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Huang W, Jiang T, He J, Ruan J, Wu B, Tao R, Xu P, Wang Y, Chen R, Wang H, Yang Q, Zhang K, Jin L, Sun D, You J. Modulation of Intestinal Flora: a Novel Immunotherapeutic Approach for Enhancing Thyroid Cancer Treatment. Probiotics Antimicrob Proteins 2025:10.1007/s12602-025-10471-z. [PMID: 39890752 DOI: 10.1007/s12602-025-10471-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/21/2025] [Indexed: 02/03/2025]
Abstract
Over the past 3 years, there has been a growing interest in clinical research regarding the potential involvement of intestinal flora in thyroid cancer (TC). This review delves into the intricate connection between intestinal flora and TC, focusing on the particular intestinal flora that is directly linked to the disease and identifying which may be able to predict potential microbial markers of TC. In order to shed light on the inflammatory pathways connected to the onset of TC, we investigated the impact of intestinal flora on immune modulation and the connection between chronic inflammation when investigating the role of intestinal flora in the pathogenesis of TC. Furthermore, the potential role of intestinal flora metabolites in the regulation of thyroid function was clarified by exploring the effects of short-chain fatty acids and lipopolysaccharide on thyroid hormone synthesis and metabolism. Based on these findings, we further explore the effects of probiotics, prebiotics, postbiotics, vitamins, and trace elements.
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Affiliation(s)
- Weiqiang Huang
- Department of General Surgery, The First People's Hospital of Jiashan, Jiashan Hospital Afliated of Jiaxing University, Jiaxing, 314100, China
| | - Tao Jiang
- Institute of Life Sciences & Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou, 325035, China
| | - Jiaxuan He
- Institute of Life Sciences & Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou, 325035, China
| | - Jing Ruan
- Institute of Life Sciences & Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou, 325035, China
| | - Baihui Wu
- Institute of Life Sciences & Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou, 325035, China
| | - Runchao Tao
- Institute of Life Sciences & Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou, 325035, China
| | - Peiye Xu
- Institute of Life Sciences & Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou, 325035, China
| | - Yongpan Wang
- Department of General Surgery, The First People's Hospital of Jiashan, Jiashan Hospital Afliated of Jiaxing University, Jiaxing, 314100, China
| | - Rongbing Chen
- Department of Biomedical Engineering, City University of Hong Kong, Hong Kong, SAR 999077, China
| | - Hanbing Wang
- The University of Hong Kong School of Biomedical Sciences, Hong Kong, 999077, SAR, China
| | - Qinsi Yang
- Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, 325000, China
| | - Kun Zhang
- Chongqing Municipality Clinical Research Center for Endocrinology and Metabolic Diseases, Chongqing University Three Gorges Hospital, Chongqing, 404000, China
| | - Libo Jin
- Institute of Life Sciences & Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou, 325035, China.
| | - Da Sun
- Institute of Life Sciences & Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou, 325035, China.
| | - Jinfeng You
- Department of Obstetrics, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Quzhou, 324000, China.
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Feitelson MA, Arzumanyan A, Medhat A, Spector I. Short-chain fatty acids in cancer pathogenesis. Cancer Metastasis Rev 2023; 42:677-698. [PMID: 37432606 PMCID: PMC10584782 DOI: 10.1007/s10555-023-10117-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Accepted: 06/05/2023] [Indexed: 07/12/2023]
Abstract
Cancer is a multi-step process that can be viewed as a cellular and immunological shift away from homeostasis in response to selected infectious agents, mutations, diet, and environmental carcinogens. Homeostasis, which contributes importantly to the definition of "health," is maintained, in part by the production of short-chain fatty acids (SCFAs), which are metabolites of specific gut bacteria. Alteration in the composition of gut bacteria, or dysbiosis, is often a major risk factor for some two dozen tumor types. Dysbiosis is often characterized by diminished levels of SCFAs in the stool, and the presence of a "leaky gut," permitting the penetration of microbes and microbial derived molecules (e.g., lipopolysaccharides) through the gut wall, thereby triggering chronic inflammation. SCFAs attenuate inflammation by inhibiting the activation of nuclear factor kappa B, by decreasing the expression of pro-inflammatory cytokines such as tumor necrosis factor alpha, by stimulating the expression of anti-inflammatory cytokines such as interleukin-10 and transforming growth factor beta, and by promoting the differentiation of naïve T cells into T regulatory cells, which down-regulate immune responses by immunomodulation. SCFA function epigenetically by inhibiting selected histone acetyltransferases that alter the expression of multiple genes and the activity of many signaling pathways (e.g., Wnt, Hedgehog, Hippo, and Notch) that contribute to the pathogenesis of cancer. SCFAs block cancer stem cell proliferation, thereby potentially delaying or inhibiting cancer development or relapse by targeting genes and pathways that are mutated in tumors (e.g., epidermal growth factor receptor, hepatocyte growth factor, and MET) and by promoting the expression of tumor suppressors (e.g., by up-regulating PTEN and p53). When administered properly, SCFAs have many advantages compared to probiotic bacteria and fecal transplants. In carcinogenesis, SCFAs are toxic against tumor cells but not to surrounding tissue due to differences in their metabolic fate. Multiple hallmarks of cancer are also targets of SCFAs. These data suggest that SCFAs may re-establish homeostasis without overt toxicity and either delay or prevent the development of various tumor types.
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Affiliation(s)
- Mark A Feitelson
- Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA, 19122, USA.
| | - Alla Arzumanyan
- Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA, 19122, USA
| | - Arvin Medhat
- Department of Molecular Cell Biology, Islamic Azad University Tehran North Branch, Tehran, 1975933411, Iran
| | - Ira Spector
- SFA Therapeutics, Jenkintown, PA, 19046, USA
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“RB-reactivator screening” as a novel cell-based assay for discoveries of molecular targeting agents including the first-in-class MEK inhibitor trametinib (trade name: Mekinist). Pharmacol Ther 2022; 236:108234. [DOI: 10.1016/j.pharmthera.2022.108234] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 06/12/2022] [Accepted: 06/16/2022] [Indexed: 01/10/2023]
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Ruzic D, Djoković N, Srdić-Rajić T, Echeverria C, Nikolic K, Santibanez JF. Targeting Histone Deacetylases: Opportunities for Cancer Treatment and Chemoprevention. Pharmaceutics 2022; 14:pharmaceutics14010209. [PMID: 35057104 PMCID: PMC8778744 DOI: 10.3390/pharmaceutics14010209] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 01/06/2022] [Accepted: 01/12/2022] [Indexed: 02/06/2023] Open
Abstract
The dysregulation of gene expression is a critical event involved in all steps of tumorigenesis. Aberrant histone and non-histone acetylation modifications of gene expression due to the abnormal activation of histone deacetylases (HDAC) have been reported in hematologic and solid types of cancer. In this sense, the cancer-associated epigenetic alterations are promising targets for anticancer therapy and chemoprevention. HDAC inhibitors (HDACi) induce histone hyperacetylation within target proteins, altering cell cycle and proliferation, cell differentiation, and the regulation of cell death programs. Over the last three decades, an increasing number of synthetic and naturally derived compounds, such as dietary-derived products, have been demonstrated to act as HDACi and have provided biological and molecular insights with regard to the role of HDAC in cancer. The first part of this review is focused on the biological roles of the Zinc-dependent HDAC family in malignant diseases. Accordingly, the small-molecules and natural products such as HDACi are described in terms of cancer therapy and chemoprevention. Furthermore, structural considerations are included to improve the HDACi selectivity and combinatory potential with other specific targeting agents in bifunctional inhibitors and proteolysis targeting chimeras. Additionally, clinical trials that combine HDACi with current therapies are discussed, which may open new avenues in terms of the feasibility of HDACi’s future clinical applications in precision cancer therapies.
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Affiliation(s)
- Dusan Ruzic
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11221 Belgrade, Serbia; (D.R.); (N.D.); (K.N.)
| | - Nemanja Djoković
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11221 Belgrade, Serbia; (D.R.); (N.D.); (K.N.)
| | - Tatjana Srdić-Rajić
- Department of Experimental Oncology, Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia;
| | - Cesar Echeverria
- Facultad de Medicina, Universidad de Atacama, Copayapu 485, Copiapo 1531772, Chile;
| | - Katarina Nikolic
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11221 Belgrade, Serbia; (D.R.); (N.D.); (K.N.)
| | - Juan F. Santibanez
- Group for Molecular Oncology, Institute for Medical Research, National Institute of the Republic of Serbia, University of Belgrade, Dr. Subotica 4, POB 102, 11129 Belgrade, Serbia
- Centro Integrativo de Biología y Química Aplicada (CIBQA), Universidad Bernardo O’Higgins, Santiago 8370854, Chile
- Correspondence: ; Tel.: +381-11-2685-788; Fax: +381-11-2643-691
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Jiang L, Wang J, Liu Z, Jiang A, Li S, Wu D, Zhang Y, Zhu X, Zhou E, Wei Z, Yang Z. Sodium Butyrate Alleviates Lipopolysaccharide-Induced Inflammatory Responses by Down-Regulation of NF-κB, NLRP3 Signaling Pathway, and Activating Histone Acetylation in Bovine Macrophages. Front Vet Sci 2020; 7:579674. [PMID: 33251265 PMCID: PMC7674777 DOI: 10.3389/fvets.2020.579674] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Accepted: 10/08/2020] [Indexed: 01/03/2023] Open
Abstract
Sodium butyrate is the sodium salt of butyric acid, which possesses many biological functions including immune system regulation, anti-oxidant and anti-inflammatory ability. The present study was designed to elucidate the anti-inflammatory effects and mechanisms of sodium butyrate on lipopolysaccharide (LPS)-stimulated bovine macrophages. The effect of sodium butyrate on the cell viability of bovine macrophages was assayed by using the CCK-8 kit. Quantitative real-time PCR (qRT-PCR) was used to detect the gene expression of interleukin-6 (IL-6), interleukin-1β (IL-1β), cyclooxygenase-2 (COX-2), and inducible Nitric Oxide Synthase (iNOS). NF-κB, NLRP3 signaling pathway, and histone deacetylase were detected by western blotting. The results showed that sodium butyrate had no significant effect on cell viability at 0-1 mM, and inhibited LPS-induced IL-6, IL-1β, COX-2, and iNOS expression. Moreover, sodium butyrate suppressed LPS (5 μg/ml)-stimulated the phosphorylation of IκB and p65, inhibited the deacetylation of histone H3K9, and has also been found to inhibit protein expression in NLRP3 inflammasomes. Thus, our finding suggested that sodium butyrate relieved LPS-induced inflammatory responses in bovine macrophage by inhibiting the canonical NF-κB, NLRP3 signaling pathway, and histone decetylation, which might be helpful to prevent cow mastitis.
