyl ester is hydrolyzed also in vivo to caffeic acid as the major metabolite and that its biological activities should be more properly assayed and compared with those of caffeic acid, its bioactive hydrolysis product. Moreover, alcohols should be carefully used in vivo as solvents for caffeic acid phenethyl ester, since they can give rise to new bioactive caffeic acid esters.
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Affiliation(s)
- Nicola Celli
- Consorzio Mario Negri Sud, Via Nazionale 8/A, 66030 Santa Maria Imbaro, Chieti, Italy.
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41
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García-Román R, Pérez-Carreón JI, Márquez-Quiñones A, Salcido-Neyoy ME, Villa-Treviño S. Persistent activation of NF-kappaB related to IkappaB's degradation profiles during early chemical hepatocarcinogenesis. J Carcinog 2007; 6:5. [PMID: 17445259 PMCID: PMC1865534 DOI: 10.1186/1477-3163-6-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2006] [Accepted: 04/19/2007] [Indexed: 01/23/2023] Open
Abstract
BACKGROUND To define the NF-kappaB activation in early stages of hepatocarcinogenesis and its IkappaB's degradation profiles in comparison to sole liver regeneration. METHODS Western-blot and EMSA analyses were performed for the NF-kappaB activation. The transcriptional activity of NF-kappaB was determined by RT-PCR of the IkappaB-alpha mRNA. The IkappaB's degradation proteins were determined by Western-blot assay. RESULTS We demonstrated the persistent activation of NF-kappaB during early stages of hepatocarcinogenesis, which reached maximal level 30 min after partial hepatectomy. The DNA binding and transcriptional activity of NF-kappaB, were sustained during early steps of hepatocarcinogenesis in comparison to only partial hepatectomy, which displayed a transitory NF-kappaB activation. In early stages of hepatocarcinogenesis, the IkappaB-alpha degradation turned out to be acute and transitory, but the low levels of IkappaB-beta persisted even 15 days after partial hepatectomy. Interestingly, IkappaB-beta degradation is not induced after sole partial hepatectomy. CONCLUSION We propose that during liver regeneration, the transitory stimulation of the transcription factor response, assures blockade of NF-kappaB until recovery of the total mass of the liver and the persistent NF-kappaB activation in early hepatocarcinogenesis may be due to IkappaB-beta and IkappaB-alpha degradation, mainly IkappaB-beta degradation, which contributes to gene transcription related to proliferation required for neoplastic progression.
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Affiliation(s)
- Rebeca García-Román
- Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del IPN, México D.F., México
| | - Julio Isael Pérez-Carreón
- Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del IPN, México D.F., México
| | - Adriana Márquez-Quiñones
- Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del IPN, México D.F., México
| | - Martha Estela Salcido-Neyoy
- Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del IPN, México D.F., México
| | - Saúl Villa-Treviño
- Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del IPN, México D.F., México
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Dallas M, Boycott HE, Atkinson L, Miller A, Boyle JP, Pearson HA, Peers C. Hypoxia suppresses glutamate transport in astrocytes. J Neurosci 2007; 27:3946-55. [PMID: 17428968 PMCID: PMC6672540 DOI: 10.1523/jneurosci.5030-06.2007] [Citation(s) in RCA: 100] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2006] [Revised: 02/26/2007] [Accepted: 02/28/2007] [Indexed: 01/14/2023] Open
Abstract
Glutamate uptake by astrocytes is fundamentally important in the regulation of CNS function. Disruption of uptake can lead to excitotoxicity and is implicated in various neurodegenerative processes as well as a consequence of hypoxic/ischemic events. Here, we investigate the effect of hypoxia on activity and expression of the key glutamate transporters excitatory amino acid transporter 1 (EAAT1) [GLAST (glutamate-aspartate transporter)] and EAAT2 [GLT-1 (glutamate transporter 1)]. Electrogenic, Na+-dependent glutamate uptake was monitored via whole-cell patch-clamp recordings from cortical astrocytes. Under hypoxic conditions (2.5 and 1% O2 exposure for 24 h), glutamate uptake was significantly reduced, and pharmacological separation of uptake transporter subtypes suggested that the EAAT2 subtype was preferentially reduced relative to the EAAT1. This suppression was confirmed at the level of EAAT protein expression (via Western blots) and mRNA levels (via real-time PCR). These effects of hypoxia to inhibit glutamate uptake current and EAAT protein levels were not replicated by desferrioxamine, cobalt, FG0041, or FG4496, agents known to mimic effects of hypoxia mediated via the transcriptional regulator, hypoxia-inducible factor (HIF). Furthermore, the effects of hypoxia were not prevented by topotecan, which prevents HIF accumulation. In stark contrast, inhibition of nuclear factor-kappaB (NF-kappaB) with SN50 fully prevented the effects of hypoxia on glutamate uptake and EAAT expression. Our results indicate that prolonged hypoxia can suppress glutamate uptake in astrocytes and that this effect requires activation of NF-kappaB but not of HIF. Suppression of glutamate uptake via this mechanism may be an important contributory factor in hypoxic/ischemic triggered glutamate excitotoxicity.
