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Kohno T, Kinoshita J, Oyama K, Saito H, Shimada M, Tsuji T, Yamamoto D, Moriyama H, Inaki N, Ohta T. Chemoprevention of esophageal adenocarcinoma in a rat surgical model by a cysteinyl leukotriene receptor‑1 antagonist. Oncol Lett 2024; 27:147. [PMID: 38385106 PMCID: PMC10879961 DOI: 10.3892/ol.2024.14280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Accepted: 01/25/2024] [Indexed: 02/23/2024] Open
Abstract
Reflux of gastroduodenal contents into the esophagus leads to the development of esophagitis and inflammation-associated pathologies, such as Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC). The role of the lipoxygenase (LOX) pathway in carcinogenesis has been recently reported; however, its involvement in esophageal carcinogenesis remains unclear. To address this, the present study investigated the potential of pranlukast, a cysteinyl leukotriene receptor-1 antagonist, to suppress the progression of BE and EAC in a rat duodenogastroesophageal reflux (DGER) model. Male Wistar rats that underwent DGER were divided into two groups. One group was fed commercial chow (control group), and the other was fed experimental chow containing pranlukast (pranlukast group). The rats were sacrificed at 10, 20, 30 and 40 weeks after surgery, and their esophagi were examined. Expression levels of 5-LOX, CD68, IL-8, VEGF and Ki-67 were investigated using immunohistochemistry, and apoptosis was analyzed using the TUNEL method. In the pranlukast group, esophagitis was milder, and the incidence of BE and EAC was significantly lower (P<0.05) compared with that in the control group at 40 weeks after surgery. The number of cells positive for IL-8 and VEGF were significantly lower in the pranlukast group compared with the control group. Proliferative activity was also lower in the pranlukast group compared with the control group (P<0.05). Pranlukast treatment increased apoptosis (P<0.05). Overall, Pranlukast suppressed esophageal carcinogenesis in a rat DGER model, decreasing inflammatory cytokines such as IL-8 and VEGF.
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Affiliation(s)
- Tatsuhiko Kohno
- Department of Gastrointestinal Surgery, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan
| | - Jun Kinoshita
- Department of Gastrointestinal Surgery, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan
| | - Katsunobu Oyama
- Department of Surgery, Public Central Hospital of Matto Ishikawa, Hakusan, Ishikawa 924-0865, Japan
| | - Hiroto Saito
- Department of Gastrointestinal Surgery, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan
| | - Mari Shimada
- Department of Gastrointestinal Surgery, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan
| | - Toshikatsu Tsuji
- Department of Gastrointestinal Surgery, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan
| | - Daisuke Yamamoto
- Department of Gastrointestinal Surgery, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan
| | - Hideki Moriyama
- Department of Gastrointestinal Surgery, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan
| | - Noriyuki Inaki
- Department of Gastrointestinal Surgery, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan
| | - Tetsuo Ohta
- Department of Gastrointestinal Surgery, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan
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Tang D, Hu Y, Gao W. 5-lipoxygenase as a target to sensitize glioblastoma to temozolomide treatment via β-catenin-dependent pathway. Neurol Res 2023; 45:1026-1034. [PMID: 37695758 DOI: 10.1080/01616412.2023.2255414] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Accepted: 08/31/2023] [Indexed: 09/13/2023]
Abstract
Sensitizing strategy is required to improve the clinical management of glioblastoma (GBM). 5-Lipoxygenase (Alox5) has been recently garnered attention due to its pro-carcinogenic roles in various cancers. This study demonstrates that Alox5 is overexpressed in GBM but not normal neuronal tissues. Alox5 depletion inhibits the growth of GBM cells, both in bulky and stem-like populations, and enhances the anti-cancer effects of temozolomide. The mechanism behind this involves a decrease in β-catenin level and activity upon Alox5 depletion. The inhibitory effects of Alox5 can be reversed by the addition of a Wnt agonist. Additionally, the study reveals that zileuton, an Alox5 inhibitor approved for asthma treatment, significantly improves the efficacy of temozolomide in mice without causing toxicity. Combination index analysis clearly demonstrates that zileuton and temozolomide act synergistically. These findings highlight the importance of Alox5 as a critical regulator of glioblastoma sensitivity and suggest the potential repurposing of zileuton for GBM treatment.
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Affiliation(s)
- Dong Tang
- Department of Neurosurgery, Jingzhou Hospital Affiliated to Yangtze University, Jingzhou, China
| | - Yue Hu
- Department of Oncology, Jingzhou Hospital Affiliated to Yangtze University, Jingzhou, China
| | - Wenhong Gao
- Department of Neurosurgery, Jingzhou Hospital Affiliated to Yangtze University, Jingzhou, China
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Huang Y, Wang J, Huang S, Zhang X, Hu J. 5-Lipoxygenase Contributes to Benzo[a]pyrene-Induced Cytotoxicity and DNA Damage in Human Bronchial Epithelial Cells. Int J Toxicol 2023; 42:172-181. [PMID: 36537154 DOI: 10.1177/10915818221146286] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Metabolic activation of indirect-acting carcinogens in target organs is a recognized mechanism of carcinogenesis. This study aimed to determine the role of benzo[a]pyrene (BaP) metabolism enzymes lipoxygenase (LOX), cytochrome P4501A1 (CYP1A1), and prostaglandin synthetase (PGS) in the cytotoxicity and DNA damage induced by BaP in the human tracheobronchial epithelial cells (HBECs) using RNA interference strategy and metabolic enzyme inhibitors. Our results showed that in three epithelial cell lines (HBE, HTR-8/SVneo, and HaCat), BaP significantly upregulated 5-LOX protein expression. 15-LOX-2 expression also increased with increasing BaP concentration, but the change was less pronounced than that of 5-LOX. BaP caused significant cytotoxicity, DNA strand breaks, and 8-hydroxy-2'-deoxyguanosine formation in HBE, which was inhibited by 5-LOXshRNA, a specific inhibitor of 5-LOX (AA861), the CYP1A1 inhibitor α-naphthoflavone, and the PGS inhibitor naproxen. The protective effects of 5-LOXshRNA were stronger than AA861, naproxen and α-naphthoflavone. We conclude that BaP may be activated more by 5-LOX than by CYP1A1 and PGS to produce cytotoxicity and DNA damage in HBE.
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Affiliation(s)
- Yun Huang
- Department of Occupational and Environmental Health, Xiangya School of Public Health, 12570Central South University, Changsha, China
| | - Jing Wang
- Shanxi Provincial Center for Disease Control and Prevention, Taiyuan, China
| | - Shaoling Huang
- 633786Changsha Center for Disease Control and Prevention, Changsha, China
| | - Xinge Zhang
- 595060Hunan Provincial Center for Disease Control and Prevention, Changsha, China
| | - Jianan Hu
- Department of Occupational and Environmental Health, Xiangya School of Public Health, 12570Central South University, Changsha, China
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Xu F, Zhou X, Lin L, Xu J, Feng Y, He Y, Hao H. BML-111, the agonist of lipoxin A4, suppresses epithelial-mesenchymal transition and migration of MCF-7 cells via regulating the lipoxygenase pathway. Int J Immunopathol Pharmacol 2023; 37:3946320231223826. [PMID: 38134963 DOI: 10.1177/03946320231223826] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2023] Open
Abstract
Introduction: Aberrant epithelial-mesenchymal transition (EMT) and migration frequently occur during tumour progression. BML-111, an analogue of lipoxin A4, has been implicated in inflammation in cancer research. Methods: 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, western blot, Reverse Transcription Polymerase Chain Reaction (RT-PCR), transwell assay, immunofluorescence, and immunohistochemistry were conducted in this study. Results: In vitro experiments revealed that BML-111 inhibited EMT and migration in CoCl2-stimulated MCF-7 cells. These effects were achieved by inhibiting MMP-2 and MMP-9, which are downregulated by 5-lipoxygenase (5-LOX). Moreover, BML-111 inhibited EMT and migration of breast cancer cells in BALB/c nude mice inoculated with MCF-7 cells. Conclusion: Our results suggest that BML-111 may be a potential therapeutic drug for breast cancer and that blocking the 5-LOX pathway could be a possible approach for mining effective drug targets.
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Affiliation(s)
- Fen Xu
- Department of General Medicine, Yangpu Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Xiaoyan Zhou
- Department of Pathophysiology, Medical College of Nanchang University, Nanchang, China
| | - Lan Lin
- Department of Pathology, Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Jing Xu
- Department of Pathology, Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Yu Feng
- Department of Pathology, Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Yuanqiao He
- Department of Laboratory Animal Science, Medical College of Nanchang University, Nanchang, China
| | - Hua Hao
- Department of Pathology, Yangpu Hospital, School of Medicine, Tongji University, Shanghai, China
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Kreiß M, Oberlis JH, Seuter S, Bischoff-Kont I, Sürün D, Thomas D, Göbel T, Schmid T, Rådmark O, Brandes RP, Fürst R, Häfner AK, Steinhilber D. Human 5-lipoxygenase regulates transcription by association to euchromatin. Biochem Pharmacol 2022; 203:115187. [PMID: 35878796 DOI: 10.1016/j.bcp.2022.115187] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 07/17/2022] [Accepted: 07/19/2022] [Indexed: 12/17/2022]
Abstract
Human 5-lipoxygenase (5-LO) is the key enzyme of leukotriene biosynthesis, mostly expressed in leukocytes and thus a crucial component of the innate immune system. In this study, we show that 5-LO, besides its canonical function as an arachidonic acid metabolizing enzyme, is a regulator of gene expression associated with euchromatin. By Crispr-Cas9-mediated 5-LO knockout (KO) in MonoMac6 (MM6) cells and subsequent RNA-Seq analysis, we identified 5-LO regulated genes which could be clustered to immune/defense response, cell adhesion, transcription and growth/developmental processes. Analysis of differentially expressed genes (DEG) identified cyclooxygenase-2 (COX2, PTGS2) and kynureninase (KYNU) as strongly regulated 5-LO target genes. 5-LO knockout affected MM6 cell adhesion and tryptophan metabolism via inhibition of the degradation of the immunoregulator kynurenine. By subsequent FAIRE-Seq and 5-LO ChIP-Seq analyses, we found an association of 5-LO with euchromatin, with prominent 5-LO binding to promoter regions in actively transcribed genes. By enrichment analysis of the ChIP-Seq results, we identified potential 5-LO interaction partners. Furthermore, 5-LO ChIP-Seq peaks resemble patterns of H3K27ac histone marks, suggesting that 5-LO recruitment mainly takes place at acetylated histones. In summary, we demonstrate a noncanonical function of 5-LO as transcriptional regulator in monocytic cells.
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Affiliation(s)
- Marius Kreiß
- Institute of Pharmaceutical Chemistry, Goethe University, Max-von-Laue-Straße 9, 60438 Frankfurt, Germany
| | - Julia H Oberlis
- Institute of Pharmaceutical Chemistry, Goethe University, Max-von-Laue-Straße 9, 60438 Frankfurt, Germany
| | - Sabine Seuter
- Institute for Cardiovascular Physiology, Goethe University, Medical Faculty, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany
| | - Iris Bischoff-Kont
- Institute of Pharmaceutical Biology, Goethe University, Max-von-Laue-Straße 9, 60438 Frankfurt, Germany
| | - Duran Sürün
- Medical Systems Biology, UCC,TU Dresden, Medical Faculty Carl Gustav Carus, Fetscherstr. 74, 01307 Dresden, Germany
| | - Dominique Thomas
- Institute for Clinical Pharmacology, Goethe University, Medical Faculty, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany
| | - Tamara Göbel
- Institute of Pharmaceutical Chemistry, Goethe University, Max-von-Laue-Straße 9, 60438 Frankfurt, Germany
| | - Tobias Schmid
- Institute of Biochemistry I, Goethe University, Medical Faculty, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany
| | - Olof Rådmark
- Division of Physiological Chemistry II, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-17177 Stockholm, Sweden
| | - Ralf P Brandes
- Institute for Cardiovascular Physiology, Goethe University, Medical Faculty, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany
| | - Robert Fürst
- Institute of Pharmaceutical Biology, Goethe University, Max-von-Laue-Straße 9, 60438 Frankfurt, Germany
| | - Ann-Kathrin Häfner
- Institute of Pharmaceutical Chemistry, Goethe University, Max-von-Laue-Straße 9, 60438 Frankfurt, Germany.
| | - Dieter Steinhilber
- Institute of Pharmaceutical Chemistry, Goethe University, Max-von-Laue-Straße 9, 60438 Frankfurt, Germany.