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Affiliation(s)
- Liqiang Jiang
- College of Life Sciences and Engineering, Foshan University, Foshan, China
| | - Jingjing Wang
- College of Veterinary Medicine, Jilin University, Changchun, China
| | - Ziyi Liu
- College of Veterinary Medicine, Jilin University, Changchun, China
| | - Aimin Jiang
- College of Veterinary Medicine, Jilin University, Changchun, China
| | - Shuangqiu Li
- College of Veterinary Medicine, Jilin University, Changchun, China
| | - Di Wu
- College of Veterinary Medicine, Jilin University, Changchun, China
| | - Yong Zhang
- College of Veterinary Medicine, Jilin University, Changchun, China
| | - Xingyi Zhu
- College of Life Sciences and Engineering, Foshan University, Foshan, China
| | - Ershun Zhou
- College of Life Sciences and Engineering, Foshan University, Foshan, China
| | - Zhengkai Wei
- College of Life Sciences and Engineering, Foshan University, Foshan, China
| | - Zhengtao Yang
- College of Life Sciences and Engineering, Foshan University, Foshan, China
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Yao Y, Suo T, Andersson R, Cao Y, Wang C, Lu J, Chui E. Dietary fibre for the prevention of recurrent colorectal adenomas and carcinomas. Cochrane Database Syst Rev 2017; 1:CD003430. [PMID: 28064440 PMCID: PMC6465195 DOI: 10.1002/14651858.cd003430.pub2] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND This is an update of the Cochrane review published in 2002.Colorectal cancer (CRC) is a major cause of morbidity and mortality in industrialised countries. Experimental evidence has supported the hypothesis that dietary fibre may protect against the development of CRC, although epidemiologic data have been inconclusive. OBJECTIVES To assess the effect of dietary fibre on the recurrence of colorectal adenomatous polyps in people with a known history of adenomatous polyps and on the incidence of CRC compared to placebo. Further, to identify the reported incidence of adverse effects, such as abdominal pain or diarrhoea, that resulted from the fibre intervention. SEARCH METHODS We identified randomised controlled trials (RCTs) from Cochrane Colorectal Cancer's Specialised Register, CENTRAL, MEDLINE and Embase (search date, 4 April 2016). We also searched ClinicalTrials.gov and WHO International Trials Registry Platform on October 2016. SELECTION CRITERIA We included RCTs or quasi-RCTs. The population were those having a history of adenomatous polyps, but no previous history of CRC, and repeated visualisation of the colon/rectum after at least two-years' follow-up. Dietary fibre was the intervention. The primary outcomes were the number of participants with: 1. at least one adenoma, 2. more than one adenoma, 3. at least one adenoma greater than or equal to 1 cm, or 4. a new diagnosis of CRC. The secondary outcome was the number of adverse events. DATA COLLECTION AND ANALYSIS Two reviewers independently extracted data, assessed trial quality and resolved discrepancies by consensus. We used risk ratios (RR) and risk difference (RD) with 95% confidence intervals (CI) to measure the effect. If statistical significance was reached, we reported the number needed to treat for an additional beneficial outcome (NNTB) or harmful outcome (NNTH). We combined the study data using the fixed-effect model if it was clinically, methodologically, and statistically reasonable. MAIN RESULTS We included seven studies, of which five studies with 4798 participants provided data for analyses in this review. The mean ages of the participants ranged from 56 to 66 years. All participants had a history of adenomas, which had been removed to achieve a polyp-free colon at baseline. The interventions were wheat bran fibre, ispaghula husk, or a comprehensive dietary intervention with high fibre whole food sources alone or in combination. The comparators were low-fibre (2 to 3 g per day), placebo, or a regular diet. The combined data showed no statistically significant difference between the intervention and control groups for the number of participants with at least one adenoma (5 RCTs, n = 3641, RR 1.04, 95% CI 0.95 to 1.13, low-quality evidence), more than one adenoma (2 RCTs, n = 2542, RR 1.06, 95% CI 0.94 to 1.20, low-quality evidence), or at least one adenoma 1 cm or greater (4 RCTs, n = 3224, RR 0.99, 95% CI 0.82 to 1.20, low-quality evidence) at three to four years. The results on the number of participants diagnosed with colorectal cancer favoured the control group over the dietary fibre group (2 RCTS, n = 2794, RR 2.70, 95% CI 1.07 to 6.85, low-quality evidence). After 8 years of comprehensive dietary intervention, no statistically significant difference was found in the number of participants with at least one recurrent adenoma (1 RCT, n = 1905, RR 0.97, 95% CI 0.78 to 1.20), or with more than one adenoma (1 RCT, n = 1905, RR 0.89, 95% CI 0.64 to 1.24). More participants given ispaghula husk group had at least one recurrent adenoma than the control group (1 RCT, n = 376, RR 1.45, 95% CI 1.01 to 2.08). Other analyses by types of fibre intervention were not statistically significant. The overall dropout rate was over 16% in these trials with no reasons given for these losses. Sensitivity analysis incorporating these missing data shows that none of the results can be considered as robust; when the large numbers of participants lost to follow-up were assumed to have had an event or not, the results changed sufficiently to alter the conclusions that we would draw. Therefore, the reliability of the findings may have been compromised by these missing data (attrition bias) and should be interpreted with caution. AUTHORS' CONCLUSIONS There is a lack of evidence from existing RCTs to suggest that increased dietary fibre intake will reduce the recurrence of adenomatous polyps in those with a history of adenomatous polyps within a two to eight year period. However, these results may be unreliable and should be interpreted cautiously, not only because of the high rate of loss to follow-up, but also because adenomatous polyp is a surrogate outcome for the unobserved true endpoint CRC. Longer-term trials with higher dietary fibre levels are needed to enable confident conclusion.
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Affiliation(s)
- Yibo Yao
- Longhua Hospital, Shanghai Traditional Chinese Medicine UniversityDepartment of Anorectal Surgery725 South Wanping Road, Xuhui DistrictShanghaiShanghaiChina200032
| | - Tao Suo
- Zhongshan Hospital, Fudan UniversityDepartment of General Surgery, Institute of General Surgery180 Fenglin Road, Xuhui DistrictShanghaiShanghaiChina200032
| | - Roland Andersson
- Faculty of Medicine, Lund UniversityDepartment of Surgery, Clinical SciencesLund University HospitalLundSwedenSE‐221 85
| | - Yongqing Cao
- Longhua Hospital, Shanghai Traditional Chinese Medicine UniversityDepartment of Anorectal Surgery725 South Wanping Road, Xuhui DistrictShanghaiShanghaiChina200032
| | - Chen Wang
- Longhua Hospital, Shanghai Traditional Chinese Medicine UniversityDepartment of Anorectal Surgery725 South Wanping Road, Xuhui DistrictShanghaiShanghaiChina200032
| | - Jingen Lu
- Longhua Hospital, Shanghai Traditional Chinese Medicine UniversityDepartment of Anorectal Surgery725 South Wanping Road, Xuhui DistrictShanghaiShanghaiChina200032
| | - Evelyne Chui
- Systematic Review Solutions Ltd5‐6 West Tashan RoadYan TaiChina264000
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Elangovan S, Pathania R, Ramachandran S, Ananth S, Padia RN, Lan L, Singh N, Martin PM, Hawthorn L, Prasad PD, Ganapathy V, Thangaraju M. The niacin/butyrate receptor GPR109A suppresses mammary tumorigenesis by inhibiting cell survival. Cancer Res 2013; 74:1166-78. [PMID: 24371223 DOI: 10.1158/0008-5472.can-13-1451] [Citation(s) in RCA: 90] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
GPR109A, a G-protein-coupled receptor, is activated by niacin and butyrate. Upon activation in colonocytes, GPR109A potentiates anti-inflammatory pathways, induces apoptosis, and protects against inflammation-induced colon cancer. In contrast, GPR109A activation in keratinocytes induces flushing by activation of Cox-2-dependent inflammatory signaling, and the receptor expression is upregulated in human epidermoid carcinoma. Thus, depending on the cellular context and tissue, GPR109A functions either as a tumor suppressor or a tumor promoter. However, the expression status and the functional implications of this receptor in the mammary epithelium are not known. Here, we show that GPR109A is expressed in normal mammary tissue and, irrespective of the hormone receptor status, its expression is silenced in human primary breast tumor tissues, breast cancer cell lines, and in tumor tissues of three different murine mammary tumor models. Functional expression of this receptor in human breast cancer cell lines decreases cyclic AMP production, induces apoptosis, and blocks colony formation and mammary tumor growth. Transcriptome analysis revealed that GPR109A activation inhibits genes, which are involved in cell survival and antiapoptotic signaling, in human breast cancer cells. In addition, deletion of Gpr109a in mice increased tumor incidence and triggered early onset of mammary tumorigenesis with increased lung metastasis in MMTV-Neu mouse model of spontaneous breast cancer. These findings suggest that GPR109A is a tumor suppressor in mammary gland and that pharmacologic induction of this gene in tumor tissues followed by its activation with agonists could be an effective therapeutic strategy to treat breast cancer.
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Affiliation(s)
- Selvakumar Elangovan
- Authors' Affiliations: Departments of Biochemistry and Molecular Biology, Biostatistics and Epidemiology, and Pathology; Cancer Center; Vision Science Discovery Institute, Georgia Regents University; Augusta, Georgia
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Sun C, Liu X, Chen Y, Liu F. Anticancer activities of trichostatin A on maligant lymphoid cells. ACTA ACUST UNITED AC 2013; 26:538-41. [PMID: 17219961 DOI: 10.1007/s11596-006-0513-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
The anticancer activity of trichostain A (TSA) on human B cell non-Hodgkin's lymphoma and its mechanism were explored. The effect of TSA on the growth of Raji cells and normal peripheral blood mononuclear cells (NPBMNC) was studied by MTT assay. The effect of TSA on the apoptosis of Raji cells and NPBMNC was studied by flow cytometry and TDT-mediated dUTP nick end labeling (TUNEL). The effect of TSA on the cell cycle of Raji cells was studied by propidium iodide method. The results showed that TSA potently inhibited proliferation of Raji cells at microgram concentrations and induced apoptosis of Raji cells in a time- and concentration-dependent manner. Treatment with TSA induced accumulation of cells in G0/G1 or G2/M and a concomitant decrease of cell population in S phase. However, NPBMNC was less sensitive to the cytotoxic effect of TSA than Raji cells. It was concluded that TSA may inhibit the proliferation of Raji cells by regulating the cell cycle and inducing the cell apoptosis. Moreover, TSA demonstrates low toxicity in NPBMNC but selectively induces apoptosis of Raji cells.