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Affiliation(s)
| | | | - Lucy Atkinson
- Biomedical Sciences, University of Leeds, Leeds LS2 9JT, United Kingdom
| | | | | | - Hugh A. Pearson
- Biomedical Sciences, University of Leeds, Leeds LS2 9JT, United Kingdom
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Márquez-Rosado L, Trejo-Solís C, Cabrales-Romero MDP, Arce-Popoca E, Sierra-Santoyo A, Alemán-Lazarini L, Fatel-Fazenda S, Carrasco-Legleu CE, Villa-Treviño S. Co-carcinogenic effect of cyclohexanol on the development of preneoplastic lesions in a rat hepatocarcinogenesis model. Mol Carcinog 2007; 46:524-33. [PMID: 17393424 DOI: 10.1002/mc.20295] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Cyclohexanol is a basic industrial chemical widely used because of its versatility as an industrial solvent. No studies have been conducted to evaluate the carcinogenic/co-carcinogenic hazards associated with cyclohexanol exposure. In male Fisher 344 rats liver preneoplastic lesions were induced by N-nitrosodiethylamine (150 mg/Kg) i.p., followed by the tumor promoter 2-acetylaminofluorene (2-AAF: 20 mg/kg) orally administered on three consecutive days before partial hepatectomy. The cyclohexanol administration in this hepatocarcinogenesis assay revealed that it has a strong tumor co-promoter potential. There is clear evidence that oxidative stress and the CYP2E1 are components of carcinogenesis. Although no changes in the lipid peroxidation levels were observed between treated and untreated animals, a significant increase in CYP2E1 expression was observed when cyclohexanol was administered 24 h after the last 2-AAF dose. On the other hand, levels of the proliferation markers PCNA and Ki-67 were not increased after treatment with cyclohexanol, but a marked downregulation of the Bax proapoptotic protein was found exclusively in mitochondrial extracts of animals treated with cyclohexanol. This study represents the first report of the ability of cyclohexanol-induced lesions, when administered simultaneously with 2-AAF, to potentiate the development of preneoplastic liver.
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Affiliation(s)
- Lucrecia Márquez-Rosado
- Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del IPN, CP. 07360 México, D.F., México
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Xiang D, Wang D, He Y, Xie J, Zhong Z, Li Z, Xie J. Caffeic acid phenethyl ester induces growth arrest and apoptosis of colon cancer cells via the beta-catenin/T-cell factor signaling. Anticancer Drugs 2006; 17:753-62. [PMID: 16926625 DOI: 10.1097/01.cad.0000224441.01082.bb] [Citation(s) in RCA: 77] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Caffeic acid phenethyl ester, an active component of propolis, has been implicated in the regulation of cell growth and apoptosis, although the exact mechanism of this activity has not been elucidated. In this study, we explored the effects of caffeic acid phenethyl ester on growth, cell cycle, apoptosis and beta-catenin/T-cell factor signaling in human colon cancer cells. Using two human sporadic colon cancer cell lines (HCT116 and SW480), we assayed for cell growth inhibition, cell cycle and apoptosis induction. We also assayed for beta-catenin and downstream target genes (cyclin D1 and c-myc) mRNA and protein expression by reverse transcriptase-polymerase chain reaction and Western blot analysis. Beta-catenin localization was detected by indirect immunofluorescence. Beta-catenin/T-cell factor transcriptional activity was determined by transient transfection and reporter gene assay. Caffeic acid phenethyl ester completely inhibited growth, and induced G1 phase arrest and apoptosis in a dose-dependent manner in both HCT116 and SW480 cells. Treatment of human colon cancer cells with apoptotic concentrations of caffeic acid phenethyl ester resulted in a dose-dependent and time-dependent loss of total beta-Catenin protein, associated with decreased nuclear beta-catenin. Caffeic acid phenethyl ester reduced the expression of cyclin D1 and c-myc in a dose-dependent and time-dependent manner. We proved that caffeic acid phenethyl ester markedly suppressed the transcriptional activity of beta-catenin/T-cell factor in both HCT116 and SW480 cells depending on the concentration of caffeic acid phenethyl ester. These results indicate that caffeic acid phenethyl ester is an excellent inhibitor of beta-catenin/T-cell factor signaling in colon cancer cell lines and suggest that caffeic acid phenethyl ester merits further study as an agent against colorectal cancers.