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Li L, Xiao Y, Xu Z, Wang S. Zileuton inhibits arachidonate-5-lipoxygenase to exert antitumor effects in preclinical cervical cancer models. Cancer Chemother Pharmacol 2021; 88:953-960. [PMID: 34477945 DOI: 10.1007/s00280-021-04343-w] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Accepted: 08/17/2021] [Indexed: 12/30/2022]
Abstract
BACKGROUND Inhibitors of arachidonate lipoxygenase 5 (ALOX5) exhibit anticancer activity. Zileuton is an FDA-approved drug for treating asthma and an ALOX5 inhibitor. This study evaluated the efficacy of zileuton in cervical cancer, determined the molecular mechanism of action, and assessed ALOX5 expression in cervical cancer patients. METHODS The effects of zileuton were evaluated using cervical cancer cell lines and xenograft mouse models. Loss-of-function analysis of ALOX5 was performed using siRNA. The levels of ALOX5 and 5-HETE were determined using immunohistochemistry and ELISA. RESULTS Zileuton resulted in cell proliferation inhibition and apoptosis induction in a dose-dependent manner, regardless of cellular origin or HPV infection. In two independent cervical cancer xenograft mouse models, zileuton at nontoxic doses significantly prevented tumor formation and decreased tumor growth. Zileuton acts on cervical cancer cells by inhibiting the ALOX5-5-HETE axis. Of note, ALOX5-5-HETE was significantly upregulated in cervical cancer compared with normal tissue. Inhibition of ALOX5 via the siRNA approach mimics the inhibitory effects of zileuton and confirms the roles of ALOX5 in cervical cancer. CONCLUSIONS Our work demonstrates that the ALOX5-5-HETE axis is activated in cervical cancer, with important roles in growth and survival, and this can be therapeutically targeted by zileuton. Our findings also provide preclinical evidence to assess the efficacy of zileuton in cervical cancer in clinical settings.
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Affiliation(s)
- Liling Li
- Department of Obstetrics and Gynecology, Hubei Provincial Hospital of Integrated Chinese and Western Medicine, Wuhan, China
| | - Yifang Xiao
- Department of Obstetrics and Gynecology, Hubei Provincial Hospital of Integrated Chinese and Western Medicine, Wuhan, China
| | - Zhengzheng Xu
- Department of Obstetrics and Gynecology, Hubei Provincial Hospital of Integrated Chinese and Western Medicine, Wuhan, China
| | - Shaoshuai Wang
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Rd 1095, Qiaokou District, Wuhan, 430030, China.
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Salgado MTSF, Lopes AC, Fernandes E Silva E, Cardoso JQ, Vidal RS, Cavalcante-Silva LHA, Carvalho DCM, Machado KDS, Rodrigues-Mascarenhas S, Rumjanek VM, Votto APDS. Relation between ABCB1 overexpression and COX2 and ALOX5 genes in human erythroleukemia cell lines. Prostaglandins Other Lipid Mediat 2021; 155:106553. [PMID: 33975019 DOI: 10.1016/j.prostaglandins.2021.106553] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 04/23/2021] [Accepted: 05/05/2021] [Indexed: 10/21/2022]
Abstract
This study aimed to characterize the relationship between the COX2 and ALOX5 genes, as well as their link with the multidrug resistance (MDR) phenotype in sensitive (K562) and MDR (K562-Lucena and FEPS) erythroleukemia cells. For this, the inhibitors of 5-LOX (zileuton) and COX-2 (acetylsalicylic acid-ASA) and cells with the silenced ABCB1 gene were used. The treatment with ASA caused an increase in the gene expression of COX2 and ABCB1 in both MDR cell lines, and a decrease in the expression of ALOX5 in the FEPS cells. Silencing the ABCB1 gene induced a decrease in COX2 expression and an increase in the ALOX5 gene. Treatment with zileuton did not alter the expression of COX2 and ABCB1. Cytometry data showed that there was an increase in ABCB1 protein expression after exposure to ASA. In addition, the increased activity of ABCB1 in the K562-Lucena cell line indicates that ASA may be a substrate for this efflux pump, corroborating the molecular docking that showed that ASA can bind to ABCB1. Regardless of the genetic alteration in COX2 and ABCB1, the direct relationship between these genes and the inverse relationship with ALOX5 remained in the MDR cell lines. We assume that ABCB1 can play a regulatory role in COX2 and ALOX5 during the transformation of the parental cell line K562, explaining the increased gene expression of COX2 and decreased ALOX5 in the MDR cell lines.
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MESH Headings
- Humans
- Cyclooxygenase 2/genetics
- Cyclooxygenase 2/metabolism
- Arachidonate 5-Lipoxygenase/metabolism
- Arachidonate 5-Lipoxygenase/genetics
- ATP Binding Cassette Transporter, Subfamily B/genetics
- ATP Binding Cassette Transporter, Subfamily B/metabolism
- Leukemia, Erythroblastic, Acute/genetics
- Leukemia, Erythroblastic, Acute/pathology
- Leukemia, Erythroblastic, Acute/metabolism
- Hydroxyurea/pharmacology
- Hydroxyurea/analogs & derivatives
- Cell Line, Tumor
- K562 Cells
- Drug Resistance, Neoplasm/genetics
- Drug Resistance, Neoplasm/drug effects
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Affiliation(s)
| | - Alessandra Costa Lopes
- Laboratório de Cultura Celular, ICB, FURG, RS, Brazil; Escola de Química e Alimentos, EQA, FURG, RS, Brazil
| | | | | | | | | | | | | | | | | | - Ana Paula de Souza Votto
- Laboratório de Cultura Celular, ICB, FURG, RS, Brazil; Programa de Pós-Graduação em Ciências Fisiológicas, ICB, FURG, RS, Brazil.
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Tang J, Zhang C, Lin J, Duan P, Long J, Zhu H. ALOX5-5-HETE promotes gastric cancer growth and alleviates chemotherapy toxicity via MEK/ERK activation. Cancer Med 2021; 10:5246-5255. [PMID: 34121352 PMCID: PMC8335819 DOI: 10.1002/cam4.4066] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2020] [Revised: 04/16/2021] [Accepted: 05/27/2021] [Indexed: 12/12/2022] Open
Abstract
Background Recent studies highlight the regulatory role of arachidonate lipoxygenase5 (Alox5) and its metabolite 5‐hydroxyeicosatetraenoic acid (5‐HETE) in cancer tumorigenesis and progression. In this study, we analyzed the expression, biological function and the downstream signaling of Alox5 in gastric cancer. Methods Alox5 protein levels were measured using IHC and ELISA. Growth, migration and survival assays were performed. Phosphorylation of molecules involved in growth and survival signaling were analyzed by WB. Analysis of variance and t‐test were used for statistic analysis. Results Alox5 and 5‐HETE levels were upregulated in gastric cancer patients. ALOX5 overexpression or 5‐HETE addition activates gastric cancer cells and reduces chemotherapy’s efficacy. In contrast, ALOX5 inhibition via genetic and pharmacological approaches suppresses gastric cancer cells and enhances chemotherapy’s efficacy. In addition, Alox5 inhibition led to suppression of ERK‐mediated signaling pathways whereas ALOX5‐5‐HETE activates ERK‐mediated signaling in gastric cancer cells. Conclusions Our work demonstrates the critical role of ALOX5‐5‐HETE in gastric cancer and provides pre‐clinical evidence to initialize clinical trial using zileuton in combination with chemotherapy for treating gastric cancer.
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Affiliation(s)
- Jianjun Tang
- Department of General Surgery, Xiangyang No.1 People's Hospital, Hubei University of Medicine, Xiangyang, China
| | - Chuang Zhang
- Department of Pediatrics, Xiangyang No.1 People's Hospital, Hubei University of Medicine, Xiangyang, China
| | - Jingjing Lin
- Department of Blood Transfusion, Xiangyang Traditional Chinese Medicine Hospital, Xiangyang, China
| | - Peng Duan
- Department of Obstetrics and Gynaecology, Xiangyang No.1 People's Hospital, Hubei University of Medicine, Xiangyang, China
| | - Jian Long
- Department of Oncology, Jingzhou Central Hospital, The Second Clinical Medical College, Yangtze University, Jingzhou, China
| | - Hongyan Zhu
- Department of Oncology, Xiangyang No.1 People's Hospital, Hubei University of Medicine, Xiangyang, China
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Mahboubi-Rabbani M, Zarghi A. Lipoxygenase Inhibitors as Cancer Chemopreventives: Discovery, Recent Developments and Future Perspectives. Curr Med Chem 2021; 28:1143-1175. [PMID: 31820690 DOI: 10.2174/0929867326666191210104820] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Revised: 10/31/2019] [Accepted: 11/10/2019] [Indexed: 11/22/2022]
Abstract
BACKGROUND Leukotrienes (LTs) constitute a bioactive group of Polyunsaturated Fatty Acid (PUFA) metabolites molded by the enzymatic activity of lipoxygenase (LO) and have a pivotal role in inflammation and allergy. Evidence is accumulating both by in vitro cell culture experiments and animal tumor model studies in support of the direct involvement of aberrant metabolism of arachidonic acid (ACD) in the development of several types of human cancers such as lung, prostate, pancreatic and colorectal malignancies. Several independent experimental data suggest a correlation between tumoral cells viability and LO gene expression, especially, 5-lipoxygenase (5-LO). Overexpressed 5-LO cells live longer, proliferate faster, invade more effectively through extracellular matrix destruction and activate the anti-apoptotic signaling mechanisms more intensively compared to the normal counterparts. Thus, some groups of lipoxygenase inhibitors may be effective as promising chemopreventive agents. METHODS A structured search of bibliographic databases for peer-reviewed research literature regarding the role of LO in the pathogenesis of cancer was performed. The characteristics of screened papers were summarized and the latest advances focused on the discovery of new LO inhibitors as anticancer agents were discussed. RESULTS More than 180 papers were included and summarized in this review; the majority was about the newly designed and synthesized 5-LO inhibitors as anti-inflammatory and anticancer agents. The enzyme's structure, 5-LO pathway, 5-LO inhibitors structure-activity relationships as well as the correlation between these drugs and a number of most prevalent human cancers were described. In most cases, it has been emphasized that dual cyclooxygenase-2/5-lipoxygenase (COX-2/5-LO) or dual 5-lipoxygenase/microsomal prostaglandin E synthase-1 (5-LO/mPGES-1) inhibitors possess considerable inhibitory activities against their target enzymes as well as potent antiproliferative effects. Several papers disclosing 5-lipoxygenase activating protein (FLAP) antagonists as a new group of 5-LO activity regulators are also subject to this review. Also, the potential of 12-lipoxygenase (12- LO) and 15-lipoxygenase (15-LO) inhibitors as chemopreventive agents was outlined to expand the scope of new anticancer agents discovery. Some peptides and peptidomimetics with anti-LT activities were described as well. In addition, the cytotoxic effects of lipoxygenase inhibitors and their adverse effects were discussed and some novel series of natural-product-derived inhibitors of LO was also discussed in this review. CONCLUSION This review gives insights into the novel lipoxygenase inhibitors with anticancer activity as well as the different molecular pharmacological strategies to inhibit the enzyme effectively. The findings confirm that certain groups of LO inhibitors could act as promising chemopreventive agents.
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Affiliation(s)
- Mohammad Mahboubi-Rabbani
- Department of Medicinal Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Afshin Zarghi
- Department of Medicinal Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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10
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Wang B, Wu L, Chen J, Dong L, Chen C, Wen Z, Hu J, Fleming I, Wang DW. Metabolism pathways of arachidonic acids: mechanisms and potential therapeutic targets. Signal Transduct Target Ther 2021; 6:94. [PMID: 33637672 PMCID: PMC7910446 DOI: 10.1038/s41392-020-00443-w] [Citation(s) in RCA: 622] [Impact Index Per Article: 155.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 10/04/2020] [Accepted: 10/15/2020] [Indexed: 01/31/2023] Open
Abstract
The arachidonic acid (AA) pathway plays a key role in cardiovascular biology, carcinogenesis, and many inflammatory diseases, such as asthma, arthritis, etc. Esterified AA on the inner surface of the cell membrane is hydrolyzed to its free form by phospholipase A2 (PLA2), which is in turn further metabolized by cyclooxygenases (COXs) and lipoxygenases (LOXs) and cytochrome P450 (CYP) enzymes to a spectrum of bioactive mediators that includes prostanoids, leukotrienes (LTs), epoxyeicosatrienoic acids (EETs), dihydroxyeicosatetraenoic acid (diHETEs), eicosatetraenoic acids (ETEs), and lipoxins (LXs). Many of the latter mediators are considered to be novel preventive and therapeutic targets for cardiovascular diseases (CVD), cancers, and inflammatory diseases. This review sets out to summarize the physiological and pathophysiological importance of the AA metabolizing pathways and outline the molecular mechanisms underlying the actions of AA related to its three main metabolic pathways in CVD and cancer progression will provide valuable insight for developing new therapeutic drugs for CVD and anti-cancer agents such as inhibitors of EETs or 2J2. Thus, we herein present a synopsis of AA metabolism in human health, cardiovascular and cancer biology, and the signaling pathways involved in these processes. To explore the role of the AA metabolism and potential therapies, we also introduce the current newly clinical studies targeting AA metabolisms in the different disease conditions.