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Affiliation(s)
- Chunyan Sun
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
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KOYAMA MAKOTO, SOWA YOSHIHIRO, HITOMI TOSHIAKI, IIZUMI YOSUKE, WATANABE MOTOKI, TANIGUCHI TOMOYUKI, ICHIKAWA MASAMI, SAKAI TOSHIYUKI. Perillyl alcohol causes G1 arrest through p15INK4b and p21WAF1/Cip1 induction. Oncol Rep 2012; 29:779-84. [DOI: 10.3892/or.2012.2167] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2012] [Accepted: 11/05/2012] [Indexed: 11/05/2022] Open
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Boghossian S, Hawash A. Chemoprevention in colorectal cancer--where we stand and what we have learned from twenty year's experience. Surgeon 2011; 10:43-52. [PMID: 22129884 DOI: 10.1016/j.surge.2011.07.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2011] [Revised: 07/18/2011] [Accepted: 07/20/2011] [Indexed: 10/14/2022]
Abstract
INTRODUCTION Colorectal chemoprevention is a strategy aimed at preventing tumour progression before irreversible changes to the proteome are in full progress. Chemoprevention is not a new concept. In fact, medical practitioners since the early 19th century have tried various herbal and medicinal products as methods that could prevent tumours. The current understanding of tumourigenesis and cellular signalling focuses on a more targeted approach and paves the way for better understanding of colorectal chemoprevention. METHODS The online databases PubMed, Medline, Medscape Oncology and Scirrus were searched for articles of relevance. The Keyword involved the following words: "Colorectal Cancer Chemoprevention", "Colorectal Cancer", "Chemoprevention", "Adenoma-Carcinoma Sequence" and "Colorectal Polyps". The search was started from the period of June 1995 until September 2010 inclusive. RESULTS More than 50 natural and synthetic compounds have been shown to have chemotherapeutic effect but the majority of these agents are still in their early experimental stages and hence far from our subject of discussion. Our discussion will focus on large scale randomised trials on human subjects or established compounds. Within the context of chemoprevention, Non-steroidal anti-inflammatory agents have undergone extensive research and have shown promising results with large scale randomised trials. Additionally, metformin, resveratrol, Histone deacetylase inhibitors, Src kinases as well monoclonal antibodies have shown promising results as well. CONCLUSION Colorectal cancer is the fourth most common cancer in the world. In the UK alone the number of cases reported in 2008 was almost 40,000 which make it the third most common tumour nationwide. Curative intent surgery or Colectomy is the treatment of choice for most cases of bowel cancer; however, in a select subpopulation of patients who have been colonoscopically diagnosed to harbour pre-malignant lesions, have a family history of colorectal cancer, or have been genetically diagnosed and treated surgically for colorectal tumours; chemoprevention might play a crucial role in deterring further tumour progression. The very latest studies that are in publication or are just accruing results are giving us encouraging data that might suggest whether mass scale ingestion of a specific medication might deter colorectal tumour progression.
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Affiliation(s)
- Shahe Boghossian
- Birmingham Heartland Hospital, Birmingham B9 5SS, United Kingdom.
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Mangian HF, Tappenden KA. Butyrate increases GLUT2 mRNA abundance by initiating transcription in Caco2-BBe cells. JPEN J Parenter Enteral Nutr 2010; 33:607-17; discussion 617. [PMID: 19892901 DOI: 10.1177/0148607109336599] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
BACKGROUND Glucose transporter 2 (GLUT2) is a high-capacity, facilitative intestinal monosaccharide transporter, known to be upregulated by short-chain fatty acids (SCFAs) derived from the intestinal microbiota during fermentation. Understanding the mechanisms regulating intestinal function is important to optimize therapies for patients with intestinal failure and ultimately reduce their dependence on parenteral nutrition. OBJECTIVE The objective was to examine the mechanism regulating the underlying response of GLUT2 to the SCFA butyrate. METHODS GLUT2 messenger RNA (mRNA) abundance was measured in differentiated Caco2-BBe monolayers treated for 0.5-24 hours with 0-20 mM butyrate using quantitative reverse transcription-polymerase chain reaction. Activation of the human GLUT2 promoter was measured using luciferase reporting in transiently transfected Caco2-BBe monolayers. RESULTS GLUT2 mRNA abundance was higher (P < .0001) with 1-4 hours of exposure to 2.5, 7.5, and 10 mM butyrate. Butyrate induced (P < .0001) promoter activity in a dose-dependent fashion. Analysis of the GLUT2 promoter indicated that regions -282/+522, -216/+522, and -145/+522 had a heightened (P < .05) response to butyrate compared with 1135/+522 and 564/+522. CONCLUSIONS Butyrate upregulates GLUT2 mRNA abundance in Caco2-BBe monolayers by activating specific regions within the human GLUT2 promoter. These results identify a cellular mechanism wherein butyrate upregulates intestinal absorption that may be relevant to patients with reduced function. Additional work is necessary to understand cellular targets of butyrate therapy and define clinically appropriate means of providing such strategies, such as consuming prebiotics and probiotics.
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Affiliation(s)
- Heather F Mangian
- Division of Nutritional Sciences, University of Illinois at Champaign-Urbana, Urbana, Illinois, USA
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Yoshida T, Horinaka M, Sakai T. "Combination-oriented molecular-targeting prevention" of cancer: a model involving the combination of TRAIL and a DR5 inducer. Environ Health Prev Med 2010; 15:203-10. [PMID: 21432546 DOI: 10.1007/s12199-009-0128-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2009] [Accepted: 12/11/2009] [Indexed: 12/28/2022] Open
Abstract
Malignant tumors carry a high risk of death, and the prevention of malignant tumors is a crucial issue in preventive medicine. To this end, many chemopreventive agents have been tested, but the effects of single agents have been found to be insufficient to justify clinical trials. We have therefore hypothesized that combinations of different chemopreventive agents may synergistically enhance the preventive effect of chemopreventive agents used singly. To provide the treating physician with some guideline by which to choose the most effective agents to be combined, we propose a strategy which we have termed the "combination-oriented molecular-targeting prevention" of cancer. As the molecular target of our model, we focused on tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which specifically causes apoptosis in malignant tumor cells. Many of these agents were found to up-regulate the expression of death receptor 5, a TRAIL receptor. They were also found to synergistically induce apoptosis in malignant tumor cells when combined with TRAIL. Here, we strongly advocate that the strategy of "combination-oriented molecular-targeting prevention" of cancer will be a practical approach for chemoprevention against human malignant tumors.
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Affiliation(s)
- Tatsushi Yoshida
- Department of Molecular-Targeting Cancer Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
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Yang Z, Song L, Huang C. Gadd45 proteins as critical signal transducers linking NF-kappaB to MAPK cascades. Curr Cancer Drug Targets 2009; 9:915-30. [PMID: 20025601 PMCID: PMC3762688 DOI: 10.2174/156800909790192383] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The growth arrest and DNA damage-inducible 45 (Gadd45) proteins are a group of critical signal transducers that are involved in regulations of many cellular functions. Accumulated data indicate that all three Gadd45 proteins (i.e., Gadd45alpha, Gadd45beta, and Gadd45gamma) play essential roles in connecting an upstream sensor module, the transcription Nuclear Factor-kappaB (NF-kappaB), to a transcriptional regulating module, mitogen-activated protein kinase (MAPK). This NF-kappaB-Gadd45(s)-MAPK pathway responds to various kinds of extracellular stimuli and regulates such cell activities as growth arrest, differentiation, cell survival, and apoptosis. Defects in this pathway can also be related to oncogenesis. In the first part of this review, the functions of Gadd45 proteins, and briefly NF-kappaB and MAPK, are summarized. In the second part, the mechanisms by which Gadd45 proteins are regulated by NF-kappaB, and how they affect MAPK activation, are reviewed.
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Affiliation(s)
- Z. Yang
- Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987, USA
| | - L. Song
- Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987, USA
- Department of Cellular Immunology, Beijing Institute of Basic Medical Sciences, 27 Taiping Road, Beijing 100850, China
| | - C. Huang
- Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987, USA
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14
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Etschmann B, Suplie A, Martens H. Change of ruminal sodium transport in sheep during dietary adaptation. Arch Anim Nutr 2009; 63:26-38. [PMID: 19271549 DOI: 10.1080/17450390802506885] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Rumen adaptation plays an important role in the productive cycle of dairy cattle. In this study, the time course of functional rumen epithelium adaptation after a change from hay feeding (ad libitum) to a mixed hay/concentrate diet was monitored by measuring Na+ transport rates in Ussing chamber experiments. A total of 18 sheep were subjected to different periods of mixed hay/concentrate feeding ranging from 0 weeks (control; hay ad libitum) to 12 weeks (800 g hay plus 800 g concentrate per day in two equal portions). For each animal, the net absorption of sodium was measured following the mixed hay/concentrate feeding period. Net Na transport, Jnet, significantly rose from 2.15 +/- 0.43 (control) to 3.73 +/- 1.02 microeq x cm(-2) x h(-1) after one week of mixed hay/ concentrate diet, reached peak levels of 4.55 +/- 0.50 microEq x cm(-2) x h(-1) after four weeks and levelled out at 3.92 +/- 0.36 microeq x cm(-2) x h(-1) after 12 weeks of mixed feeding. Thus, 73% of functional adaptation occurred during the first week after diet change. This is in apparent contrast to findings that morphological adaptation takes approximately six weeks to reach peak levels. Hence, early functional adaptation to a mixed hay/concentrate diet is characterised by enhanced Na absorption rates per epithelial cell. Absorption rates are likely to be further enhanced by proliferative effects on the rumen epithelium (number and size of papillae) when concentrate diets are fed over longer periods of time. Early functional adaptation without surface area enlargement of the rumen epithelium appears to be the first step in coping with altered fermentation rates following diet change.