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Affiliation(s)
- Debing Xiang
- Cancer Center, Daping Hospital and Institute of Surgery, Third Military Medical University, Chongqing, PRC
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Carrasco-Legleu CE, Sánchez-Pérez Y, Márquez-Rosado L, Fattel-Fazenda S, Arce-Popoca E, Hernández-García S, Villa-Treviño S. A single dose of caffeic acid phenethyl ester prevents initiation in a medium-term rat hepatocarcinogenesis model. World J Gastroenterol 2006; 12:6779-85. [PMID: 17106925 PMCID: PMC4087431 DOI: 10.3748/wjg.v12.i42.6779] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To study of the effect of caffeic acid phenethyl ester (CAPE) on the initiation period in a medium-term assay of hepatocarcinogenesis.
METHODS: Male Wistar rats were subjected to a carcinogenic treatment (CT) and sacrificed at 25th d; altered hepatic foci (AHF) were generated efficiently. To a second group of rats a single 20 mg/kg doses of CAPE was given 12 h before initiation with CT and were sacrificed at 25th d. We evaluated the expression of preneoplastic markers as γ-glutamyltranspeptidase (GGT) and glutathione S-transferase type pi protein (GSTp) by histochemistry, RT-PCR and Western blot analyses, respectively. We measured thiobarbituric acid reactive substances (TBARS) in homogenates of liver and used Unscheduled DNA Synthesis (UDS) assay by incorporation of [3H] thymidine (3HdT) in primary hepatocyte cultures (PHC).
RESULTS: At 25th d after CT CAPE reduced the observed increase of GGT+AHF by 84% and liver expression of ggt mRNA by 100%. In case of the GSTp protein, the level was reduced by 90%. As indicative of oxidative stress generated by diethylnitrosamine (DEN) 12 h after its administration, we detected a 68% increase of TBARS. When CAPE was administered before DEN, it completely protected from liver TBARS induction. To have an indication of the sole effect of CAPE on initiation, two carcinogens were tested in a UDS assay in PHC, we used methyl-n-nitrosoguanidine as a direct carcinogen and DEN, as indirect carcinogen. In this assay, genotoxic damage caused by carcinogens was abolished at 5μM CAPE concentration.
CONCLUSION: Our results demonstrated that CAPE possesses anti-genotoxic and antineoplastic capabilities, by an anti-oxidative and free-radical scavenging mechanism.
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MESH Headings
- 2-Acetylaminofluorene
- Animals
- Caffeic Acids/administration & dosage
- Caffeic Acids/pharmacology
- Carcinogens
- Cell Proliferation/drug effects
- Cell Transformation, Neoplastic/chemically induced
- Cell Transformation, Neoplastic/drug effects
- Cell Transformation, Neoplastic/metabolism
- Cell Transformation, Neoplastic/pathology
- Cytotoxins/administration & dosage
- Cytotoxins/pharmacology
- Diethylnitrosamine/metabolism
- Dose-Response Relationship, Drug
- Gene Expression Regulation, Enzymologic/drug effects
- Glutathione S-Transferase pi/genetics
- Glutathione S-Transferase pi/metabolism
- Lipid Peroxidation/drug effects
- Liver Neoplasms, Experimental/chemically induced
- Liver Neoplasms, Experimental/metabolism
- Liver Neoplasms, Experimental/pathology
- Liver Neoplasms, Experimental/prevention & control
- Male
- NF-kappa B/antagonists & inhibitors
- Oxidative Stress/drug effects
- Phenylethyl Alcohol/administration & dosage
- Phenylethyl Alcohol/analogs & derivatives
- Phenylethyl Alcohol/pharmacology
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- Rats
- Rats, Wistar
- gamma-Glutamyltransferase/genetics
- gamma-Glutamyltransferase/metabolism
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Affiliation(s)
- Claudia-Esther Carrasco-Legleu
- Departamento de Biología Celular, Laboratorio 50, Centro de Investigación y de Estudios Avanzados del IPN (Cinvestav). Ave. IPN #2508. Col. San Pedro Zacatenco, C.P. 07360, México, D.F., México
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46