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Affiliation(s)
- Bei Wang
- Division of Cardiology, Department of Internal Medicine and Gene Therapy Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Huazhong University of Science and Technology, Hubei Province, Wuhan, China
- Department of Rheumatology and Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei, Wuhan, China
| | - Lujin Wu
- Division of Cardiology, Department of Internal Medicine and Gene Therapy Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Huazhong University of Science and Technology, Hubei Province, Wuhan, China
| | - Jing Chen
- Division of Cardiology, Department of Internal Medicine and Gene Therapy Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Huazhong University of Science and Technology, Hubei Province, Wuhan, China
| | - Lingli Dong
- Department of Rheumatology and Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei, Wuhan, China
| | - Chen Chen
- Division of Cardiology, Department of Internal Medicine and Gene Therapy Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Huazhong University of Science and Technology, Hubei Province, Wuhan, China
| | - Zheng Wen
- Division of Cardiology, Department of Internal Medicine and Gene Therapy Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Huazhong University of Science and Technology, Hubei Province, Wuhan, China
| | - Jiong Hu
- Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Frankfurt am Main, Germany
| | - Ingrid Fleming
- Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Frankfurt am Main, Germany
| | - Dao Wen Wang
- Division of Cardiology, Department of Internal Medicine and Gene Therapy Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Huazhong University of Science and Technology, Hubei Province, Wuhan, China.
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11
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Saier L, Peyruchaud O. Emerging role of cysteinyl LTs in cancer. Br J Pharmacol 2021; 179:5036-5055. [PMID: 33527344 DOI: 10.1111/bph.15402] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Revised: 12/28/2020] [Accepted: 01/23/2021] [Indexed: 01/31/2023] Open
Abstract
Cysteinyl leukotrienes (CysLTs) are inflammatory lipid mediators that play a central role in the pathophysiology of several inflammatory diseases. Recently, there has been an increased interest in determining how these lipid mediators orchestrate tumour development and metastasis through promoting a pro-tumour micro-environment. Up-regulation of CysLTs receptors and CysLTs production is found in a number of cancers and has been associated with increased tumorigenesis. Understanding the molecular mechanisms underlying the role of CysLTs and their receptors in cancer progression will help investigate the potential of targeting CysLTs signalling for anti-cancer therapy. This review gives an overview of the biological effects of CysLTs and their receptors, along with current knowledge of their regulation and expression. It also provides a recent update on the molecular mechanisms that have been postulated to explain their role in tumorigenesis and on the potential of anti-CysLTs in the treatment of cancer.
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Affiliation(s)
- Lou Saier
- INSERM, Unit 1033, LYOS, Lyon, France.,Université Claude Bernard Lyon 1, Lyon, France
| | - Olivier Peyruchaud
- INSERM, Unit 1033, LYOS, Lyon, France.,Université Claude Bernard Lyon 1, Lyon, France
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12
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Cornwell AC, Feigin ME. Unintended Effects of GPCR-Targeted Drugs on the Cancer Phenotype. Trends Pharmacol Sci 2020; 41:1006-1022. [PMID: 33198923 PMCID: PMC7672258 DOI: 10.1016/j.tips.2020.10.001] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 08/28/2020] [Accepted: 10/01/2020] [Indexed: 12/11/2022]
Abstract
G protein-coupled receptors (GPCRs) are the most common class of therapeutic targets, accounting for ~35% of all FDA-approved drugs. Cancer patients receive numerous medications not only to combat cancer but also to alleviate pain, nausea, and anxiety, many of which target GPCRs. Emerging evidence has implicated GPCRs as drivers of cancer progression, therapeutic resistance, and metastasis. Therefore, the effects of commonly prescribed GPCR-targeted drugs must be reevaluated in the context of cancer. Epidemiological and experimental evidence indicate that widely used GPCR-targeted drugs may promote or inhibit cancer progression. It is crucial that we more fully understand the indirect effects of GPCR-targeted drugs on the cancer phenotype. This review summarizes recent advances in characterizing these interactions and highlights future research opportunities.
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Affiliation(s)
- Abigail C Cornwell
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Michael E Feigin
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
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13
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Hsu KC, HuangFu WC, Lin TE, Chao MW, Sung TY, Chen YY, Pan SL, Lee JC, Tzou SC, Sun CM, Yang JM. A site-moiety map and virtual screening approach for discovery of novel 5-LOX inhibitors. Sci Rep 2020; 10:10510. [PMID: 32601404 PMCID: PMC7324578 DOI: 10.1038/s41598-020-67420-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Accepted: 06/04/2020] [Indexed: 11/09/2022] Open
Abstract
The immune system works in conjunction with inflammation. Excessive inflammation underlies various human diseases, such as asthma, diabetes and heart disease. Previous studies found that 5-lipoxygenase (5-LOX) plays a crucial role in metabolizing arachidonic acid into inflammatory mediators and is a potential therapeutic target. In this study, we performed an in silico approach to establish a site-moiety map (SiMMap) to screen for new 5-LOX inhibitors. The map is composed of several anchors that contain key residues, moiety preferences, and their interaction types (i.e., electrostatic (E), hydrogen-bonding (H), and van der Waals (V) interactions) within the catalytic site. In total, we identified one EH, one H, and five V anchors, within the 5-LOX catalytic site. Based on the SiMMap, three 5-LOX inhibitors (YS1, YS2, and YS3) were identified. An enzyme-based assay validated inhibitory activity of YS1, YS2, and YS3 against 5-LOX with an IC50 value of 2.7, 4.2, and 5.3 μM, respectively. All three inhibitors significantly decrease LPS-induced TNF-α and IL-6 production, which suggests its potential use an anti-inflammatory agent. In addition, the identified 5-LOX inhibitors contain a novel scaffold. The discovery of these inhibitors presents an opportunity for designing specific anti-inflammatory drugs.
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Affiliation(s)
- Kai-Cheng Hsu
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
- Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
- Ph.D. Program in Biotechnology Research and Development, College of Pharmacy, Taipei Medical University, Taipei, Taiwan
- Biomedical Commercialization Center, Taipei Medical University, Taipei, Taiwan
| | - Wei-Chun HuangFu
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
- Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
- Ph.D. Program in Biotechnology Research and Development, College of Pharmacy, Taipei Medical University, Taipei, Taiwan
| | - Tony Eight Lin
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
- Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
| | - Min-Wu Chao
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
| | - Tzu-Ying Sung
- Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Hsinchu, Taiwan
| | - Yi-Ying Chen
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
| | - Shiow-Lin Pan
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
- Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
- Ph.D. Program in Biotechnology Research and Development, College of Pharmacy, Taipei Medical University, Taipei, Taiwan
- Biomedical Commercialization Center, Taipei Medical University, Taipei, Taiwan
| | - Jih-Chin Lee
- Department of Otolaryngology-Head and Neck Surgery, Tri-Service General Hospital, Taipei, Taiwan
- Department of Otolaryngology-Head and Neck Surgery, National Defense Medical Center, Taipei, Taiwan
| | - Shey-Cherng Tzou
- Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan
| | - Chung-Ming Sun
- Department of Applied Chemistry, National Chiao Tung University, Hsinchu, Taiwan
| | - Jinn-Moon Yang
- Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Hsinchu, Taiwan.
- Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan.
- Center for Intelligent Drug Systems and Smart Bio-Devices, National Chiao Tung University, Hsinchu, Taiwan.
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14
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Schlag K, Steinhilber D, Karas M, Sorg BL. Analysis of proximal ALOX5 promoter binding proteins by quantitative proteomics. FEBS J 2020; 287:4481-4499. [PMID: 32096311 DOI: 10.1111/febs.15259] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Revised: 10/15/2019] [Accepted: 02/23/2020] [Indexed: 01/01/2023]
Abstract
5-Lipoxygenase (5-LO) is the initial enzyme in the biosynthesis of leukotrienes, which are mediators involved in pathophysiological conditions such as asthma and certain cancer types. Knowledge of proteins involved in 5-LO pathway regulation, including gene regulatory proteins, is needed to evaluate all options for therapeutic intervention in these diseases. Here, we present a mass spectrometric screening of ALOX5 promoter-interacting proteins, obtained by DNA pulldown and label-free quantitative mass spectrometry. Protein preparations from myeloid and B-lymphocytic cell lines were screened for promoter DNA interactors. Through statistical analysis, 66 proteins were identified as specific ALOX5 promotor binding proteins. Among those, the 15 most likely candidates for a prominent role in ALOX5 gene regulation are the known ALOX5 interactors Sp1 and Sp3, the related factor Sp2, two Krüppel-like factors (KLF13 and KLF16) and six other zinc finger proteins (MAZ, PRDM10, VEZF1, ZBTB7A, ZNF281 and ZNF579). Intriguingly, we also identified two helicases (BLM and DHX36) and the proteins hnRNPD and hnRNPK, which are, together with the protein MAZ, known to interact with DNA G-quadruplex structures. As G-quadruplexes are implicated in gene regulation, spectroscopic and antibody-based methods were used to confirm their presence within the GC-rich sequence of the ALOX5 promoter. In summary, we have systematically characterized the interactome of the ALOX5 promoter, identifying several zinc finger proteins as novel potential ALOX5 gene regulators. Further, we have shown that the ALOX5 promoter can form DNA G-quadruplex structures, which may play a functional role in ALOX5 gene regulation.
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Affiliation(s)
- Katharina Schlag
- Institute of Pharmaceutical Chemistry/ZAFES, Goethe-University, Frankfurt am Main, Germany
| | - Dieter Steinhilber
- Institute of Pharmaceutical Chemistry/ZAFES, Goethe-University, Frankfurt am Main, Germany
| | - Michael Karas
- Institute of Pharmaceutical Chemistry/ZAFES, Goethe-University, Frankfurt am Main, Germany
| | - Bernd L Sorg
- Institute of Pharmaceutical Chemistry/ZAFES, Goethe-University, Frankfurt am Main, Germany
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15
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Li Q, Dong H, Yang G, Song Y, Mou Y, Ni Y. Mouse Tumor-Bearing Models as Preclinical Study Platforms for Oral Squamous Cell Carcinoma. Front Oncol 2020; 10:212. [PMID: 32158692 PMCID: PMC7052016 DOI: 10.3389/fonc.2020.00212] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Accepted: 02/06/2020] [Indexed: 12/16/2022] Open
Abstract
Preclinical animal models of oral squamous cell carcinoma (OSCC) have been extensively studied in recent years. Investigating the pathogenesis and potential therapeutic strategies of OSCC is required to further progress in this field, and a suitable research animal model that reflects the intricacies of cancer biology is crucial. Of the animal models established for the study of cancers, mouse tumor-bearing models are among the most popular and widely deployed for their high fertility, low cost, and molecular and physiological similarity to humans, as well as the ease of rearing experimental mice. Currently, the different methods of establishing OSCC mouse models can be divided into three categories: chemical carcinogen-induced, transplanted and genetically engineered mouse models. Each of these methods has unique advantages and limitations, and the appropriate application of these techniques in OSCC research deserves our attention. Therefore, this review comprehensively investigates and summarizes the tumorigenesis mechanisms, characteristics, establishment methods, and current applications of OSCC mouse models in published papers. The objective of this review is to provide foundations and considerations for choosing suitable model establishment methods to study the relevant pathogenesis, early diagnosis, and clinical treatment of OSCC.
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Affiliation(s)
- Qiang Li
- Central Laboratory, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China
| | - Heng Dong
- Central Laboratory, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China
- Department of Oral Implantology, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China
| | - Guangwen Yang
- Central Laboratory, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China
| | - Yuxian Song
- Central Laboratory, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China
| | - Yongbin Mou
- Central Laboratory, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China
- Department of Oral Implantology, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China
- *Correspondence: Yongbin Mou
| | - Yanhong Ni
- Central Laboratory, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China
- Yanhong Ni
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16
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Finotello R, Schiavo L, Ressel L, Frohmader A, Silvestrini P, Verin R. Lipoxygenase-5 Expression in Canine Urinary Bladder: Normal Urothelium, Cystitis and Transitional Cell Carcinoma. J Comp Pathol 2019; 170:1-9. [PMID: 31375151 DOI: 10.1016/j.jcpa.2019.05.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Revised: 04/15/2019] [Accepted: 05/06/2019] [Indexed: 02/07/2023]
Abstract
Transitional cell carcinoma (TCC) is the most common canine urinary tract tumour and mimics human invasive TCC. Human TCCs overexpress lipoxygenase (LOX)-5 and the use of target inhibitors has proven effective in inhibiting neoplastic growth. In this study, we investigated the immunohistochemical expression of LOX-5 in normal canine urinary bladder, cystitis and TCC. The comparative expression of LOX-5, cyclo-oxygenase (COX)-1 and COX-2 among the three tissue groups was also examined. Biopsy samples from cases of cystitis and TCC were reviewed from 2012 to 2016; samples of histologically normal bladder were used as controls. Dogs were excluded if they had received glucocorticoids, non-steroidal anti-inflammatory drugs (NSAIDs) and/or chemotherapy prior to tissue collection. LOX-5 was expressed in 95% of TCCs, 23% of cases of cystitis and 10% of controls. LOX-5 and COX-2 immunohistochemistry scores were significantly (P <0.01) higher in TCCs versus cystitis and normal bladders. Results of this study support the rationale for further investigation of the use of NSAIDs with dual anti COX-2 and LOX-5 effect for the treatment of canine TCC.