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Affiliation(s)
- Benjamin Etschmann
- Institute of Veterinary Physiology, Faculty of Veterinary Medicine, Freie Universität Berlin, Germany
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Hernández A, López-Lluch G, Navas P, Pintor-Toro JA. HDAC and Hsp90 inhibitors down-regulatePTTG1/securin but do not induce aneuploidy. Genes Chromosomes Cancer 2009; 48:194-201. [DOI: 10.1002/gcc.20630] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
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Histone deacetylase inhibitors: mechanisms and clinical significance in cancer: HDAC inhibitor-induced apoptosis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2008; 615:261-98. [PMID: 18437899 DOI: 10.1007/978-1-4020-6554-5_13] [Citation(s) in RCA: 114] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Epigenic modifications, mainly DNA methylation and acetylation, are recognized as the main mechanisms contributing to the malignant phenotype. Acetylation and deacetylation are catalyzed by specific enzymes, histone acetyltransferases (HATs) and histone deacetylases (HDACs), respectively. While histones represent a primary target for the physiological function of HDACs, the antitumor effect of HDAC inhibitors might also be attributed to transcription-independent mechanisms by modulating the acetylation status of a series of non-histone proteins. HDAC inhibitors may act through the transcriptional reactivation of dormant tumor suppressor genes. They also modulate expression of several other genes related to cell cycle, apoptosis, and angiogenesis. Several HDAC inhibitors are currently in clinical trials both for solid and hematologic malignancies. Thus, HDAC inhibitors, in combination with DNA-demethylating agents, chemopreventive, or classical chemotherapeutic drugs, could be promising candidates for cancer therapy. Here, we review the molecular mechanisms and therapeutic potential of HDAC inhibitors for the treatment of cancer.
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Yokota T, Matsuzaki Y, Koyama M, Hitomi T, Kawanaka M, Enoki-Konishi M, Okuyama Y, Takayasu J, Nishino H, Nishikawa A, Osawa T, Sakai T. Sesamin, a lignan of sesame, down-regulates cyclin D1 protein expression in human tumor cells. Cancer Sci 2007; 98:1447-53. [PMID: 17640297 PMCID: PMC11159746 DOI: 10.1111/j.1349-7006.2007.00560.x] [Citation(s) in RCA: 74] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2007] [Revised: 05/24/2007] [Accepted: 05/29/2007] [Indexed: 11/26/2022] Open
Abstract
Sesamin is a major lignan constituent of sesame and possesses multiple functions such as antihypertensive, cholesterol-lowering, lipid-lowering and anticancer activities. Several groups have previously reported that sesamin induces growth inhibition in human cancer cells. However, the nature of this growth inhibitory mechanism remains unknown. The authors here report that sesamin induces growth arrest at the G1 phase in cell cycle progression in the human breast cancer cell line MCF-7. Furthermore, sesamin dephosphorylates tumor-suppressor retinoblastoma protein (RB). It is also shown that inhibition of MCF-7 cell proliferation by sesamin is correlated with down-regulated cyclin D1 protein expression, a proto-oncogene that is overexpressed in many human cancer cells. It was found that sesamin-induced down-regulation of cyclin D1 was inhibited by proteasome inhibitors, suggesting that sesamin suppresses cyclin D1 protein expression by promoting proteasome degradation of cyclin D1 protein. Sesamin down-regulates cyclin D1 protein expression in various kinds of human tumor cells, including lung cancer, transformed renal cells, immortalized keratinocyte, melanoma and osteosarcoma. Furthermore, depletion of cyclin D1 protein using small interfering RNA rendered MCF-7 cells insensitive to the growth inhibitory effects of sesamin, implicating that cyclin D1 is at least partially related to the antiproliferative effects of sesamin. Taken together, these results suggest that the ability of sesamin to down-regulate cyclin D1 protein expression through the activation of proteasome degradation could be one of the mechanisms of the antiproliferative activity of this agent.
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Affiliation(s)
- Tomoya Yokota
- Department of Molecular-Targeting Cancer Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
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Koyama M, Matsuzaki Y, Yogosawa S, Hitomi T, Kawanaka M, Sakai T. ZD1839 induces p15INK4b and causes G1 arrest by inhibiting the mitogen-activated protein kinase/extracellular signal–regulated kinase pathway. Mol Cancer Ther 2007; 6:1579-87. [PMID: 17513607 DOI: 10.1158/1535-7163.mct-06-0814] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Inactivation of the retinoblastoma protein pathway is the most common abnormality in malignant tumors. We therefore tried to detect agents that induce the cyclin-dependent kinase inhibitor p15(INK4b) and found that ZD1839 (gefitinib, Iressa) could up-regulate p15(INK4b) expression. ZD1839 has been shown to inhibit cell cycle progression through inhibition of signaling pathways such as phosphatidylinositol 3'-kinase-Akt and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) cascades. However, the mechanism responsible for the differential sensitivity of the signaling pathways to ZD1839 remains unclear. We here showed that ZD1839 up-regulated p15(INK4b), resulting in retinoblastoma hypophosphorylation and G(1) arrest in human immortalized keratinocyte HaCaT cells. p15(INK4b) induction was caused by MAPK/ERK kinase inhibitor (PD98059), but not by Akt inhibitor (SH-6, Akt-III). Moreover, mouse embryo fibroblasts lacking p15(INK4b) were resistant to the growth inhibitory effects of ZD1839 compared with wild-type mouse embryo fibroblasts. Additionally, the status of ERK phosphorylation was related to the antiproliferative activity of ZD1839 in human colon cancer HT-29 and Colo320DM cell lines. Our results suggest that induction of p15(INK4b) by inhibition of the MAPK/ERK pathway is associated with the antiproliferative effects of ZD1839.
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Affiliation(s)
- Makoto Koyama
- Department of Molecular-Targeting Cancer Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
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Ammerpohl O, Trauzold A, Schniewind B, Griep U, Pilarsky C, Grutzmann R, Saeger HD, Janssen O, Sipos B, Kloppel G, Kalthoff H. Complementary effects of HDAC inhibitor 4-PB on gap junction communication and cellular export mechanisms support restoration of chemosensitivity of PDAC cells. Br J Cancer 2006; 96:73-81. [PMID: 17164759 PMCID: PMC2360208 DOI: 10.1038/sj.bjc.6603511] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease and one of the cancer entities with the lowest life expectancy. Beside surgical therapy, no effective therapeutic options are available yet. Here, we show that 4-phenylbutyrate (4-PB), a known and well-tolerable inhibitor of histone deacetylases (HDAC), induces up to 70% apoptosis in all cell lines tested (Panc 1, T4M-4, COLO 357, BxPc3). In contrast, it leads to cell cycle arrest in only half of the cell lines tested. This drug increases gap junction communication between adjacent T3M-4 cells in a concentration-dependent manner and efficiently inhibits cellular export mechanisms in Panc 1, T4M-4, COLO 357 and BxPc3 cells. Consequently, in combination with gemcitabine 4-PB shows an overadditive effect on induction of apoptosis in BxPc3 and T3M-4 cells (up to 4.5-fold compared to single drug treatment) with accompanied activation of Caspase 8, BH3 interacting domain death agonist (Bid) and poly (ADP-ribose) polymerase family, member 1 (PARP) cleavage. Although the inhibition of the mitogen-activated protein kinase-pathway has no influence on fulminant induction of apoptosis, the inhibition of the JNK-pathway by SP600125 completely abolishes the overadditive effect induced by the combined application of both drugs, firstly reported by this study.
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Affiliation(s)
- O Ammerpohl
- Section Molecular Oncology, Clinic for General Surgery and Thoracic Surgery, University Hospital Schleswig-Holstein Campus Kiel, Arnold-Heller Strasse 7, Kiel 24105, Germany
| | - A Trauzold
- Section Molecular Oncology, Clinic for General Surgery and Thoracic Surgery, University Hospital Schleswig-Holstein Campus Kiel, Arnold-Heller Strasse 7, Kiel 24105, Germany
| | - B Schniewind
- Section Molecular Oncology, Clinic for General Surgery and Thoracic Surgery, University Hospital Schleswig-Holstein Campus Kiel, Arnold-Heller Strasse 7, Kiel 24105, Germany
| | - U Griep
- Section Molecular Oncology, Clinic for General Surgery and Thoracic Surgery, University Hospital Schleswig-Holstein Campus Kiel, Arnold-Heller Strasse 7, Kiel 24105, Germany
| | - C Pilarsky
- Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technical University of Dresden, Dresden 01307, Germany
| | - R Grutzmann
- Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technical University of Dresden, Dresden 01307, Germany
| | - H-D Saeger
- Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technical University of Dresden, Dresden 01307, Germany
| | - O Janssen
- Institute of Immunology, University Hospital Schleswig-Holstein Campus Kiel, Kiel 24105, Germany
| | - B Sipos
- Institute of Pathology, University Hospital Schleswig-Holstein Campus Kiel, Kiel 24105, Germany
| | - G Kloppel
- Institute of Pathology, University Hospital Schleswig-Holstein Campus Kiel, Kiel 24105, Germany
| | - H Kalthoff
- Section Molecular Oncology, Clinic for General Surgery and Thoracic Surgery, University Hospital Schleswig-Holstein Campus Kiel, Arnold-Heller Strasse 7, Kiel 24105, Germany
- E-mail:
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20
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Schniewind B, Heintz K, Kurdow R, Ammerpohl O, Trauzold A, Emme D, Dohrmann P, Kalthoff H. Combination phenylbutyrate/gemcitabine therapy effectively inhibits in vitro and in vivo growth of NSCLC by intrinsic apoptotic pathways. J Carcinog 2006; 5:25. [PMID: 17123441 PMCID: PMC1665446 DOI: 10.1186/1477-3163-5-25] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2006] [Accepted: 11/23/2006] [Indexed: 01/03/2023] Open
Abstract
Background Standard chemotherapy protocols in NSCLC are of limited clinical benefit. Histone deacetylase (HDAC) inhibitors represent a new strategy in human cancer therapy. In this study the combination of the HDAC inhibitor phenylbutyrate (PB) and the nucleoside analogue gemcitabine (GEM) was evaluated and the mechanisms underlying increased cell death were analyzed. Methods Dose escalation studies evaluating the cytotoxicity of PB (0.01–100 mM), GEM (0.01–100 μg/ml) and a combination of the two were performed on two NSCLC cell lines (BEN and KNS62). Apoptotic cell death was quantified. The involvement of caspase-dependent cell death and MAP-kinase activation was analyzed. Additionally, mitochondrial damage was determined. In an orthotopic animal model the combined effect of PB and GEM on therapy was analyzed. Results Applied as a single drug both GEM and PB revealed limited potential to induce apoptosis in KNS62 and Ben cells. Combination therapy was 50–80% (p = 0.012) more effective than either agent alone. On the caspase level, combination therapy significantly increased cleavage of the pro-forms compared to single chemotherapy. The broad spectrum caspase-inhibitor zVAD was able to inhibit caspase cleavage completely, but reduced the frequency of apoptotic cells only by 30%. Combination therapy significantly increased changes in MTP and the release of cyto-c, AIF and Smac/Diabolo into the cytoplasm. Furthermore, the inhibitors of apoptosis c-IAP1 and c-IAP2 were downregulated and it was shown that in combination therapy JNK activation contributed significantly to induction of apoptosis. The size of the primary tumors growing orthotopically in SCID mice treated for 4 weeks with GEM and PB was significantly reduced (2.2–2.7 fold) compared to GEM therapy alone. The Ki-67 (KNS62: p = 0.015; Ben: p = 0.093) and topoisomerase IIα (KNS62: p = 0.008; Ben: p = 0.064) proliferation indices were clearly reduced in tumors treated by combination therapy, whereas the apoptotic index was comparably low in all groups. Conclusion Therapy combining GEM and the HDAC inhibitor PB initiates a spectrum of apoptosis-inducing mitochondrial and further JNK-dependent events, thereby overcoming the therapeutic resistance of NSCLC tumor cells. In vivo, the combination therapy substantially reduced tumor cell proliferation, suggesting that the well tolerated PB is a useful supplemental therapeutic agent in NSCLC.