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Pérez-Carreón JI, López-García C, Fattel-Fazenda S, Arce-Popoca E, Alemán-Lazarini L, Hernández-García S, Le Berre V, Sokol S, Francois JM, Villa-Treviño S. Gene expression profile related to the progression of preneoplastic nodules toward hepatocellular carcinoma in rats. Neoplasia 2006; 8:373-83. [PMID: 16790086 PMCID: PMC1592455 DOI: 10.1593/neo.05841] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
In this study, we investigated the time course gene expression profile of preneoplastic nodules and hepatocellular carcinomas (HCC) to define the genes implicated in cancer progression in a resistant hepatocyte model. Tissues that included early nodules (1 month, ENT-1), persistent nodules (5 months, ENT-5), dissected HCC (12 months), and normal livers (NL) from adult rats were analyzed by cDNA arrays including 1185 rat genes. Differential genes were derived in each type of sample (n = 3) by statistical analysis. The relationship between samples was described in a Venn diagram for 290 genes. From these, 72 genes were shared between tissues with nodules and HCC. In addition, 35 genes with statistical significance only in HCC and with extreme ratios were identified. Differential expression of 11 genes was confirmed by comparative reverse transcription-polymerase chain reaction, whereas that of 2 genes was confirmed by immunohistochemistry. Members involved in cytochrome P450 and second-phase metabolism were downregulated, whereas genes involved in glutathione metabolism were upregulated, implicating a possible role of glutathione and oxidative regulation. We provide a gene expression profile related to the progression of nodules into HCC, which contributes to the understanding of liver cancer development and offers the prospect for chemoprevention strategies or early treatment of HCC.
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Affiliation(s)
- Julio Isael Pérez-Carreón
- Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del IPN, Mexico, DF, Mexico
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47
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He YJ, Liu BH, Xiang DB, Qiao ZY, Fu T, He YH. Inhibitory effect of caffeic acid phenethyl ester on the growth of SW480 colorectal tumor cells involves beta-catenin associated signaling pathway down-regulation. World J Gastroenterol 2006; 12:4981-4985. [PMID: 16937493 PMCID: PMC4087400 DOI: 10.3748/wjg.v12.i31.4981] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2006] [Revised: 05/15/2006] [Accepted: 05/25/2006] [Indexed: 02/06/2023] Open
Abstract
AIM To study the anti-tumor effect of caffeic acid phenethyl ester (CAPE) and the influence of CAPE on beta-catenin associated signaling pathway in SW480 colorectal cancer (CRC) cells. METHODS SW480 cells were treated with CAPE at serial concentrations. The proliferative status of cells was measured by methabenzthiazuron (MTT) assay. Cell cycle and cell apoptosis were analyzed using flow cytometry (FCM). Western blotting assay was used to evaluate the protein level of beta-catenin, c-myc and cyclinD1. Beta-catenin localization was determined by indirect immunofluorescence. RESULTS CAPE displayed a strong inhibitory effect in a significant dose- and time-dependent manner on SW480 cell growth. FCM analysis showed that the ratio of G0/G1 phase cells increased, S phase ratio decreased and apoptosis rate increased after SW480 cells were exposed to CAPE for 24 h. Pretreatment of SW480 cells with CAPE significantly suppressed beta-catenin, c-myc and cyclinD1 protein expression. CAPE treatment was associated with decreased accumulation of beta-catenin protein in nucleus and cytoplasm, and concurrently increased its accumulation on the surface of cell membrane. CONCLUSION CAPE can inhibit SW480 cell proliferation by inducing cell cycle arrest and apoptosis. Decreased beta-catenin and the associated signaling pathway target gene expression may mediate the anti-tumor effects of CAPE.
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Affiliation(s)
- Yu-Jun He
- Department of General Surgery, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing 400042, China.