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Affiliation(s)
- Riccardo Finotello
- Department of Small Animal Clinical Science, Institute of Veterinary Science, University of Liverpool, Leahurst Campus, Neston, UK.
| | - Luca Schiavo
- Department of Small Animal Clinical Science, Institute of Veterinary Science, University of Liverpool, Leahurst Campus, Neston, UK
| | - Lorenzo Ressel
- Department of Veterinary Pathology and Public Health, Institute of Veterinary Science, University of Liverpool, Leahurst Campus, Neston, UK
| | - Ava Frohmader
- Institute of Veterinary Science, University of Liverpool, Liverpool, UK
| | - Paolo Silvestrini
- Department of Small Animal Clinical Science, Institute of Veterinary Science, University of Liverpool, Leahurst Campus, Neston, UK
| | - Ranieri Verin
- Department of Veterinary Pathology and Public Health, Institute of Veterinary Science, University of Liverpool, Leahurst Campus, Neston, UK
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17
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Oguh-Olayinka L, Agarwal V, Ranatunge D, Campbell A, Laufer S, Cawkwell L, Lind MJ. The Investigation of Lipoxygenases as Therapeutic Targets in Malignant Pleural Mesothelioma. Pathol Oncol Res 2019; 26:985-995. [PMID: 30941737 PMCID: PMC7242492 DOI: 10.1007/s12253-019-00652-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Accepted: 03/20/2019] [Indexed: 11/30/2022]
Abstract
Advanced malignant pleural mesothelioma (MPM) has an extremely poor prognosis with limited chemotherapy options, therefore the identification of new therapeutic targets would aid in disease management. Arachidonic acid is metabolised by cyclooxygenase and lipoxygenase enzymes. The lipoxygenase isoenzymes 5-LOX and 12-LOX have been implicated in carcinogenesis. We aimed to examine 5-LOX and 12-LOX protein expression in a large retrospective series of mesothelioma samples. Further to this, the in vitro cytotoxic effects of lipoxygenase pathway inhibitors were investigated in mesothelioma cells. Archival samples from 83 patients with MPM were examined by immunohistochemistry for expression of the 5-LOX and 12-LOX proteins. The MTS assay was used to assess cell viability following 72 h treatment with the lipoxygenase pathway inhibitors baicalein, licofelone, MK-886 and zileuton in the MPM cell lines NCI-H2052, NCI-H2452 and MSTO-211H. Positive 12-LOX protein expression was recorded in 69/83 (83%) and positive 5-LOX expression was observed in 56/77 (73%) of MPM tissue samples. Co-expression of 5-LOX with 12-LOX was seen in 46/78 (58%) of MPM samples. Positive expression of 5-LOX, 12-LOX and COX-2 proteins was identified in the NCI-H2052, NCI-H2452 and MSTO-211H MPM cell lines. Baicalein (12-LOX and 15-LOX inhibitor) was effective in 3/3 MPM cell lines at low concentrations with an IC50 range of 9.6 μM to 20.7 μM. We have demonstrated that the 5-LOX and 12-LOX proteins are expressed in a significant proportion of MPM samples (73% and 83% respectively) and may represent novel therapeutic targets in this disease. We have demonstrated that the inhibition of the LOX pathway using baicalein may be effective as a novel treatment for MPM, however further human pharmacokinetic studies are required in order to establish whether the concentration used in vitro is clinically achievable.
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Affiliation(s)
- Lily Oguh-Olayinka
- Research Laboratories, Hull York Medical School, Daisy Building, Castle Hill Hospital, Hull, HU16 5JQ, UK.
| | - Vijay Agarwal
- Research Laboratories, Hull York Medical School, Daisy Building, Castle Hill Hospital, Hull, HU16 5JQ, UK.,Queens Centre for Oncology and Haematology, Hull and East Yorkshire NHS Trust, Hull, UK
| | - Dulani Ranatunge
- Research Laboratories, Hull York Medical School, Daisy Building, Castle Hill Hospital, Hull, HU16 5JQ, UK
| | - Anne Campbell
- Histopathology Department, Hull and East Yorkshire NHS Trust, Hull, UK
| | - Stefan Laufer
- Department of Pharmaceutical Chemistry, Eberhard Karls University, Tübingen, Germany
| | - Lynn Cawkwell
- Research Laboratories, Hull York Medical School, Daisy Building, Castle Hill Hospital, Hull, HU16 5JQ, UK.,Department of Biomedical Science, University of Hull, Hull, UK
| | - Michael J Lind
- Research Laboratories, Hull York Medical School, Daisy Building, Castle Hill Hospital, Hull, HU16 5JQ, UK.,Queens Centre for Oncology and Haematology, Hull and East Yorkshire NHS Trust, Hull, UK
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18
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Chandrasekharan JA, Sharma-Walia N. Arachidonic Acid Derived Lipid Mediators Influence Kaposi's Sarcoma-Associated Herpesvirus Infection and Pathogenesis. Front Microbiol 2019; 10:358. [PMID: 30915039 PMCID: PMC6422901 DOI: 10.3389/fmicb.2019.00358] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2018] [Accepted: 02/11/2019] [Indexed: 12/30/2022] Open
Abstract
Kaposi’s sarcoma-associated herpesvirus (KSHV) infection, particularly latent infection is often associated with inflammation. The arachidonic acid pathway, the home of several inflammation and resolution associated lipid mediators, is widely altered upon viral infections. Several in vitro studies show that these lipid mediators help in the progression of viral pathogenesis. This review summarizes the findings related to human herpesvirus KSHV infection and arachidonic acid pathway metabolites. KSHV infection has been shown to promote inflammation by upregulating cyclooxygenase-2 (COX-2), 5 lipoxygenase (5LO), and their respective metabolites prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) to promote latency and an inflammatory microenvironment. Interestingly, the anti-inflammatory lipid mediator lipoxin is downregulated during KSHV infection to facilitate infected cell survival. These studies aid in understanding the role of arachidonic acid pathway metabolites in the progression of viral infection, the host inflammatory response, and pathogenesis. With limited therapeutic options to treat KSHV infection, use of inhibitors to these inflammatory metabolites and their synthetic pathways or supplementing anti-inflammatory lipid mediators could be an effective alternative therapeutic.
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Affiliation(s)
- Jayashree A Chandrasekharan
- Department of Microbiology and Immunology, H.M. Bligh Cancer Research Laboratories, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, United States
| | - Neelam Sharma-Walia
- Department of Microbiology and Immunology, H.M. Bligh Cancer Research Laboratories, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, United States
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19
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Emerging Role of Garcinol in Targeting Cancer Stem Cells of Non-small Cell Lung Cancer. ACTA ACUST UNITED AC 2019. [DOI: 10.1007/s40495-019-00169-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
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20
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Merchant N, Bhaskar LVKS, Momin S, Sujatha P, Reddy ABM, Nagaraju GP. 5-Lipoxygenase: Its involvement in gastrointestinal malignancies. Crit Rev Oncol Hematol 2018; 127:50-55. [PMID: 29891111 DOI: 10.1016/j.critrevonc.2018.05.012] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Revised: 04/16/2018] [Accepted: 05/14/2018] [Indexed: 12/11/2022] Open
Abstract
Lipoxygenases (LOXs) are dioxygenases that catalyze the peroxidation of linoleic acid (LA) or arachidonic acid (AA), in the presence of molecular oxygen. The existence of inflammatory component in the tumor microenvironment intimately links the LOXs to gastrointestinal (GI) cancer progression. Amongst the six-different human LOX-isoforms, 5-LOX is the most vital enzyme for leukotriene (LT) biosynthesis, which is the main inflammation intermediaries. As recent investigations have shown the association of 5-LOX with tumor metastasis, there has also been significant progress in discovering the function of 5-LOX pathway in GI cancer. Studies on GI cancer cells using the pharmacological drugs targeting 5-LOX pathway have shown antiproliferative and proapoptotic effects. Pharmacogenetic discoveries in other diseases have revealed strong heritable basis for the leukotriene pathway, which helps in exploring the mechanistic source of genetic alteration within the leukotriene pathway and offer insights into GI cancer pathogenesis and future prospects for treatment and prevention. This review recapitulates the current research status of 5-LOX activity in GI malignancies.
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Affiliation(s)
- Neha Merchant
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, 30322, USA
| | | | - Saimila Momin
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, 30322, USA
| | - Peela Sujatha
- Department of Biotechnology, Dr. B.R. Ambedkar University, Etcherla, Srikakulam, Andhra Pradesh, 532410, India
| | - Aramati B M Reddy
- Department of Animal Biology, School of Life Sciences, University of Hyderabad, Hyderabad, 500046, India
| | - Ganji Purnachandra Nagaraju
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, 30322, USA.
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21
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Scherma ME, Madzzuduli G, Silva RA, Garay MI, Repossi G, Brunotto M, Pasqualini ME. The effects of ω-6 and ω-3 fatty-acids on early stages of mice DMBA submandibular glands tumorigenesis. Prostaglandins Leukot Essent Fatty Acids 2017; 125:48-55. [PMID: 28987722 DOI: 10.1016/j.plefa.2017.08.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2016] [Revised: 08/16/2017] [Accepted: 08/21/2017] [Indexed: 01/28/2023]
Abstract
The aim of this work was: to assess the impact of diets enriched in polyunsaturated fatty acids ω-3 and ω-6 families on the lipid profile of cell membrane and their effect on cycle regulation and apoptosis, evaluated by TP53 and Ki-67 expression in 9,10-dimethyl-1,2-benzanthracene (DMBA) induced tumor development in submandibular glands (SMG) in murine models. To generate tumorigenic changes, SMG mice in the experimental group were injected with 50μl of 0.5% of DMBA. Both control (no DMBA) and experimental groups of BALB/c mice were fed with: chia oil (ChO), rich in ω-3 fatty acid; corn oil (CO), rich in ω-6/ω-3 fatty acid; and safflower (SO) oil, rich in ω-6fatty acid. Results demonstrate novel differential effects of ω-3 and ω-6 PUFAs on the regulation of early tumorigenesis events in murine SMG injected with DMBA. This knowledge may help to develop chemoprotective treatments, therapeutic agents and health promotion and prevention activities in humans.
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Affiliation(s)
- M E Scherma
- Departamento de Biología Bucal, Facultad de Odontología, Universidad Nacional de Córdoba, Argentina
| | - G Madzzuduli
- Instituto de Investigaciones en Ciencias de la Salud, (INICSA-CONICET-UNC), Argentina
| | - R A Silva
- Cátedra de Biología Celular, Histología y Embriología, Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Argentina
| | - M I Garay
- Cátedra de Biología Celular, Histología y Embriología, Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Argentina; Instituto de Investigaciones en Ciencias de la Salud, (INICSA-CONICET-UNC), Argentina
| | - G Repossi
- Cátedra de Biología Celular, Histología y Embriología, Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Argentina; Instituto de Investigaciones en Ciencias de la Salud, (INICSA-CONICET-UNC), Argentina
| | - M Brunotto
- Departamento de Biología Bucal, Facultad de Odontología, Universidad Nacional de Córdoba, Argentina
| | - M E Pasqualini
- Cátedra de Biología Celular, Histología y Embriología, Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Argentina; Instituto de Investigaciones en Ciencias de la Salud, (INICSA-CONICET-UNC), Argentina.
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22
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Sommakia S, Baker OJ. Regulation of inflammation by lipid mediators in oral diseases. Oral Dis 2017; 23:576-597. [PMID: 27426637 PMCID: PMC5243936 DOI: 10.1111/odi.12544] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2016] [Revised: 07/08/2016] [Accepted: 07/13/2016] [Indexed: 02/06/2023]
Abstract
Lipid mediators (LM) of inflammation are a class of compounds derived from ω-3 and ω-6 fatty acids that play a wide role in modulating inflammatory responses. Some LM possess pro-inflammatory properties, while others possess proresolving characteristics, and the class switch from pro-inflammatory to proresolving is crucial for tissue homeostasis. In this article, we review the major classes of LM, focusing on their biosynthesis and signaling pathways, and their role in systemic and, especially, oral health and disease. We discuss the detection of these LM in various body fluids, focusing on diagnostic and therapeutic applications. We also present data showing gender-related differences in salivary LM levels in healthy controls, leading to a hypothesis on the etiology of inflammatory diseases, particularly Sjögren's syndrome. We conclude by enumerating open areas of research where further investigation of LM is likely to result in therapeutic and diagnostic advances.