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Affiliation(s)
- Bodo Schniewind
- Hospital for General and Thoracic Surgery, Schleswig-Holstein University Hospitals, Campus Kiel, Arnold-Heller-Str 7, Kiel, Germany
| | - Kirsten Heintz
- Molecular Oncology Section, Schleswig-Holstein University Hospitals, Campus Kiel, Arnold-Heller-Str 7, Kiel, Germany
| | - Roland Kurdow
- Hospital for General and Thoracic Surgery, Schleswig-Holstein University Hospitals, Campus Kiel, Arnold-Heller-Str 7, Kiel, Germany
| | - Ole Ammerpohl
- Molecular Oncology Section, Schleswig-Holstein University Hospitals, Campus Kiel, Arnold-Heller-Str 7, Kiel, Germany
| | - Anna Trauzold
- Molecular Oncology Section, Schleswig-Holstein University Hospitals, Campus Kiel, Arnold-Heller-Str 7, Kiel, Germany
| | - Doris Emme
- Molecular Oncology Section, Schleswig-Holstein University Hospitals, Campus Kiel, Arnold-Heller-Str 7, Kiel, Germany
| | - Peter Dohrmann
- Hospital for General and Thoracic Surgery, Schleswig-Holstein University Hospitals, Campus Kiel, Arnold-Heller-Str 7, Kiel, Germany
| | - Holger Kalthoff
- Molecular Oncology Section, Schleswig-Holstein University Hospitals, Campus Kiel, Arnold-Heller-Str 7, Kiel, Germany
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Wang YF, Chen NS, Chung YP, Chang LH, Chiou YH, Chen CY. Sodium butyrate induces apoptosis and cell cycle arrest in primary effusion lymphoma cells independently of oxidative stress and p21(CIP1/WAF1) induction. Mol Cell Biochem 2006; 285:51-9. [PMID: 16477379 DOI: 10.1007/s11010-005-9054-x] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2005] [Accepted: 10/14/2005] [Indexed: 10/25/2022]
Abstract
Primary effusion lymphoma, a peculiar type of B cell non-Hodgkin lymphoma, preferentially develops in immunodeficient individuals and its pathogenesis is closely linked with human herpesvirus 8 (HHV-8). HHV-8 is present primarily persistence in primary effusion lymphoma cells, and the lytic cycle of HHV-8 can be induced by sodium butyrate (NaB) treatment. HHV-8 gene expression is affected by NaB in BCBL-1 cells, but the cellular response of BCBL-1 cells upon NaB treatment has not been investigated to date. Using BCBL-1 cells, a HHV-8 harboring cell line, we demonstrated that sodium butyrate could induce the reactive oxygen species generation, apoptosis and cell cycle arrest in BCBL-1 cells. The sodium butyrate-induce cell cycle arrest was associated with the decrease of Cdc2, Cdk4 and cyclin A in BCBL-1 cells without altering the protein levels of p21(CIP1/WAF1). The apoptosis induced by sodium butyrate in BCBL-1 cells was independent of oxidative stress.
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Affiliation(s)
- Yi-Fen Wang
- Department of Medical Technology, Fooyin University, 151 Chin-Hsuen Road, Ta-Liao, Kaohsiung Hsien, Taiwan, Republic of China.
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22
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Ruscetti FW, Akel S, Bartelmez SH. Autocrine transforming growth factor-beta regulation of hematopoiesis: many outcomes that depend on the context. Oncogene 2005; 24:5751-63. [PMID: 16123808 DOI: 10.1038/sj.onc.1208921] [Citation(s) in RCA: 91] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Transforming growth factor-beta (TGF-beta) is a pleiotropic regulator of all stages of hematopoieis. The three mammalian isoforms (TGF-beta1, 2 and 3) have distinct but overlapping effects on hematopoiesis. Depending on the differentiation stage of the target cell, the local environment and the concentration and isoform of TGF-beta, in vivo or in vitro, TGF-beta can be pro- or antiproliferative, pro- or antiapoptotic, pro- or antidifferentiative and can inhibit or increase terminally differentiated cell function. TGF-beta is a major regulator of stem cell quiescence, at least in vitro. TGF-beta can act directly or indirectly through effects on the bone marrow microenvironment. In addition, paracrine and autocrine actions of TGF-beta have overlapping but distinct regulatory effects on hematopoietic stem/progenitor cells. Since TGF-beta can act in numerous steps in the hematopoietic cascade, loss of function mutations in hematopoeitic stem cells (HSC) have different effects on hematopoiesis than transient blockade of autocrine TGF-beta1. Transient neutralization of autocrine TGF-beta in HSC has therapeutic potential. In myeloid and erythroid leukemic cells, autocrine TGF-beta1 and/or its Smad signals controls the ability of these cells to respond to various differentiation inducers, suggesting that this pathway plays a role in determining the cell fate of leukemic cells.
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Affiliation(s)
- Francis W Ruscetti
- Laboratory of Experimental Immunology, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD 21702-1201, USA.
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Oki T, Sowa Y, Hirose T, Takagaki N, Horinaka M, Nakanishi R, Yasuda C, Yoshida T, Kanazawa M, Satomi Y, Nishino H, Miki T, Sakai T. Genistein induces Gadd45 gene and G2/M cell cycle arrest in the DU145 human prostate cancer cell line. FEBS Lett 2005; 577:55-9. [PMID: 15527761 DOI: 10.1016/j.febslet.2004.09.085] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2004] [Revised: 09/25/2004] [Accepted: 09/26/2004] [Indexed: 11/24/2022]
Abstract
Genistein is the most abundant isoflavone of soybeans and has been shown to cause growth arrest in various human cancer cell lines. However, the precise mechanism for this is still unclear. We report here that the growth arrest and DNA damage-inducible gene 45 (gadd45) gene is induced by genistein via its promoter in a DU145 human prostate cancer cell line. The binding of transcription factor nuclear factor-Y to the CCAAT site of the gadd45 promoter appears to be important for this activation by genistein.
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Affiliation(s)
- Teruki Oki
- Department of Molecular-Targeting Cancer Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
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24
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Jung JW, Cho SD, Ahn NS, Yang SR, Park JS, Jo EH, Hwang JW, Jung JY, Kim SH, Kang KS, Lee YS. Ras/MAP kinase pathways are involved in Ras specific apoptosis induced by sodium butyrate. Cancer Lett 2004; 225:199-206. [PMID: 15978324 DOI: 10.1016/j.canlet.2004.11.029] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2004] [Revised: 11/08/2004] [Accepted: 11/19/2004] [Indexed: 01/12/2023]
Abstract
Histone deacetylase inhibitors such as TSA, SAHA, and NaBu etc. are prospective cancer therapeutics of growing interest. Here, we demonstrated that oncogenic ras-transformed rat liver epithelial (WB-ras) cells were specifically undergone apoptosis by 48 h treatment of NaBu. During this, inhibition of ras proteins, especially farnesylated form of ras, and down-regulation of ERK1/2 were observed, which suggest ras/raf/MEK/ERK down-regulation, while p38 MAP kinase was maintained up-regulated. In addition, up-regulation of pro-apoptotic proteins such as p53 and p21CIP1/WAF1, and down-regulation of cell cycle regulator/anti-apoptotic proteins such as cdk2, -4 and phosphorylated Akt were observed concurrently with an increase in apoptotic cell portion. A phosphatase inhibitor, sodium orthovanadate (SOV), efficiently blocked apoptosis and restored responsible proteins for each phenomenon including ERK1/2 while SB203580, a specific p38 MAP kinase inhibitor, showed minor effect on them. Thus, ras/ERK signaling pathway can be considered in chemotherapeutic strategies of NaBu regardless of its inhibitory action on histone deacetylase.
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Affiliation(s)
- Ji-Won Jung
- Department of Veterinary Public Health, College of Veterinary Medicine, Seoul National University, Seoul 151-742, South Korea
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Yokota T, Matsuzaki Y, Sakai T. Trichostatin A activates p18INK4c gene: differential activation and cooperation with p19INK4d gene. FEBS Lett 2004; 574:171-5. [PMID: 15358560 DOI: 10.1016/j.febslet.2004.08.025] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2004] [Revised: 08/12/2004] [Accepted: 08/12/2004] [Indexed: 11/15/2022]
Abstract
We have reported that histone deacetylase (HDAC) inhibitors activate a member of the INK4 family, the p19INK4d gene, causing G1 phase arrest. We report here that HDAC inhibitor, Trichostatin A, activates another member of the INK4 family, the p18INK4c gene, through its promoter in Jurkat cells. Interestingly, the activation patterns of the p18INK4c gene were different from those of p19INK4d. Furthermore, mouse embryo fibroblasts lacking p18Ink4c or p18Ink4c/p19Ink4d were resistant to the growth inhibitory effects of TSA as compared to their wild-type counterpart. Our findings suggest that p18INK4c is involved in TSA-mediated cell growth inhibition and cooperates with p19INK4d.
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Affiliation(s)
- Tomoya Yokota
- Department of Molecular-Targeting Cancer Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
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26
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Matsuzaki Y, Koyama M, Hitomi T, Kawanaka M, Sakai T. Indole-3-carbinol activates the cyclin-dependent kinase inhibitor p15INK4bgene. FEBS Lett 2004; 576:137-40. [PMID: 15474025 DOI: 10.1016/j.febslet.2004.09.002] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2004] [Revised: 09/02/2004] [Accepted: 09/05/2004] [Indexed: 12/19/2022]
Abstract
Indole-3-carbinol (I3C) is a naturally occurring compound found in vegetables such as broccoli and cauliflower, and has been shown to arrest human tumor cells in the G1 phase of the cell cycle. However, the molecular mechanism responsible for this effect has not been sufficiently elucidated. We report here that I3C activates the cyclin-dependent kinase (CDK) inhibitor p15INK4b gene through its promoter, accompanied by cell growth inhibition in HaCaT cells. Treatment with I3C almost did not affect the expressions of the other CDK inhibitors such as p19INK4d, p21WAF1 and p27Kip1. These results suggest that p15INK4b is an important molecular target of I3C among CDK inhibitors.