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48
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Surh YJ, Kundu JK, Na HK, Lee JS. Redox-sensitive transcription factors as prime targets for chemoprevention with anti-inflammatory and antioxidative phytochemicals. J Nutr 2005; 135:2993S-3001S. [PMID: 16317160 DOI: 10.1093/jn/135.12.2993s] [Citation(s) in RCA: 253] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Oxidative stress has been implicated in various pathological conditions including cancer. However, the human body has an intrinsic ability to fight against oxidative stress. A wide array of phase 2 detoxifying or antioxidant enzymes constitutes a fundamental cellular defense system against oxidative and electrophilic insults. Transcriptional activation of genes encoding detoxifying and antioxidant enzymes by NF-E2 related factor 2 (Nrf2), a member of the cap'n'collar family of basic leucine zipper transcription factors, may protect cells and tissues from oxidative damage. Many chemopreventive and chemoprotective phytochemicals have been found to enhance cellular antioxidant capacity through activation of this particular transcription factor, thereby blocking initiation of carcinogenesis. A new horizon in chemoprevention research is the recent discovery of molecular links between inflammation and cancer. Components of the cell signaling pathways, especially those that converge on redox-sensitive transcription factors, including nuclear factor-kappaB (NF-kappaB) and activator protein 1 (AP-1) involved in mediating inflammatory response, have been implicated in carcinogenesis. A wide variety of chemopreventive and chemoprotective agents can alter or correct undesired cellular functions caused by abnormal proinflammatory signal transmission mediated by inappropriately activated NF-kappaB and AP-1. The modulation of cellular signaling by anti-inflammatory phytochemicals hence provides a rational and pragmatic strategy for molecular target-based chemoprevention.
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Affiliation(s)
- Young-Joon Surh
- National Research Laboratory of Molecular Carcinogenesis and Chemoprevention, College of Pharmacy, Seoul National University, Seoul 151-742, South Korea.
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49
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Shen G, Jeong WS, Hu R, Kong ANT. Regulation of Nrf2, NF-kappaB, and AP-1 signaling pathways by chemopreventive agents. Antioxid Redox Signal 2005; 7:1648-63. [PMID: 16356127 DOI: 10.1089/ars.2005.7.1648] [Citation(s) in RCA: 67] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
The inhibition of carcinogenesis by chemopreventive agents has been demonstrated in many tumorigenesis animal models. The chemopreventive mechanisms of those phytochemicals have been investigated extensively, though mostly in in vitro cell culture systems. The cellular signaling cascades mediated by transcription factors, including nuclear factor E2-related factor 2 (Nrf2), nuclear factor-kappaB (NF-kappaB), and activator protein-1 (AP-1), have been shown to play pivotal roles in tumor initiation, promotion, and progression processes. Thus, as demonstrated by previous substantive mechanistic studies, they appear to be ideal targets for cancer chemoprevention. In this review, we discuss the current progress and future challenges on our understanding of the molecular mechanisms in cancer chemoprevention by phytochemicals, focusing on the regulation of Nrf2, NF-kappaB, and AP-1 signaling pathways.
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Affiliation(s)
- Guoxiang Shen
- Department of Pharmaceutics and Graduate Program in Pharmaceutical Science, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA
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50
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Márquez-Rosado L, Trejo-Solís MC, García-Cuéllar CM, Villa-Treviño S. Celecoxib, a cyclooxygenase-2 inhibitor, prevents induction of liver preneoplastic lesions in rats. J Hepatol 2005; 43:653-60. [PMID: 16023763 DOI: 10.1016/j.jhep.2005.02.032] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2004] [Revised: 01/17/2005] [Accepted: 02/03/2005] [Indexed: 12/28/2022]
Abstract
BACKGROUND/AIMS Several studies suggest that cyclooxygenase-2 (COX-2) inhibitors are chemopreventive agents against colon, breast and skin cancer. In this study, we evaluated the chemopreventive effect of celecoxib, a specific COX-2 inhibitor, on the development of liver preneoplastic lesions in rats. METHODS Male Sprague-Dawley rats were fed during 5 weeks either a control or an experimental diet containing 1500 ppm celecoxib on a medium-term hepatocarcinogenesis protocol. Livers were collected and evaluated by histological and biochemical assays. RESULTS A reduction by 80 and 90% both in the number and size of altered hepatic foci was observed in the group treated with celecoxib during hepatocarcinogenesis treatment, respectively. No evidence of apoptosis was observed in our present study, however, the expression of the proliferation markers such as PCNA and Ki-67 was drastically reduced. Interestingly, neither COX-2 expression nor prostaglandin-E2 (PGE2) production were altered by the hepatocarcinogenic treatment or celecoxib treatment. Finally, celecoxib inhibited the translocation of Rel A/p65 to the nucleus with significant effect on stability of the repressor IkappaB-alpha. CONCLUSIONS This is the first demonstration that a specific COX-2 inhibitor, celecoxib, possesses striking chemopreventive activity, inhibiting preneoplastic lesions during hepatocarcinogenesis in vivo, suggesting that celecoxib effects are mediated by PGE2-independent mechanisms.
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Affiliation(s)
- Lucrecia Márquez-Rosado
- Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del IPN (Cinvestav), Ave. IPN No. 2508. Col. San Pedro, Zacatenco, C.P. 07360, México, DF, Mexico
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