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Affiliation(s)
- Salah Sommakia
- School of Dentistry, The University of Utah, Salt Lake City, UT, USA
| | - Olga J. Baker
- School of Dentistry, The University of Utah, Salt Lake City, UT, USA
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Yarla NS, Bishayee A, Sethi G, Reddanna P, Kalle AM, Dhananjaya BL, Dowluru KSVGK, Chintala R, Duddukuri GR. Targeting arachidonic acid pathway by natural products for cancer prevention and therapy. Semin Cancer Biol 2016; 40-41:48-81. [PMID: 26853158 DOI: 10.1016/j.semcancer.2016.02.001] [Citation(s) in RCA: 250] [Impact Index Per Article: 27.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2015] [Revised: 01/23/2016] [Accepted: 02/01/2016] [Indexed: 12/16/2022]
Abstract
Arachidonic acid (AA) pathway, a metabolic process, plays a key role in carcinogenesis. Hence, AA pathway metabolic enzymes phospholipase A2s (PLA2s), cyclooxygenases (COXs) and lipoxygenases (LOXs) and their metabolic products, such as prostaglandins and leukotrienes, have been considered novel preventive and therapeutic targets in cancer. Bioactive natural products are a good source for development of novel cancer preventive and therapeutic drugs, which have been widely used in clinical practice due to their safety profiles. AA pathway inhibitory natural products have been developed as chemopreventive and therapeutic agents against several cancers. Curcumin, resveratrol, apigenin, anthocyans, berberine, ellagic acid, eugenol, fisetin, ursolic acid, [6]-gingerol, guggulsteone, lycopene and genistein are well known cancer chemopreventive agents which act by targeting multiple pathways, including COX-2. Nordihydroguaiaretic acid and baicalein can be chemopreventive molecules against various cancers by inhibiting LOXs. Several PLA2s inhibitory natural products have been identified with chemopreventive and therapeutic potentials against various cancers. In this review, we critically discuss the possible utility of natural products as preventive and therapeutic agents against various oncologic diseases, including prostate, pancreatic, lung, skin, gastric, oral, blood, head and neck, colorectal, liver, cervical and breast cancers, by targeting AA pathway. Further, the current status of clinical studies evaluating AA pathway inhibitory natural products in cancer is reviewed. In addition, various emerging issues, including bioavailability, toxicity and explorability of combination therapy, for the development of AA pathway inhibitory natural products as chemopreventive and therapeutic agents against human malignancy are also discussed.
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Affiliation(s)
- Nagendra Sastry Yarla
- Department of Biochemisty/Bionformatics, Institute of Science, GITAM University, Rushikonda, Visakhapatnam 530 045, Adhra Pradesh, India
| | - Anupam Bishayee
- Department of Pharmaceutical Sciences, College of Pharmacy, Larkin Health Sciences Institute, 18301 N. Miami Avenue, Miami, FL 33169, USA.
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore; School of Biomedical Sciences, Curtin Health Innovation Research Institute, Biosciences Research Precinct, Curtin University, Western Australia 6009, Australia
| | - Pallu Reddanna
- Department of Animal Biology, School of Life Sciences, University of Hyderabad, Gachibowli, Hyderabad 500 046, Telagana, India
| | - Arunasree M Kalle
- Department of Animal Biology, School of Life Sciences, University of Hyderabad, Gachibowli, Hyderabad 500 046, Telagana, India; Department of Environmental Health Sciences, Laboratory of Human Environmental Epigenomes, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA
| | - Bhadrapura Lakkappa Dhananjaya
- Toxinology/Toxicology and Drug Discovery Unit, Center for Emerging Technologies, Jain Global Campus, Jain University, Kanakapura Taluk, Ramanagara 562 112, Karnataka, India
| | - Kaladhar S V G K Dowluru
- Department of Biochemisty/Bionformatics, Institute of Science, GITAM University, Rushikonda, Visakhapatnam 530 045, Adhra Pradesh, India; Department of Microbiology and Bioinformatics, Bilaspur University, Bilaspur 495 001, Chhattisgarh, India
| | - Ramakrishna Chintala
- Department of Environmental Sciences, Institute of Science, GITAM University, Rushikonda, Visakhapatnam 530 045, Adhra Pradesh, India
| | - Govinda Rao Duddukuri
- Department of Biochemisty/Bionformatics, Institute of Science, GITAM University, Rushikonda, Visakhapatnam 530 045, Adhra Pradesh, India.
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Singh S, Awasthi M, Pandey VP, Dwivedi UN. Lipoxygenase directed anti-inflammatory and anti-cancerous secondary metabolites: ADMET-based screening, molecular docking and dynamics simulation. J Biomol Struct Dyn 2016; 35:657-668. [PMID: 26942689 DOI: 10.1080/07391102.2016.1159985] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Lipoxygenases (LOXs), key enzymes involved in the biosynthesis of leukotrienes, are well known to participate in the inflammatory and immune responses. With the recent reports of involvement of 5-LOX (one of the isozymes of LOX in human) in cancer, there is a need to find out selective inhibitors of 5-LOX for their therapeutic application. In the present study, plant-derived 300 anti-inflammatory and anti-cancerous secondary metabolites (100 each of alkaloids, flavonoids and terpenoids) have been screened for their pharmacokinetic properties and subsequently docked for identification of potent inhibitors of 5-LOX. Pharmacokinetic analyses revealed that only 18 alkaloids, 26 flavonoids, and 9 terpenoids were found to fulfill all the absorption, distribution, metabolism, excretion, and toxicity descriptors as well as those of Lipinski's Rule of Five. Docking analyses of pharmacokinetically screened metabolites and their comparison with a known inhibitor (drug), namely zileuton revealed that only three alkaloids, six flavonoids and three terpenoids were found to dock successfully with 5-LOX with the flavonoid, velutin being the most potent inhibitor among all. The results of the docking analyses were further validated by performing molecular dynamics simulation and binding energy calculations for the complexes of 5-LOX with velutin, galangin, chrysin (in order of LibDock scores), and zileuton. The data revealed stabilization of all the complexes within 15 ns of simulation with velutin complex exhibiting least root-mean-square deviation value (.285 ± .007 nm) as well as least binding energy (ΔGbind = -203.169 kJ/mol) as compared to others during the stabilization phase of simulation.
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Affiliation(s)
- Swati Singh
- a Bioinformatics Infrastructure Facility, Center of Excellence in Bioinformatics, Department of Biochemistry , University of Lucknow , Lucknow 226007 , Uttar Pradesh , India
| | - Manika Awasthi
- a Bioinformatics Infrastructure Facility, Center of Excellence in Bioinformatics, Department of Biochemistry , University of Lucknow , Lucknow 226007 , Uttar Pradesh , India
| | - Veda P Pandey
- a Bioinformatics Infrastructure Facility, Center of Excellence in Bioinformatics, Department of Biochemistry , University of Lucknow , Lucknow 226007 , Uttar Pradesh , India
| | - Upendra N Dwivedi
- a Bioinformatics Infrastructure Facility, Center of Excellence in Bioinformatics, Department of Biochemistry , University of Lucknow , Lucknow 226007 , Uttar Pradesh , India
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25
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Castrillo JI, Oliver SG. Alzheimer's as a Systems-Level Disease Involving the Interplay of Multiple Cellular Networks. Methods Mol Biol 2016; 1303:3-48. [PMID: 26235058 DOI: 10.1007/978-1-4939-2627-5_1] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Alzheimer's disease (AD), and many neurodegenerative disorders, are multifactorial in nature. They involve a combination of genomic, epigenomic, interactomic and environmental factors. Progress is being made, and these complex diseases are beginning to be understood as having their origin in altered states of biological networks at the cellular level. In the case of AD, genomic susceptibility and mechanisms leading to (or accompanying) the impairment of the central Amyloid Precursor Protein (APP) processing and tau networks are widely accepted as major contributors to the diseased state. The derangement of these networks may result in both the gain and loss of functions, increased generation of toxic species (e.g., toxic soluble oligomers and aggregates) and imbalances, whose effects can propagate to supra-cellular levels. Although well sustained by empirical data and widely accepted, this global perspective often overlooks the essential roles played by the main counteracting homeostatic networks (e.g., protein quality control/proteostasis, unfolded protein response, protein folding chaperone networks, disaggregases, ER-associated degradation/ubiquitin proteasome system, endolysosomal network, autophagy, and other stress-protective and clearance networks), whose relevance to AD is just beginning to be fully realized. In this chapter, an integrative perspective is presented. Alzheimer's disease is characterized to be a result of: (a) intrinsic genomic/epigenomic susceptibility and, (b) a continued dynamic interplay between the deranged networks and the central homeostatic networks of nerve cells. This interplay of networks will underlie both the onset and rate of progression of the disease in each individual. Integrative Systems Biology approaches are required to effect its elucidation. Comprehensive Systems Biology experiments at different 'omics levels in simple model organisms, engineered to recapitulate the basic features of AD may illuminate the onset and sequence of events underlying AD. Indeed, studies of models of AD in simple organisms, differentiated cells in culture and rodents are beginning to offer hope that the onset and progression of AD, if detected at an early stage, may be stopped, delayed, or even reversed, by activating or modulating networks involved in proteostasis and the clearance of toxic species. In practice, the incorporation of next-generation neuroimaging, high-throughput and computational approaches are opening the way towards early diagnosis well before irreversible cell death. Thus, the presence or co-occurrence of: (a) accumulation of toxic Aβ oligomers and tau species; (b) altered splicing and transcriptome patterns; (c) impaired redox, proteostatic, and metabolic networks together with, (d) compromised homeostatic capacities may constitute relevant 'AD hallmarks at the cellular level' towards reliable and early diagnosis. From here, preventive lifestyle changes and tailored therapies may be investigated, such as combined strategies aimed at both lowering the production of toxic species and potentiating homeostatic responses, in order to prevent or delay the onset, and arrest, alleviate, or even reverse the progression of the disease.
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Affiliation(s)
- Juan I Castrillo
- Department of Biochemistry & Cambridge Systems Biology Centre, University of Cambridge, Sanger Building, 80 Tennis Court Road, Cambridge, CB2 1GA, UK,
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Tuncer S, Banerjee S. Eicosanoid pathway in colorectal cancer: Recent updates. World J Gastroenterol 2015; 21:11748-11766. [PMID: 26557000 PMCID: PMC4631974 DOI: 10.3748/wjg.v21.i41.11748] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Revised: 06/25/2015] [Accepted: 08/31/2015] [Indexed: 02/06/2023] Open
Abstract
Enzymatic metabolism of the 20C polyunsaturated fatty acid (PUFA) arachidonic acid (AA) occurs via the cyclooxygenase (COX) and lipoxygenase (LOX) pathways, and leads to the production of various bioactive lipids termed eicosanoids. These eicosanoids have a variety of functions, including stimulation of homeostatic responses in the cardiovascular system, induction and resolution of inflammation, and modulation of immune responses against diseases associated with chronic inflammation, such as cancer. Because chronic inflammation is essential for the development of colorectal cancer (CRC), it is not surprising that many eicosanoids are implicated in CRC. Oftentimes, these autacoids work in an antagonistic and highly temporal manner in inflammation; therefore, inhibition of the pro-inflammatory COX-2 or 5-LOX enzymes may subsequently inhibit the formation of their essential products, or shunt substrates from one pathway to another, leading to undesirable side-effects. A better understanding of these different enzymes and their products is essential not only for understanding the importance of eicosanoids, but also for designing more effective drugs that solely target the inflammatory molecules found in both chronic inflammation and cancer. In this review, we have evaluated the cancer promoting and anti-cancer roles of different eicosanoids in CRC, and highlighted the most recent literature which describes how those molecules affect not only tumor tissue, but also the tumor microenvironment. Additionally, we have attempted to delineate the roles that eicosanoids with opposing functions play in neoplastic transformation in CRC through their effects on proliferation, apoptosis, motility, metastasis, and angiogenesis.