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Affiliation(s)
- Youichirou Matsuzaki
- Department of Molecular-Targeting Cancer Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
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Yokota T, Matsuzaki Y, Miyazawa K, Zindy F, Roussel MF, Sakai T. Histone deacetylase inhibitors activate INK4d gene through Sp1 site in its promoter. Oncogene 2004; 23:5340-9. [PMID: 15107822 DOI: 10.1038/sj.onc.1207689] [Citation(s) in RCA: 71] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Histone deacetylase (HDAC) inhibitors are known to arrest human tumor cells at the G1 phase of the cell cycle and activate the cyclin-dependent kinase inhibitor, p21(WAF1/Cip1). However, several studies have suggested the existence of a p21(WAF1/Cip1)-independent molecular pathway. We report here that HDAC inhibitors activate a member of the INK4 family, the INK4d gene, causing G1 phase arrest, in the human T cell leukemia cell line, Jurkat. One of the major Trichostatin A (TSA)-responsive elements is a specific Sp1 binding site in the INK4d promoter. Electrophoretic mobility-shift assay revealed that Sp1 and Sp3 can specifically interact with this Sp1 binding site. Furthermore, using chromatin immunoprecipitation assay, we demonstrated that HDAC2 was present in the INK4d proximal promoter region in the absence, but not the presence, of TSA. Taken together, these results suggest that treatment with TSA transcriptionally activates INK4d by releasing HDAC2 from the histone-DNA complex at the INK4d promoter. Using a p21(WAF1/Cip1)-deleted human colorectal carcinoma cell line, HCT116 p21 (-/-), we show that upregulation of p19(INK4d) by TSA is associated with inhibition of cell proliferation. Moreover, mouse embryo fibroblasts lacking Ink4d were resistant to the growth inhibitory effects of TSA as compared to their wild-type counterpart. Our findings suggest that p19(INK4d) in addition to p21(WAF1/Cip1) is an important molecular target of HDAC inhibitors inducing growth arrest.
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Affiliation(s)
- Tomoya Yokota
- Department of Molecular-Targeting Cancer Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
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Chopin V, Toillon RA, Jouy N, Le Bourhis X. P21(WAF1/CIP1) is dispensable for G1 arrest, but indispensable for apoptosis induced by sodium butyrate in MCF-7 breast cancer cells. Oncogene 2004; 23:21-9. [PMID: 14712207 DOI: 10.1038/sj.onc.1207020] [Citation(s) in RCA: 78] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Sodium butyrate (NaB) has been proposed as a potential anticancer agent. However, its mechanism of action is not totally elucidated. Here, we showed that NaB-induced cell cycle arrest and apoptosis were associated with an increase of P21(waf1/cip1) in MCF-7 breast cancer cells. This increase was more important in the nuclei, as revealed by immunofluorescence analysis. Transient transfections of MCF-7 cells with p21 deficient for interaction with CDK, but not with p21 deficient for interaction with PCNA (p21PCNA-), abrogated NaB-induced cell cycle arrest. This indicated that cell cycle blockage involved the interaction of P21(waf1/cip1) with CDK. However, P21(waf1/cip1) was dispensable, since p21 antisense did not modify cell cycle arrest. On the other hand, NaB-induced apoptosis was abolished by p21 antisense or p21PCNA-. In addition, NaB decreased PCNA levels, but increased the association of PCNA with P21(waf1/cip1). These results suggested that NaB-induced apoptosis required P21(waf1/cip1) and its interaction with PCNA.
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Affiliation(s)
- Valérie Chopin
- Equipe facteurs de croissance, Laboratoire de Biologie du Développement (UPRES 1033), IFR 118, Université des Sciences et Technologies de Lille, Villeneuve d'Ascq Cedex 59655, France
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29
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Abstract
TRAIL-R2 promoter does not have a typical TATA-box but two functional Sp1-binding sites. TRAIL-R2 promoter belongs to the class of TATA-less and GC-box-containing promoters. The minimal promoter element is contained in the region spanning -198 to -116 upstream of translational initiation codon ATG. Computer analysis shows putative transcription factor binding sites such as c-Ets, AML-1a, c-Myb, Sp1, and GATA-1 in TRAIL-R2 promoter. Hypermethylation of TRAIL-R2 is not frequent compared with that of TRAIL-R3 and TRIAL-R4. There are no potential transcription factor binding sites in highly homologous regions between TRAIL-R2 promoter and TRAIL-R1 promoter, or between TRAIL-R2 promoter and mouse homologue mouse killer (MK) promoter. TRAIL-R2 is known to be a downstream gene of p53, a tumor-suppressor gene, and a p53-binding site in TRAIL-R2 intron 1 is responsible for p53-dependent transcription. Thapsigargin, endoplasmic reticulum Ca(2+)-ATPase inhibitor calcium releaser, upregulates TRAIL-R2 expression via the promoter region. Many regulators of TRAIL-R2 have been reported. However, it has not been demonstrated whether they regulate TRAIL-R2 via the promoter region. Here, we show a list of these regulators. Finally, we demonstrate the possibility of cancer therapy using regulation of TRAIL-R2 promoter.
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Affiliation(s)
- Tatsushi Yoshida
- Department of Molecular-Targeting Cancer Prevention Graduate School of Medical Science, Kyoto Prefectural University of Medicine Kyoto 602-8566, Japan
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Hitomi T, Matsuzaki Y, Yokota T, Takaoka Y, Sakai T. p15(INK4b) in HDAC inhibitor-induced growth arrest. FEBS Lett 2003; 554:347-50. [PMID: 14623092 DOI: 10.1016/s0014-5793(03)01186-4] [Citation(s) in RCA: 60] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Histone deacetylase (HDAC) inhibitors arrest human tumor cells at the G1 phase of the cell cycle and activate the cyclin-dependent kinase inhibitor, p21(WAF1/Cip1). However, several studies have suggested the existence of a p21(WAF1/Cip1)-independent molecular pathway. We report here that HDAC inhibitors, trichostatin A (TSA) and sodium butyrate, activate the p15(INK4b) gene, a member of the INK4 gene family, through its promoter in HaCaT cells. Furthermore, we show that up-regulation of p15(INK4b) by TSA is associated with cell growth inhibition of HCT116 p21 (-/-) cells. Our findings suggest that p15(INK4b) is one of the important molecular targets of HDAC inhibitors.
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Affiliation(s)
- Toshiaki Hitomi
- Department of Molecular-Targeting Cancer Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
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Matsuzaki Y, Sowa Y, Hirose T, Yokota T, Sakai T. Histone deacetylase inhibitors -Promising agents for 'gene-regulating chemoprevention' and 'molecular-targeting prevention' of cancer-. Environ Health Prev Med 2003; 8:157-60. [PMID: 21432092 PMCID: PMC2723507 DOI: 10.1007/bf02897908] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2003] [Accepted: 09/17/2003] [Indexed: 10/22/2022] Open
Abstract
One of the best approaches against cancer is prevention. Inactivation of the p53 or p16(INK4a) genes has been extensively reported in most human cancer cells. Both p53 and p16(INK4a) function as tumor suppressors. Therefore, functional restoration of these molecules is considered to be one of the most useful methods for cancer prevention and therapy. We have proposed a concept termed 'gene-regulating chemoprevention and chemotherapy' regarding the above pathway. This concept assumes that transcriptional regulation by drugs on tumor-suppressor genes, downstream target genes or functionally similar genes (for example, family genes) of the tumor-suppressor genes would contribute to the prevention of human malignancies. Histone deacetylase (HDAC) inhibitors have been shown to be potent inducers of growth arrest, differentiation and apoptotic cell death. Previously, we demonstrated that HDAC inhibitors, such as sodium butyrate and trichostatin A (TSA), transcriptionally induce the cyclin-dependent kinase inhibitor p21(WAF1/Cip1), a downstream target gene of p53, in a p53-independent manner. Furthermore, we have recently shown that HDAC inhibitors activate Gadd45, another downstream target gene of p53, and p19(INK4d), a gene functionally similar to p16(INK4a). Our results, taken together with previous findings, suggest that HDAC inhibitors may be one of the most attractive and promising agents for 'gene-regulating chemoprevention' and 'molecular-targeting prevention' of cancer.
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Affiliation(s)
- Youichirou Matsuzaki
- Department of Molecular-Targeting Cancer Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, 602-8566 Kyoto, Japan
| | - Yoshihiro Sowa
- Department of Molecular-Targeting Cancer Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, 602-8566 Kyoto, Japan
| | - Tohru Hirose
- Department of Molecular-Targeting Cancer Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, 602-8566 Kyoto, Japan
| | - Tomoya Yokota
- Department of Molecular-Targeting Cancer Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, 602-8566 Kyoto, Japan
| | - Toshiyuki Sakai
- Department of Molecular-Targeting Cancer Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, 602-8566 Kyoto, Japan
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Hirose T, Sowa Y, Takahashi S, Saito S, Yasuda C, Shindo N, Furuichi K, Sakai T. p53-independent induction of Gadd45 by histone deacetylase inhibitor: coordinate regulation by transcription factors Oct-1 and NF-Y. Oncogene 2003; 22:7762-73. [PMID: 14586402 DOI: 10.1038/sj.onc.1207091] [Citation(s) in RCA: 96] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2002] [Revised: 08/06/2003] [Accepted: 08/07/2003] [Indexed: 11/09/2022]
Abstract
Histone deacetylase (HDAC) inhibitors cause growth arrest at the G1 and/or G2/M phases, and induce differentiation and/or apoptosis in a wide variety of tumour cells. The growth arrest at G1 phase by HDAC inhibitors is thought to be highly dependent on the upregulation of p21/WAF1, but the precise mechanism by which HDAC inhibitors cause G2/M arrest or apoptosis in tumour cells is unknown. Gadd45 causes cell cycle arrest at the G2/M phase transition and participates in genotoxic stress-induced apoptosis. We show here that it is also induced by a typical HDAC inhibitor, trichostatin A (TSA), through its promoter, in a p53-independent manner. To identify the mechanism of activation of the gadd45 promoter, we performed luciferase reporter analyses and electrophoretic mobility shift assays. These revealed that both the Oct-1 and CCAAT sites are needed for the full activation by TSA. We also found that the transcription factors Oct-1 and NF-Y specifically bind to each site. Thus, HDAC inhibitors can induce Gadd45 through its promoter without the need for functional p53, and both the Oct-1 and NF-Y concertedly participate in TSA-induced activation of the gadd45 promoter.
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Affiliation(s)
- Tohru Hirose
- Department of Preventive Medicine, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto 602-8566, Japan
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Rahmani M, Yu C, Reese E, Ahmed W, Hirsch K, Dent P, Grant S. Inhibition of PI-3 kinase sensitizes human leukemic cells to histone deacetylase inhibitor-mediated apoptosis through p44/42 MAP kinase inactivation and abrogation of p21CIP1/WAF1 induction rather than AKT inhibition. Oncogene 2003; 22:6231-42. [PMID: 13679862 DOI: 10.1038/sj.onc.1206646] [Citation(s) in RCA: 82] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Effects of the PI-3 kinase inhibitor LY294002 (LY) have been examined in relation to responses of human leukemia cells to histone deacetylase inhibitors (HDIs). Coexposure of U937 cells for 24 h to marginally toxic concentrations of LY294002 (e.g., 30 microM) and sodium butyrate (SB; 1 mM) resulted in a marked increase in mitochondrial damage (e.g., cytochrome c and Smac/DIABLO release, loss of DeltaPsi(m)), caspase activation, and apoptosis. Similar results were observed in Jurkat, HL-60, and K562 leukemic cells and with other HDIs (e.g., SAHA, MS-275). Exposure of cells to SB/LY was associated with Bcl-2 and Bid cleavage, XIAP and Mcl-1 downregulation, and diminished CD11b expression. While LY blocked SB-mediated Akt activation, enforced expression of a constitutively active (myristolated) Akt failed to attenuate SB/LY-mediated lethality. Unexpectedly, treatment of cells with SB+/-LY resulted in a marked reduction in phosphorylation (activation) of p44/42 mitogen-activated protein (MAP) kinase. Moreover, enforced expression of a constitutively active MEK1 construct partially but significantly attenuated SB/LY-induced apoptosis. Lastly, cotreatment with LY blocked SB-mediated induction of p21(CIP1/WAF1); moreover, enforced expression of p21(CIP1/WAF1) significantly reduced SB/LY-mediated apoptosis. Together, these findings indicate that LY promotes SB-mediated apoptosis through an AKT-independent process that involves MEK/MAP kinase inactivation and interference with p21(CIP1/WAF1) induction.
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Affiliation(s)
- Mohamed Rahmani
- Department of Medicine, Medical College of Viriginia, Virginia Commonwealth University, Richmond, VA 23298, USA
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Abstract
This article reviews the effects of the short-chain fatty acid butyrate on histone deacetylase (HDAC) activity. Sodium butyrate has multiple effects on cultured mammalian cells that include inhibition of proliferation, induction of differentiation and induction or repression of gene expression. The observation that butyrate treatment of cells results in histone hyperacetylation initiated a flurry of activity that led to the discovery that butyrate inhibits HDAC activity. Butyrate has been an essential agent for determining the role of histone acetylation in chromatin structure and function. Interestingly, inhibition of HDAC activity affects the expression of only 2% of mammalian genes. Promoters of butyrate-responsive genes have butyrate response elements, and the action of butyrate is often mediated through Sp1/Sp3 binding sites (e.g., p21(Waf1/Cip1)). We demonstrated that Sp1 and Sp3 recruit HDAC1 and HDAC2, with the latter being phosphorylated by protein kinase CK2. A model is proposed in which inhibition of Sp1/Sp3-associated HDAC activity leads to histone hyperacetylation and transcriptional activation of the p21(Waf1/Cip1) gene; p21(Waf1/Cip1) inhibits cyclin-dependent kinase 2 activity and thereby arrests cell cycling. Pending the cell background, the nonproliferating cells may enter differentiation or apoptotic pathways. The potential of butyrate and HDAC inhibitors in the prevention and treatment of cancer is presented.
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Affiliation(s)
- James R Davie
- Manitoba Institute of Cell Biology, Winnipeg, Manitoba, Canada.
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Chen Z, Clark S, Birkeland M, Sung CM, Lago A, Liu R, Kirkpatrick R, Johanson K, Winkler JD, Hu E. Induction and superinduction of growth arrest and DNA damage gene 45 (GADD45) alpha and beta messenger RNAs by histone deacetylase inhibitors trichostatin A (TSA) and butyrate in SW620 human colon carcinoma cells. Cancer Lett 2002; 188:127-40. [PMID: 12406558 DOI: 10.1016/s0304-3835(02)00322-1] [Citation(s) in RCA: 74] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
Histone deacetylase (HDAC) inhibitors such as trichostatin (TSA) and butyrate have been shown to inhibit cancer cell proliferation, induce apoptosis and regulate the expression of genes involved in cell cycle. Although the precise mechanism underlying HDAC inhibitor-induced cell growth arrest is not fully understood, induction of cell cycle related genes such as p21(cip/waf), is thought to be important. Here we showed that in the SW620 human colon cancer cell line, TSA and butyrate induced the growth arrest and DNA damage gene 45alpha (GADD45alpha) and GADD45beta. Furthermore, GADD45beta and p21(cip/waf) messenger RNA were induced in the absence of protein synthesis, indicating that both genes were immediate target genes for TSA. Cyclohexamide and TSA super-induced the expression of GADD45alpha and beta, but not p21(cip/waf). Interestingly while mitogen-activated kinase (MEK) inhibitor PD98059 and p38 kinase inhibitor SB242235 were unable to affect GADD45 induction, two serine/threonine protein kinase inhibitors (H7 and H8) as well as curcumin completely blocked the super-induction. Concomitant to the inhibition of GADD45 induction, H7 and H8 also blocked TSA-induced apoptosis. Taken together, these results suggest that GADD45 induction may play important role in TSA-induced cellular effects.
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Affiliation(s)
- Zunxuan Chen
- Department of Vascular Biology, GlaxoSmithKline Pharmaceutical Inc., Room 25-2088, 709 Swedeland Road, King of Prussia, PA 19406, USA
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Matsuzaki Y, Miyazawa K, Yokota T, Hitomi T, Yamagishi H, Sakai T. Molecular cloning and characterization of the human p19(INK4d) gene promoter. FEBS Lett 2002; 517:272-6. [PMID: 12062451 DOI: 10.1016/s0014-5793(02)02647-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
p19(INK4d), a member of the INK4 family of cyclin-dependent kinase (CDK) inhibitors, negatively regulates the cyclin D-CDK4/6 complexes, which promote G1/S transition by phosphorylating the retinoblastoma tumor-suppressor gene product. To investigate the mechanism of transcriptional regulation of the p19(INK4d) gene, we characterized the 5'-flanking region of the human p19(INK4d) gene. The cap-site hunting method revealed that the transcription starts at -16 nucleotide (nt) upstream of the initiation codon. The 5'-flanking region of the human p19(INK4d) gene was ligated to a luciferase reporter gene and possessed functional promoter activity. Luciferase assay with a series of truncated 5'-flanking regions indicated that the region from -81 to -2 nt could drive the transcription of the p19(INK4d) gene. Several Sp1 and activating protein 2 binding sites are located within the region from -81 to -2 nt. Mutation of the second Sp1 binding site from -33 to -25 nt decreased the promoter activity. Collectively, it was demonstrated that the human p19(INK4d) gene is under the control of TATA-less promoter and the Sp1 binding site is involved in the transcription.
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Affiliation(s)
- Youichirou Matsuzaki
- Department of Preventive Medicine, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, Japan
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Liu JR, Li BX, Chen BQ, Han XH, Xue YB, Yang YM, Zheng YM, Liu RH. Effect of cis-9, trans-11-conjugated linoleic acid on cell cycle of gastric adenocarcinoma cell line (SGC-7901). World J Gastroenterol 2002; 8:224-9. [PMID: 11925596 PMCID: PMC4658355 DOI: 10.3748/wjg.v8.i2.224] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2001] [Revised: 09/01/2001] [Accepted: 09/05/2001] [Indexed: 02/06/2023] Open
Abstract
AIM To determine the effect of cis -9, trans -11-conjugated linoleic acid (c9, t11-CLA) on the cell cycle of gastric cancer cells (SGC-7901) and its possible mechanism in inhibition cancer growth. METHODS Using cell culture and immunocytochemical techniques, we examined the cell growth, DNA synthesis, expression of PCNA, cyclin A, B(1), D(1), p16(ink4a) and p21(cip/waf1) of SGC-7901 cells which were treated with various c9, t11-CLA concentrations (25, 50, 100 and 200 micromol.L(-1))of c 9, t 11-CLA for 24 and 48h, with a negative control (0.1% ethane). RESULTS The cell growth and DNA synthesis of SGC-7901 cells were inhibited by c9, t11-CLA.SGC-7901 cells. Eight day after treatment with various concentrations of c9, t11-CLA mentioned above, the inhibition rates were 5.92%, 20.15%, 75.61% and 82.44%, respectively and inhibitory effect of c9, t11-CLA on DNA synthesis (except for 25 micromol.L, 24h) showed significantly less (3)H-TdR incorporation than that in the negative controls (P<0.05 and P<0.01). Immunocytochemical staining demonstrated that SGC-7901 cells preincubated in media supplemented with different c9, t11-CLA concentrations at various times significantly decreased the expressions of PCNA (the expression rates were 7.2-3.0%, 24h and 9.1-0.9% at 48h, respectively), Cyclin A (11.0-2.3%, 24h and 8.5-0.5%,48h), B(1) (4.8-1.8% at 24h and 5.5-0.6% at 48h)and D(1) (3.6-1.4% at 24h and 3.7%-0 at 48h) as compared with those in the negative controls(the expressions of PCNA, Cyclin A, B(1) and D(1) were 6.5% at 24h and 9.0% at 48h, 4.2% at 24h and 5.1% at 48h, 9.5% at 24h and 6.0% at 48h,respectively)(P<0.01), whereas the expressions of P16(ink4a) and P21(cip/waf1), cyclin-dependent kinases inhibitors(CDKI), were increased. CONCLUSION The cell growth and proliferation of SGC-7901 cell is inhibited by c9, t11-CLA via blocking the cell cycle, with reduced expressions of cyclin A,B(1) and D(1) and enhanced expressions of CDKI(P16(ink4a) and p21(cip/waf1)).
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Affiliation(s)
- Jia-Ren Liu
- Department of Toxicological Health, Public Health College, Harbin Medical University, 199 Dongdazhi Street, Nangang District, Harbin 150001, Heilongjiang Province, China.