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27
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Wang X, Chen Y, Zhang S, Zhang L, Liu X, Zhang L, Li X, Chen D. Co-expression of COX-2 and 5-LO in primary glioblastoma is associated with poor prognosis. J Neurooncol 2015; 125:277-85. [PMID: 26334317 DOI: 10.1007/s11060-015-1919-6] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2015] [Accepted: 08/29/2015] [Indexed: 12/27/2022]
Abstract
Cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LO) are important factors in tumorigenesis and malignant progression; however, studies of their roles in glioblastoma have produced conflicting results. To define the frequencies of COX-2 and 5-LO expression and their correlation with clinicopathological features and prognosis, tumor tissues from 76 cases of newly diagnosed primary ordinary glioblastoma were examined for COX-2 and 5-LO expression by immunohistochemistry. The expression levels of COX-2 and 5-LO and the relationships between the co-expression of COX-2/5-LO and patient age and gender, edema index (EI), Karnofsky Performance Scale and overall survival (OS) were analyzed. COX-2 and 5-LO were expressed in 73.7 % (56/76) and 92.1 % (70/76) of the samples, respectively. Among the clinicopathological characteristics, only age (>60 years) exhibited a significant association with the high expression of COX-2. No statistically significant correlations were found in the 5-LO cohort. A significant positive correlation was revealed between the COX-2 and 5-LO scores (r = 0.374; p = 0.001). The elevated co-expression of COX-2 and 5-LO was observed primarily in the patients over the age of 60 years. Patients with a high expression of COX-2 had a significantly shorter OS (p < 0.01), whereas the immunoexpression of 5-LO was not associated with the OS of patients with glioblastoma. Survival analysis indicated that simultaneous high levels of COX-2 and 5-LO expression were significantly correlated with poor OS and, conversely, that a low/low expression pattern of these two proteins was significantly associated with better OS (p < 0.05). Moreover, the Cox multivariable proportional hazard model showed that a high expression of COX-2, high co-expression of COX-2 and 5-LO, and a high Ki-67 index were significant predictors of shorter OS in primary glioblastoma, independent of age, gender, EI, 5-LO expression and p53 status. The hazard ratios for OS were 2.347 (95 % CI 1.30-4.25, p = 0.005), 1.900 (95 % CI 1.30-2.78, p = 0.001), and 2.210 (95 % CI 1.19-4.09, p = 0.011), respectively. These results suggest that COX-2 and 5-LO play roles in tumorigenesis and the progression of primary glioblastoma and that the co-expression pattern of COX-2/5-LO may be used as an independent prognostic factor in this disease.
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Affiliation(s)
- Xingfu Wang
- Department of Pathology, The First Affiliated Hospital of Fujian Medical University, No. 20 Chazhong Road, Taijiang Ditrict, Fuzhou City, 350005, China.
| | - Yupeng Chen
- Department of Pathology, The First Affiliated Hospital of Fujian Medical University, No. 20 Chazhong Road, Taijiang Ditrict, Fuzhou City, 350005, China.
| | - Sheng Zhang
- Department of Pathology, The First Affiliated Hospital of Fujian Medical University, No. 20 Chazhong Road, Taijiang Ditrict, Fuzhou City, 350005, China.
| | - Lifeng Zhang
- Department of Endocrinology, Fujian Province Governmental Hospital, No. 67 Guping Road, Gulou Ditrict, Fuzhou City, 350003, China.
| | - Xueyong Liu
- Department of Pathology, The First Affiliated Hospital of Fujian Medical University, No. 20 Chazhong Road, Taijiang Ditrict, Fuzhou City, 350005, China.
| | - Li Zhang
- Department of Pathology, The First Affiliated Hospital of Fujian Medical University, No. 20 Chazhong Road, Taijiang Ditrict, Fuzhou City, 350005, China.
| | - Xiaoling Li
- Department of Pathology, The First Affiliated Hospital of Fujian Medical University, No. 20 Chazhong Road, Taijiang Ditrict, Fuzhou City, 350005, China.
| | - Dayang Chen
- Department of Pathology, The First Affiliated Hospital of Fujian Medical University, No. 20 Chazhong Road, Taijiang Ditrict, Fuzhou City, 350005, China.
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28
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Bessadóttir M, Eiríksson FF, Becker S, Ögmundsdóttir MH, Ómarsdóttir S, Thorsteinsdóttir M, Ögmundsdóttir HM. Anti-proliferative and pro-apoptotic effects of lichen-derived compound protolichesterinic acid are not mediated by its lipoxygenase-inhibitory activity. Prostaglandins Leukot Essent Fatty Acids 2015; 98:39-47. [PMID: 25964147 DOI: 10.1016/j.plefa.2015.04.009] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2014] [Revised: 04/01/2015] [Accepted: 04/19/2015] [Indexed: 10/23/2022]
Abstract
Lipoxygenases (LOXs) and their products are involved in several biological functions and have been associated with carcinogenesis. Protolichesterinic acid (PA), a lichen metabolite, inhibits 5- and 12-LOX and has anti-proliferative effects on various cancer cell lines. Here, PA was shown to inhibit proliferation of multiple myeloma cells, RPMI 8226 and U266, and pancreatic cancer cells AsPC-1. Apoptosis was induced only in multiple myeloma cells. Cell-cycle associated changes in expression and sub-cellular localization of 5- and 12-LOX were not affected by PA but increased cytoplasmic localisation was found to accompany morphological changes at later stages. Assessment by mass spectrometry showed that PA entered the pancreatic cancer cells. However, effects on LOX metabolites were only evident after treatment with concentrations exceeding those having anti-proliferative effects and no effects were measurable in the myeloma cells. We conclude that the anti-proliferative and pro-apoptotic effects of PA are not mediated directly through inhibition of LOX activity.
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Affiliation(s)
- M Bessadóttir
- Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland; Faculty of Pharmaceutical Sciences, University of Iceland, 101 Reykjavik, Iceland
| | - F F Eiríksson
- Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland; Faculty of Pharmaceutical Sciences, University of Iceland, 101 Reykjavik, Iceland
| | - S Becker
- Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland
| | | | - S Ómarsdóttir
- Faculty of Pharmaceutical Sciences, University of Iceland, 101 Reykjavik, Iceland
| | - M Thorsteinsdóttir
- Faculty of Pharmaceutical Sciences, University of Iceland, 101 Reykjavik, Iceland
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Katoumas K, Nikitakis N, Perrea D, Dontas I, Sklavounou A. In Vivo Antineoplastic Effects of the NSAID Sulindac in an Oral Carcinogenesis Model. Cancer Prev Res (Phila) 2015; 8:642-9. [PMID: 25939347 DOI: 10.1158/1940-6207.capr-14-0447] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2014] [Accepted: 04/27/2015] [Indexed: 11/16/2022]
Abstract
The antineoplastic properties of the NSAID sulindac have long been studied. The purpose of this study was to explore sulindac's in vivo effects on oral squamous cell carcinoma (SCC) oncogenesis using the hamster cheek pouch oral carcinogenesis model (HOCM). Thirty Syrian golden hamsters were divided into three experimental and two control groups (n = 6 each). The animals' right buccal pouches were treated with carcinogen for 9 weeks in one experimental and one control group and for 14 weeks in all other three groups. The animals of two experimental groups received sulindac from the 1st week and those of the third experimental group from the 10th week. After the end of carcinogenesis, treated buccal pouches were removed and examined. In animals treated with carcinogen for 14 weeks, development of oral SCC and tumor volume were significantly lower in animals that received sulindac from the first week of the experiment. Oral SCC developing in animals that received sulindac were more frequently well differentiated compared with the control group. In animals treated with carcinogen for 9 weeks, the animals that received sulindac developed lower grade of epithelial dysplasia. Proliferation index Ki-67 and positivity for the antiapoptotic molecule survivin were lower in the animals that received sulindac. Treatment with sulindac appears to delays the progression of oral premalignant lesions to oral SCC in the HOCM, also resulting in smaller and better differentiated tumors. These in vivo antineoplastic effects may be related to sulindac's ability to decrease cell proliferation and to prevent survivin expression.
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Affiliation(s)
- Konstantinos Katoumas
- Department of Oral Medicine and Pathology, Dental School, National and Kapodistrian University of Athens, Greece.
| | - Nikolaos Nikitakis
- Department of Oral Medicine and Pathology, Dental School, National and Kapodistrian University of Athens, Greece
| | - Despina Perrea
- Laboratory of Experimental Surgery and Surgical Research "N.S. Christeas," School of Medicine, National and Kapodistrian University of Athens, Greece
| | - Ismene Dontas
- Laboratory of Experimental Surgery and Surgical Research "N.S. Christeas," School of Medicine, National and Kapodistrian University of Athens, Greece
| | - Alexandra Sklavounou
- Department of Oral Medicine and Pathology, Dental School, National and Kapodistrian University of Athens, Greece
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30
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Zhu X, Xiong L, Zhang X, Shi N, Zhang Y, Ke J, Sun Z, Chen T. Lyophilized strawberries prevent 7,12-dimethylbenz[α]anthracene (DMBA)-induced oral squamous cell carcinogenesis in hamsters. J Funct Foods 2015. [DOI: 10.1016/j.jff.2015.03.011] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
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Zhou GX, Ding XL, Wu SB, Zhang HF, Cao W, Qu LS, Zhang H. Inhibition of 5-lipoxygenase triggers apoptosis in pancreatic cancer cells. Oncol Rep 2015; 33:661-668. [PMID: 25483364 DOI: 10.3892/or.2014.3650] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2014] [Accepted: 10/22/2014] [Indexed: 01/11/2023] Open
Abstract
The 5-lipoxygenase (5-LOX) pathway has been associated with a variety of inflammatory diseases including asthma, atherosclerosis, rheumatoid arthritis, cancer and liver fibrosis. Several classes of 5-LOX inhibitors have been identified, but only one drug, zileuton, a redox inhibitor of 5-LOX, has been approved for clinical use. In the present study, 5-LOX was found to be overexpressed not only in pancreatic cancer cell lines but also in tissue samples of patients suffering from pancreatic adenocarcinoma. There was a close correlation between the tumor expression levels of 5-LOX mRNA and protein and the clinicopathological patient characteristics including lymph node metastasis and TNM stage. Zileuton suppressed the proliferation of SW1990 cells in a concentration- and time‑dependent manner. In addition, zileuton induced SW1990 cells to undergo apoptosis and significantly decreased 5-LOX expression. The number of apoptotic cells, estimated by flow cytometry, Annexin V/PI assay, TUNEL staining and sub‑diploid population was significantly higher than that of the control. These results suggest that the level of 5-LOX expression was increased in pancreatic cancer tissues and may be related to lymph node metastasis and TNM stage.
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Affiliation(s)
- Guo-Xiong Zhou
- Department of Gastroenterology, Affliliated Hospital of Nantong University, Jiangsu, Nantong 226001, P.R. China
| | - Xiao-Ling Ding
- Department of Gastroenterology, Affliliated Hospital of Nantong University, Jiangsu, Nantong 226001, P.R. China
| | - Sheng-Bao Wu
- Department of Gastroenterology, Affliliated Hospital of Nantong University, Jiangsu, Nantong 226001, P.R. China
| | - Hai-Feng Zhang
- Department of Gastroenterology, Affliliated Hospital of Nantong University, Jiangsu, Nantong 226001, P.R. China
| | - Wei Cao
- Department of Gastroenterology, Affliliated Hospital of Nantong University, Jiangsu, Nantong 226001, P.R. China
| | - Li-Shuai Qu
- Department of Gastroenterology, Affliliated Hospital of Nantong University, Jiangsu, Nantong 226001, P.R. China
| | - Hong Zhang
- Department of Gastroenterology, Affliliated Hospital of Nantong University, Jiangsu, Nantong 226001, P.R. China
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Gamal-Eldeen AM, Fouad LM, El-Daly SM, El-Hussieny EA, El Denshary ES. Photodynamic therapeutic role of indocyanine green in tumor-associated inflammation in skin cancer. Photodiagnosis Photodyn Ther 2014; 11:239-49. [PMID: 24632333 DOI: 10.1016/j.pdpdt.2014.03.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Revised: 02/28/2014] [Accepted: 03/01/2014] [Indexed: 01/08/2023]
Abstract
BACKGROUND Indocyanine green (ICG) is a promising water-soluble photosensitizer for photodynamic therapy (PDT) of tumors. It was reported to have promising phototoxic effect on different cell lines. This study aimed to evaluate the efficacy of ICG as an efficient PS agent for skin cancer induced in mice. METHODS Skin squamous cell carcinoma was induced in female CD-1 mice by 7,12-dimethylbenzanthracene and 12-O-tetradecanoyl-phorbol-13-acetate followed by an ICG/PDT treatment. The laser irradiation for PDT was adjusted to cover the whole body of the mice to make sure that the treatment protocol will be delivered to multiple tumors. RESULTS The treatment of skin cancer by ICG/PDT using intravenously injected ICG initiated tumor cell death and significantly decreased cell proliferation as indicated by the reduction in proliferating cell nuclear antigen positivity. A significant reduction in the inflammatory mediators; tumor necrosis factor-α, nitric oxide and 5-lipoxygenase was reported, however the level of cyclooxygenase-2 (COX-2) was significantly elevated after ICG/PDT treatment. CONCLUSION The proposed ICG/PDT treatment modality showed a significant anti-tumor and anti-inflammatory activity against skin cancer accompanied with COX-2 elevation.
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Affiliation(s)
- Amira M Gamal-Eldeen
- Cancer Biology Laboratory, Center of Excellence for Advanced Sciences, National Research Center, Cairo, Egypt; Department of Biochemistry, National Research Center, Cairo, Egypt.
| | - Lamiaa M Fouad
- Pharmaceutical Technical Examination, Egyptian Patent Office, Academy of Scientific Research and Technology, Cairo, Egypt
| | - Sherien M El-Daly
- Department of Medical Biochemistry, National Research Center, Cairo, Egypt
| | - Enas A El-Hussieny
- Zoology Department, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Ezzeddin S El Denshary
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
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Inhibitor of 5-lipoxygenase, zileuton, suppresses prostate cancer metastasis by upregulating E-cadherin and paxillin. Urology 2014; 82:1452.e7-14. [PMID: 24295266 DOI: 10.1016/j.urology.2013.08.060] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2013] [Revised: 08/07/2013] [Accepted: 08/31/2013] [Indexed: 11/22/2022]
Abstract
OBJECTIVE To investigate the expression of 5-lipoxygenase (5-LOX) in metastatic prostate cancer and whether zileuton, the inhibitor of 5-LOX, plays a role in the metastasis of prostate cancer. METHODS An enzyme-linked immunosorbent assay was used to measure 5-hydroxyeicosatetraenoic acid (5-HETE) in patient and TRAMP mice blood samples. Kaplan-Meier analysis and the log-rank test were used to analyze the survival of the mice. Immunofluorescence and immunohistochemistry were used to assay the expression of 5-LOX in the samples. After treatment with 10 μM zileuton, cell motility and the invasion of PC-3 cells were assayed using immunofluorescence, Western blotting, and transwell. TRAMP mice were treated with zileuton (600 mg/kg and 1200 mg/kg) at 24 weeks of age. Ten weeks later, the mice were killed, and the tumors (size and number) were measured. RESULTS The levels of 5-HETE were significantly greater in the TRAMP mice with metastasis than in the tumors in situ. However, no such difference was found in the human samples. The lifespan of the mice was shorter at high levels of 5-HETE (>2.4 ng/mL). The expression of 5-LOX in the metastasis sample was notably greater than that in the tumors in situ. After treatment with zileuton, the expression of paxillin and E-cadherin in PC-3 and LNCaP cells was upregulated. In the transwell experiments, the motility of PC-3 was suppressed after treatment with zileuton. The mice treated with a high level of zileuton (1200 mg/kg) also had fewer tumors; however, the size did not show a significant difference. CONCLUSION The inhibitor of 5-LOX, zileuton, can suppress prostate cancer metastasis by repaired expression of E-cadherin and paxillin.
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Dionne KR, Warnakulasuriya S, Zain RB, Cheong SC. Potentially malignant disorders of the oral cavity: current practice and future directions in the clinic and laboratory. Int J Cancer 2014; 136:503-15. [PMID: 24482244 DOI: 10.1002/ijc.28754] [Citation(s) in RCA: 89] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2013] [Revised: 01/12/2014] [Accepted: 01/15/2014] [Indexed: 12/28/2022]
Abstract
Despite commendable progress in the prevention, detection, and treatment of a wide variety of solid tumor types, oral squamous cell carcinoma (OSCC) remains a significant health burden across the globe. OSCC carcinogenesis involves accumulation of genetic alterations that coincide with the multistep malignant transformation of normal oral epithelium. OSCC is often first diagnosed at late stages of the disease (advanced regional disease and/or metastasis). Delayed diagnosis precludes successful treatment and favorable outcomes. In clinical practice, opportunities exist to identify patients with oral potentially malignant disorders (OPMDs), which precede the development of cancer. This review addresses the current status of laboratory and clinical research on OPMDs, with emphasis on leukoplakia and erythroplakia. OSF is also presented, though there is a paucity of published studies on this disorder. We focus on findings that could translate into earlier diagnosis and more efficacious treatment of those lesions with significant malignant potential. We explore how markers of OPMD malignant transformation might be implemented into current diagnostic practice to help clinicians objectively stratify patients into treatment/follow-up groups according to relative risk. We provide an overview of recently concluded and ongoing OPMD chemoprevention trials. We describe laboratory OPMD models that can be used to not only to reveal the genetic and molecular intricacies of oral cancer but also to develop novel screening methods and therapeutic approaches. Finally, we call for targeted screening programs of at-risk populations in order to facilitate diagnosis and treatment of OPMD and early OSCC.
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Affiliation(s)
- Kalen R Dionne
- Faculty of Dentistry, Oral Cancer Research and Co-ordinating Centre (OCRCC), University of Malaya, Kuala Lumpur, Malaysia; Oral Cancer Research Team, Cancer Research Initiatives Foundation (CARIF), Subang Jaya, Selangor Darul Ehsan, Malaysia; Medical Scientist Training Program, University of Colorado Denver-Anschutz Medical Campus, Aurora, CO
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The Kaposi's sarcoma-associated herpesvirus (KSHV)-induced 5-lipoxygenase-leukotriene B4 cascade plays key roles in KSHV latency, monocyte recruitment, and lipogenesis. J Virol 2013; 88:2131-56. [PMID: 24335295 DOI: 10.1128/jvi.02786-13] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Kaposi's sarcoma-associated herpesvirus (KSHV) is etiologically associated with Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL). KS lesions are characterized by endothelial cells with multiple copies of the latent KSHV episomal genome, lytic replication in a low percentage of infiltrating monocytes, and inflammatory cytokines plus growth factors. We demonstrated that KSHV utilizes inflammatory cyclooxygenase 2/prostaglandin E2 to establish and maintain latency (Sharma-Walia, N., A. G. Paul, V. Bottero, S. Sadagopan, M. V. Veettil, N. Kerur, and B. Chandran, PLoS Pathog 6:e1000777, 2010 [doi:10.1371/journal.ppat.1000777]). Here, we evaluated the role of 5-lipoxygenase (5LO) and its chemotactic metabolite leukotriene B4 (LTB4) in KSHV biology. Abundant staining of 5LO was detected in human KS tissue sections. We observed elevated levels of 5LO and high levels of secretion of LTB4 during primary KSHV infection of endothelial cells and in PEL B cells (BCBL-1 and BC-3 cells). Blocking the 5LO/LTB4 cascade inhibited viral latent ORF73, immunomodulatory K5, viral macrophage inflammatory protein 1 (MIP-1), and viral MIP-2 gene expression, without much effect on lytic switch ORF50, immediate early lytic K8, and viral interferon-regulatory factor 2 gene expression. 5LO inhibition significantly downregulated latent viral Cyclin and latency-associated nuclear antigen 2 levels in PEL cells. 5LO/LTB4 inhibition downregulated TH2-related cytokine secretion, elevated TH1-related cytokine secretion, and reduced human monocyte recruitment, adhesion, and transendothelial migration. 5LO/LTB4 inhibition reduced fatty acid synthase (FASN) promoter activity and its expression. Since FASN, a key enzyme required in lipogenesis, is important in KSHV latency, these findings collectively suggest that 5LO/LTB4 play important roles in KSHV biology and that effective inhibition of the 5LO/LTB4 pathway could potentially be used in treatment to control KS/PEL.
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Fang H, Declerck YA. Targeting the tumor microenvironment: from understanding pathways to effective clinical trials. Cancer Res 2013; 73:4965-77. [PMID: 23913938 DOI: 10.1158/0008-5472.can-13-0661] [Citation(s) in RCA: 208] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
It is clear that tumor cells do not act alone but in close interaction with the extracellular matrix and with stromal cells in the tumor microenvironment (TME). As our understanding of tumor cell-stroma interactions increased over the last two decades, significant efforts have been made to develop agents that interfere with these interactions. Here, we discuss four different therapeutic strategies that target the TME, focusing on agents that are at the most advanced stage of preclinical or clinical development. We end this review by outlining some of the lessons we have learned so far from the development of TME-targeting agents.
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Affiliation(s)
- Hua Fang
- Division of Hematology-Oncology, University of Southern California, Los Angeles, Los Angeles, USA
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Kabadere S, Kus G, Uyar R, Oztopcu-Vatan P. Licofelone abolishes survival of carcinogenic fibroblasts by inducing apoptosis. Drug Chem Toxicol 2013; 37:1-7. [PMID: 23834160 DOI: 10.3109/01480545.2013.806525] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Dual inhibitors of cyclooxygenase (COX) and lipoxygenase (LOX) pathways of arachidonic acid metabolism prevent cancer development and induce apoptosis. One of the most promising compounds that blocks both of these pathways is licofelone. We questioned whether licofelone affects the survival and/or promotes apoptosis of H-ras transformed rat embryonic fibroblast (5RP7) cells in vitro. Using 5-fluorouracil (5-FU) and colchicine as positive controls, we determined cell viability with 3-3-(4,5-D-methylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, thyazolyl blue (MTT), apoptosis with flow cytometry and activity of caspase enzyme with real-time reverse transcription polymerase chain reaction (PCR). Compared to the control, all used six doses (10, 50, 100, 150, 250 and 250 µM) of 5-FU, colchicine and licofelone, which were cytotoxic and reduced the number of H-Ras transformed 5RP7 cells by as much as 78, 72 and 92%, respectively. In addition, we found that 150, 200 and 250 µM of licofelone induced apoptosis and necrosis of H-Ras transformed 5RP7 cells in a dose- and time-dependent manner. Each three tested drugs at 250 µM also increased the level of caspase-3 enzyme up to 5-fold. Although colchicine was effective in inducing early apoptosis, licofelone had much more capacity to induce the total of early plus late apoptosis by approximately 96% in cells after 48 hours. The present study reveals the possibility that licofelone posseses strong dose- and time-dependent anticancer and apoptotic properties on carcinogenic fibroblasts.
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Affiliation(s)
- Selda Kabadere
- Department of Physiology, Faculty of Medicine, Eskisehir Osmangazi University , Eskisehir , Turkey
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Mohebati A, Milne GL, Zhou XK, Duffield-Lillico AJ, Boyle JO, Knutson A, Bosworth BP, Kingsley PJ, Marnett LJ, Brown PH, Akpa EG, Szabo E, Dannenberg AJ. Effect of zileuton and celecoxib on urinary LTE4 and PGE-M levels in smokers. Cancer Prev Res (Phila) 2013; 6:646-55. [PMID: 23682075 PMCID: PMC3707304 DOI: 10.1158/1940-6207.capr-13-0083] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
COX-2 and 5-lipoxygenase (5-LO) use arachidonic acid for the synthesis of eicosanoids that have been implicated in carcinogenesis and cardiovascular disease. The ability of celecoxib, a selective COX-2 inhibitor, to redirect arachidonic acid into the 5-LO pathway can potentially reduce its efficacy as a chemopreventive agent and increase the risk of cardiovascular complications. Levels of urinary prostaglandin E metabolite (PGE-M) and leukotriene E4 (LTE4), biomarkers of the COX and 5-LO pathways, are elevated in smokers. Here, we investigated the effects of zileuton, a 5-LO inhibitor, versus zileuton and celecoxib for 6 ± 1 days on urinary PGE-M and LTE4 levels in smokers. Treatment with zileuton led to an 18% decrease in PGE-M levels (P = 0.03); the combination of zileuton and celecoxib led to a 62% reduction in PGE-M levels (P < 0.001). Levels of LTE4 decreased by 61% in subjects treated with zileuton alone (P < 0.001) and were unaffected by the addition of celecoxib. Although zileuton use was associated with a small overall decrease in PGE-M levels, increased PGE-M levels were found in a subset (19 of 52) of subjects. Notably, the addition of celecoxib to the 5-LO inhibitor protected against the increase in urinary PGE-M levels (P = 0.03). In conclusion, zileuton was an effective inhibitor of 5-LO activity resulting in marked suppression of urinary LTE4 levels and possible redirection of arachidonic acid into the COX-2 pathway in a subset of subjects. Combining celecoxib and zileuton was associated with inhibition of both the COX-2 and 5-LO pathways manifested as reduced levels of urinary PGE-M and LTE4.
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Affiliation(s)
- Arash Mohebati
- Department of Surgery (Head and Neck Service), Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College, New York, NY 10065, USA
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Martin CK, Dirksen WP, Carlton MM, Lanigan LG, Pillai SP, Werbeck JL, Simmons JK, Hildreth BE, London CA, Toribio RE, Rosol TJ. Combined zoledronic acid and meloxicam reduced bone loss and tumour growth in an orthotopic mouse model of bone-invasive oral squamous cell carcinoma. Vet Comp Oncol 2013; 13:203-17. [PMID: 23651067 DOI: 10.1111/vco.12037] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2013] [Revised: 03/27/2013] [Accepted: 03/29/2013] [Indexed: 02/02/2023]
Abstract
Oral squamous cell carcinoma (OSCC) is common in cats and humans and invades oral bone. We hypothesized that the cyclooxygenase (COX)-2 inhibitor, meloxicam, with the bisphosphonate, zoledronic acid (ZOL), would inhibit tumour growth, osteolysis and invasion in feline OSCC xenografts in mice. Human and feline OSCC cell lines expressed COX-1 and COX-2 and the SCCF2 cells had increased COX-2 mRNA expression with bone conditioned medium. Luciferase-expressing feline SCCF2Luc cells were injected beneath the perimaxillary gingiva and mice were treated with 0.1 mg kg(-1) ZOL twice weekly, 0.3 mg kg(-1) meloxicam daily, combined ZOL and meloxicam, or vehicle. ZOL inhibited osteoclastic bone resorption at the tumour-bone interface. Meloxicam was more effective than ZOL at reducing xenograft growth but did not affect osteoclastic bone resorption. Although a synergistic effect of combined ZOL and meloxicam was not observed, combination therapy was well-tolerated and may be useful in the clinical management of bone-invasive feline OSCC.