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Salomone B, Ponti R, Gasco MR, Ugazio E, Quaglino P, Osella-Abate S, Bernengo MG. In vitro effects of cholesteryl butyrate solid lipid nanospheres as a butyric acid pro-drug on melanoma cells: evaluation of antiproliferative activity and apoptosis induction. Clin Exp Metastasis 2002; 18:663-73. [PMID: 11827070 DOI: 10.1023/a:1013186331662] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Literature data show that butyric acid derivatives bear a dose-dependent differentiative anti-proliferative activity on cancer cell lines and that apoptosis induction may play a major role. Although it was recently shown that solid lipid nanospheres (SLNs) are a suitable tool for several in vivo drug administration routes, there is little available information on melanoma cell lines. This study was aimed at evaluating the anti-proliferative and apoptotic in vitro effects of cholesteryl butyrate (chol-but) SLNs on melanoma cells. Increasing concentrations of chol-but SLNs were used to test two melanoma cell lines. Both cell lines were treated with Na-butyrate (Na-but) and chol-but SLNs for viability. Those tested with chol-but SLNs were more effective than Na-butirate (3 to 72 h). The apoptotic effects of chol-but SLNs were evaluated between 3 and 72 h by annexin-V (ANX-V)/propidium iodide (PI) staining and the antiproliferative effect by PI staining. Apoptosis anti-proliferative-regulatory proteins as bcl-2, Fas/APO1 (CD95) and PCNA (PC10) were also investigated. Flow cytometric analyses evidenced a G(0/1)-S transition block and a 'sub-G(0/1)' apoptotic peak from 0.5 to 1.0 mM butyric acid. In ANX-V/PI flow cytometric staining, a dose- and time-dependent increase in the apoptotic cell percentage (ANX-V+) coupled with a down-regulation of PC10 and bcl-2 and a parallel up-regulation of Fas/APO1 (CD95) were found in both lines started after 3 to 24 h of chol-but SLNs treatment. Results show that chol-but SLNs exerts a dose/time-dependent effect in melanoma cell apoptosis induction between 3 and 24 h and a dose but not time-dependent effect after 24 h of treatment.
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Affiliation(s)
- B Salomone
- Department of Medical and Surgical Specialties, University of Turin, Italy
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Abstract
Siah-1, the human homologue of Drosophila seven in absentia, is related to apoptosis and tumor suppression. Although it was reported that the expression of Siah-1 is induced by p53 and p21/WAF1, little is known about the transcriptional regulation of the Siah-1 gene. To investigate the transcriptional regulation, we isolated and sequenced the genomic fragment of the Siah-1 promoter region. The Siah-1 promoter has no typical TATA box or CCAAT box. Transient transfection assays using reporter plasmids in which the promoter region of the Siah-1 gene was deleted or mutated showed that one Sp1 site was responsible for the basal promoter activity. In Northern blotting analysis, the expression of the Siah-1 gene was upregulated by p53, but activation of the reporter plasmid by the p53 co-transfection assay was not shown, suggesting that a p53 responsive element does not exist in the promoter region we examined in this study but might be present in another region.
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Affiliation(s)
- Ayaka Maeda
- Department of Preventive Medicine, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, 602-8566, Kyoto, Japan
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Abstract
The leukemias are complex diseases with a wide range of clinical, morphologic, biologic, molecular, and clinical features and a consequent array of possible responses to any given intervention. Although progress has been made in the management of the leukemias, most patients who fail to respond to front-line therapies or who relapse after an initial response die from progressive disease. The balance between efficacy and toxicity of traditional cytotoxic therapies is increasingly unacceptable. As a consequence, the search for therapeutic advances is more focused on affecting the critical steps involved in the development, propagation, and mutation of malignant clones. This article briefly reviews current data on some agents being developed for the treatment of patients with leukemia, with an emphasis on modulators of angiogenesis, inhibitors of the ubiquitin-proteasome pathway, novel nucleoside analogues, and gene hypomethylation agents.
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Affiliation(s)
- Francis J Giles
- Section of Developmental Therapeutics, Department of Leukemia, MD Anderson Cancer Center, Houston, Texas 77030, USA.
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Abstract
BACKGROUND Colorectal cancer (CRC) is a major cause of morbidity and mortality in industrialized countries. Experimental evidence has supported the hypothesis that dietary fibre may be protective for the development of CRC, although epidemiologic data have been inconclusive. OBJECTIVES We have conducted a systematic review and meta-analysis to assess the effect of dietary fibre on the incidence or recurrence of colorectal adenomas, the incidence of CRC, and the development of adverse events. SEARCH STRATEGY We identified randomized controlled trials from Medline, Embase, and the Cochrane Controlled Trials Register up to Oct 2001 SELECTION CRITERIA Randomized or quasi-randomized controlled trials were assessed. The population included all subjects that had adenomatous polyps but no previous history of colorectal cancer (CRC), a documented "clean colon" at baseline and repeated visualization of the colon/rectum after at least two years of follow-up. Dietary fibre was the intervention. The primary outcomes were the number of subjects with: a) at least one adenoma, b) more than one adenoma, c) at least one adenoma greater than or equal to 1 cm or d) a new diagnosis of CRC. The secondary outcome was the number of adverse events. DATA COLLECTION AND ANALYSIS Two reviewers independently extracted data, assessed trial quality and resolved discrepancies by consensus. The outcomes were reported as relative risks (RR) and risk difference (RD) with 95% confidence intervals (CI). If statistical significance was reached, the number need to treat (NNTT) or harm (NNTH) was reported. The study data were combined with the fixed effects model if it was clinically, methodologically, and statistically reasonable. MAIN RESULTS Five studies with 4349 subjects met the inclusion criteria. The interventions were wheat bran fibre, ispaghula husk, or a comprehensive dietary intervention with high fibre whole food sources alone or in combination. When the data were combined there was no difference between the intervention and control groups for the number of subjects with at least one adenoma [RR 1.04 (95% CI 0.95,1.13); RD 0.01 (95% CI 0.02,0.04)]. As well, the combined results for the number of subjects with more than one adenoma [RR 1.02 (95% CI 0.89,1.17), RD 0.00 (-0.02,0.03)] or at least one adenoma 1 cm or greater [RR 0.94 (95% CI 0.77,1.15), RD -0.01 (-0.02,0.01)] were not statistically significant. Other primary and secondary outcomes and subanalyses by type of fibre intervention were not statistically or clinically significant. REVIEWER'S CONCLUSIONS There is currently no evidence from RCTs to suggest that increased dietary fibre intake will reduce the incidence or recurrence of adenomatous polyps within a two to four year period.
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Affiliation(s)
- T Asano
- General Surgery, University of Toronto, Mount Sinai Hospital, 600 University Avenue, Suite 449, Toronto, Ontario, Canada, M5G 1X5.
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42
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Yoshida T, Maeda A, Tani N, Sakai T. Promoter structure and transcription initiation sites of the human death receptor 5/TRAIL-R2 gene. FEBS Lett 2001; 507:381-5. [PMID: 11696376 DOI: 10.1016/s0014-5793(01)02947-7] [Citation(s) in RCA: 107] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
The death receptor 5 (DR5) is a receptor for tumor necrosis factor-related apoptosis-inducing ligand and is able to induce apoptosis in various tumor cells. The expression of DR5 is up-regulated at the transcriptional level by p53, genotoxic stress and so on. To investigate the structure of the DR5 gene promoter, we screened and sequenced a genomic clone containing the 5'-flanking region of the DR5 gene. RNase protection assays showed two major transcription start sites around -122 and -137 upstream of the translation initiation codon ATG. Transient transfections with serial 5'-deletion mutants identified the minimal promoter element spanning -198 to -116. Site-directed mutagenesis demonstrated that the DR5 gene promoter has no typical TATA-box, but has two Sp1 sites responsible for the basal transcription activity of the DR5 gene promoter.
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Affiliation(s)
- T Yoshida
- Department of Preventive Medicine, Kyoto Prefectural University of Medicine, Japan
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Guandalini S, Gokhale R. Update on immunologic basis of celiac disease. Curr Opin Gastroenterol 2001; 17:545-50. [PMID: 17031216 DOI: 10.1097/00001574-200111000-00011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
During the past few years several seminal studies have greatly expanded our knowledge on celiac disease pathogenesis. This review focuses on aspects that have been most properly addressed and where substantial new information has been gathered include. Topics covered include (a) the identification of T-cell epitopes in gluten and the mechanisms of specific T-cell response in celiac disease small intestine; (b) the mechanisms of induction of mucosal lesion; and (c) the putative role of non-T-cell factors in driving mucosal response to gliadin. After discussing a brief history of the "quest for the cause of celiac disease," we examine the development of the typical celiac lesion (the crypt hyperplastic mucosal atrophy) as it generally unfolds: the increased entry of dietary antigens; the early changes, linked to specific components of the innate immunity rather than to its adaptive branch; the most thoroughly investigated subsequent response, involving a strong T-cell response and cytokines; and the factors responsible for enterocytes' death. The emerging pattern is that of a complex interaction of factors, although far from being completely understood, but fascinating as it opens an incredible window of knowledge on an autoimmune disorder whose environmental factor is known, whose autoantigen is known, whose autoantibodies are known: a truly unique situation in medicine.
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Affiliation(s)
- S Guandalini
- University of Chicago, Department of Pediatrics, Section of Gastroenterology, Hepatology and Nutrition, Chicago, Illinois 60637, USA.
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44
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Abstract
Histone deacetylase inhibitors are potent inducers of growth arrest, differentiation, or apoptotic cell death in a variety of transformed cells in culture and in tumor bearing animals. Histone deacetylases and the family of histone acetyl transferases are involved in determining the acetylation of histones, which play a role in regulation of gene expression. Radiograph crystallographic studies reveal that the histone deacetylase inhibitors, suberoylanilide hydroxamic acid and trichostatin A, fit into the catalytic site of histone deacetylase, which has a tubular structure with a zinc atom at its base. The hydroxamic acid moiety of the inhibitor binds to the zinc. Histone deacetylase inhibitors cause acetylated histones to accumulate in both tumor and peripheral circulating mononuclear cells. Accumulation of acetylated histones has been used as a marker of the biologic activity of the agents. Hydroxamic acid-based histone deacetylase inhibitors limit tumor cell growth in animals with little or no toxicity. These compounds act selectively on genes, altering the transcription of only approximately 2% of expressed genes in cultured tumor cells. A number of proteins other than histones are substrates for histone deacetylases. The role that these other targets play in histone deacetylase inducement of cell growth arrest, differentiation, or apoptotic cell death is not known. This review summarizes the characteristics of a variety of inhibitors of histone deacetylases and their effects on transformed cells in culture and tumor growth in animal models. Several structurally different histone deacetylase inhibitors are in phase I or II clinical trials in patients with cancers.
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Affiliation(s)
- P A Marks
- Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
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