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Affiliation(s)
- C K Martin
- Department of Veterinary Biosciences, College of Veterinary Medicine, Columbus, OH, USA
| | - W P Dirksen
- Department of Veterinary Biosciences, College of Veterinary Medicine, Columbus, OH, USA
| | - M M Carlton
- Small Animal Imaging Center Shared Resource, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - L G Lanigan
- Department of Veterinary Biosciences, College of Veterinary Medicine, Columbus, OH, USA
| | - S P Pillai
- Department of Veterinary Biosciences, College of Veterinary Medicine, Columbus, OH, USA
| | - J L Werbeck
- Department of Veterinary Biosciences, College of Veterinary Medicine, Columbus, OH, USA
| | - J K Simmons
- Department of Veterinary Biosciences, College of Veterinary Medicine, Columbus, OH, USA
| | - B E Hildreth
- Department of Veterinary Biosciences, College of Veterinary Medicine, Columbus, OH, USA
| | - C A London
- Department of Veterinary Biosciences, College of Veterinary Medicine, Columbus, OH, USA
| | - R E Toribio
- Department of Veterinary Biosciences, College of Veterinary Medicine, Columbus, OH, USA
| | - T J Rosol
- Department of Veterinary Biosciences, College of Veterinary Medicine, Columbus, OH, USA
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Leef G, Thomas SM. Molecular communication between tumor-associated fibroblasts and head and neck squamous cell carcinoma. Oral Oncol 2013; 49:381-6. [PMID: 23357526 DOI: 10.1016/j.oraloncology.2012.12.014] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2012] [Revised: 12/17/2012] [Accepted: 12/24/2012] [Indexed: 12/16/2022]
Abstract
Over the past few decades, it has become increasingly clear that the lethality of cancers depends on more than the malignant cells themselves. The environment those malignant cells are exposed to is just as important a determinant of their behavior. Head and neck squamous cell carcinoma (HNSCC) is both common and deadly. It is the 6th most frequently occurring cancers, and prognosis is still generally poor. Recent evidence indicates that activated fibroblasts residing within the tumor stroma play a significant role in promoting the aggressive spread often seen in head and neck cancer. Tumor associated fibroblasts (TAFs) have also been implicated in facilitating angiogenesis and suppressing the normal anti-tumor function of immune cells. Studying the signaling molecules involved in these processes will facilitate the development of promising targets and inhibitors to prevent tumor-associated fibroblasts from exerting their reinforcing effects on the tumor. In this article, we review the recent literature on the signals used in tumor associated fibroblast communication, with a focus on potential therapeutic targets. Further, we highlight the lead candidates for TAF-targeted therapeutic interventions. Future anti-cancer strategies may achieve better results than current approaches by targeting the support cells in tumor stroma in addition to the cancerous cells.
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Affiliation(s)
- George Leef
- Department of Otolaryngology, University of Pittsburgh and University of Pittsburgh Cancer Institute, USA
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Aparoy P, Reddy KK, Reddanna P. Structure and ligand based drug design strategies in the development of novel 5- LOX inhibitors. Curr Med Chem 2012; 19:3763-78. [PMID: 22680930 PMCID: PMC3480706 DOI: 10.2174/092986712801661112] [Citation(s) in RCA: 108] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2011] [Revised: 01/30/2012] [Accepted: 02/07/2012] [Indexed: 12/26/2022]
Abstract
Lipoxygenases (LOXs) are non-heme iron containing dioxygenases involved in the oxygenation of polyunsaturated fatty acids (PUFAs) such as arachidonic acid (AA). Depending on the position of insertion of oxygen, LOXs are classified into 5-, 8-, 9-, 12- and 15-LOX. Among these, 5-LOX is the most predominant isoform associated with the formation of 5-hydroperoxyeicosatetraenoic acid (5-HpETE), the precursor of non-peptido (LTB4) and peptido (LTC4, LTD4, and LTE4) leukotrienes. LTs are involved in inflammatory and allergic diseases like asthma, ulcerative colitis, rhinitis and also in cancer. Consequently 5-LOX has become target for the development of therapeutic molecules for treatment of various inflammatory disorders. Zileuton is one such inhibitor of 5-LOX approved for the treatment of asthma. In the recent times, computer aided drug design (CADD) strategies have been applied successfully in drug development processes. A comprehensive review on structure based drug design strategies in the development of novel 5-LOX inhibitors is presented in this article. Since the crystal structure of 5-LOX has been recently solved, efforts to develop 5-LOX inhibitors have mostly relied on ligand based rational approaches. The present review provides a comprehensive survey on these strategies in the development of 5-LOX inhibitors.
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Rao CV, Janakiram NB, Mohammed A. Lipoxygenase and Cyclooxygenase Pathways and Colorectal Cancer Prevention. CURRENT COLORECTAL CANCER REPORTS 2012; 8:316-324. [PMID: 23293573 PMCID: PMC3535427 DOI: 10.1007/s11888-012-0146-1] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Colorectal cancer is one of the commonest malignancies in both men and women. In spite of significant progress in screening and in surgical and therapeutic interventions, colorectal cancer (CRC) is still a major public health problem. Accumulating evidence suggests that targeting inflammatory pathways may provide protection against the development of CRC. Eicosanoids derived from the enzymes cyclooxygenase (COX) and lipoxygenase (LOX) may contribute to CRC carcinogenesis. Approaches for targeting COX-1 and COX-2 with traditional nonsteroidal anti-inflammatory agents or targeting COX-2 with specific inhibitors are highly successful at the preclinical and clinical levels; however, large-scale clinical applicability of these agents is limited owing to unwanted side effects. Emerging studies suggests that 5-LOX-derived leukotrienes may contribute to colon tumor development and risk of thrombotic events. Thus, developing drugs that target both 5-LOX and COX-2 may provide a safer strategy. In this review, we discuss evidence for the involvement of 5-LOX in colon tumor development and targeting 5-LOX and COX-2 with synthetic and naturally occurring agents for CRC prevention.
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Affiliation(s)
- Chinthalapally V Rao
- Center for Cancer Prevention and Drug Development, Medical Oncology, Department of Medicine, PC Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
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Chen X, Zhang X, Lu Y, Shim JY, Sang S, Sun Z, Chen X. Chemoprevention of 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster cheek pouch carcinogenesis by a 5-lipoxygenase inhibitor, garcinol. Nutr Cancer 2012; 64:1211-1218. [PMID: 23137051 PMCID: PMC3780792 DOI: 10.1080/01635581.2012.718032] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Our previous studies have shown that aberrant arachidonic acid metabolism, especially the 5-lipoxygenase (5-Lox) pathway, is involved in oral carcinogenesis and can be targeted for cancer prevention. To develop potent topical agents for oral cancer chemoprevention, 5 known 5-Lox inhibitors from dietary and synthetic sources (Zileuton, ABT-761, licofelone, curcumin, and garcinol) were evaluated in silico for their potential efficacy. Garcinol, a polyisoprenylated benzophenone from the fruit rind of Garcinia spp., was found to be a promising agent based on the calculation of a theoretical activity index. Computer modeling showed that garcinol well fit the active site of 5-Lox, and potentially inhibited enzyme activity through interactions between the phenolic hydroxyl groups and the non-heme catalytic iron. In a short-term study on 7,12-dimethylbenz[a]anthracene (DMBA)-treated hamster cheek pouch, topical garcinol suppressed leukotriene B4 (LTB4) biosynthesis and inhibited inflammation and cell proliferation in the oral epithelium. In a long-term carcinogenesis study, topical garcinol significantly reduced the size of visible tumors, the number of cancer lesions, cell proliferation, and LTB4 biosynthesis. These results demonstrated that topical application of a 5-Lox inhibitor, garcinol, had chemopreventive effect on DMBA-induced hamster cheek pouch carcinogenesis.
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Affiliation(s)
- Xin Chen
- School of Pharmaceutical & Life Sciences, Changzhou University, Jiangsu 213164, China
| | - Xinyan Zhang
- Stomatological Hospital & School of Stomatology, Capital Medical University, 4 Tiantanxili, Dongcheng District, Beijing 100050, China
- Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University, Durham, NC 27707, USA
| | - Ye Lu
- Stomatological Hospital & School of Stomatology, Capital Medical University, 4 Tiantanxili, Dongcheng District, Beijing 100050, China
| | - Joong-Youn Shim
- Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University, Durham, NC 27707, USA
| | - Shengmin Sang
- Center for Excellence in Post-Harvest Technologies, North Carolina A&T State University, North Carolina Research Campus, UNC Nutrition Research Building, Kannapolis, NC 28081
| | - Zheng Sun
- Stomatological Hospital & School of Stomatology, Capital Medical University, 4 Tiantanxili, Dongcheng District, Beijing 100050, China
| | - Xiaoxin Chen
- Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University, Durham, NC 27707, USA
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Yang H, Jia X, Chen X, Yang CS, Li N. Time-selective chemoprevention of vitamin E and selenium on esophageal carcinogenesis in rats: the possible role of nuclear factor kappaB signaling pathway. Int J Cancer 2012; 131:1517-1527. [PMID: 22223226 DOI: 10.1002/ijc.27423] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2011] [Accepted: 12/29/2011] [Indexed: 01/15/2023]
Abstract
Previous human intervention trial demonstrated that vitamin E (Ve) and selenium (Se) supplementation decreased esophageal cancer deaths among younger participants, but may have no effect or produce an opposite effect among older ones. In our study, we intended to mimic this human nutritional trial to determine the chemopreventive effects of Ve/Se supplementation at the early or late stage of esophageal carcinogenesis in rats. Esophageal squamous cell carcinoma (ESCC) was induced in Fischer 344 rats with N-nitrosomethylbenzylamine (NMBzA, 0.35 mg/kg BW, s.c., three times per week for 5 weeks). The rats were maintained on a modified AIN-93M diet with low levels of Ve/Se or supplemented with high levels of Ve/Se at different stages. At Week 25, the number and volume of visible tumors, the numbers of dysplasia and ESCC were significantly lower in rats of supplementation during the early stage (Group C) or during the entire experimental period (Group E), but not during the late stage (Group D). Ve/Se supplementation at the early stage also significantly decreased cell proliferation, nuclear factor kappaB (NFκB) activation, protein and mRNA expression of cyclooxygenase 2 and 5-lipoxygenase and biosynthesis of prostaglandin E2 and leukotriene B4 during the carcinogenesis of rat esophagus. Our results demonstrated that the chemopreventive efficacy of Ve/Se supplementation on NMBzA-induced esophageal cancer is time selective and that supplementation during the early stage is clearly effective but probably ineffective during the late stage of carcinogenesis. NFκB signaling pathway activation and aberrant arachidonic acid metabolism might be the underlying mechanism.
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Affiliation(s)
- Hui Yang
- Department of Toxicology, Institute of Nutrition and Food Safety, Chinese Center for Disease Control and Prevention, Beijing, China
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Kelly C, Feng P, Kawashima T, Wilmes A, Miller J. Two-stage model-free tests of synergy in drug combinations. J Biopharm Stat 2012; 22:54-71. [PMID: 22204527 DOI: 10.1080/10543406.2010.504314] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2022]
Abstract
Laska et al. ( 1994 ) proposed a model-free method of detecting synergy in two drug combinations that requires no assumptions about the underlying dose-response curves of the drugs, just an estimate of the potency ratio of the two drugs. It was noted that the power of this method is highly dependent on the accuracy of the potency ratio estimated, with low power when the estimate is inaccurate. Additionally, the test used to detect synergy (the Min test) has been shown to be conservative in many practical applications, and non-monotonic alternative tests that have greater power have been proposed. We suggest a two-stage, non-monotonic alternative to the Laska et al. model-free test that is less dependent on the accuracy of potency ratio estimate and has greater power in many situations. We illustrate the method with an example of two chemotherapeutic agents.
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Affiliation(s)
- Colleen Kelly
- Kelly Statistical Consulting, Carlsbad, CA 92011, USA.
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Stauber RH, Knauer SK, Habtemichael N, Bier C, Unruhe B, Weisheit S, Spange S, Nonnenmacher F, Fetz V, Ginter T, Reichardt S, Liebmann C, Schneider G, Krämer OH. A combination of a ribonucleotide reductase inhibitor and histone deacetylase inhibitors downregulates EGFR and triggers BIM-dependent apoptosis in head and neck cancer. Oncotarget 2012; 3:31-43. [PMID: 22289787 PMCID: PMC3292890 DOI: 10.18632/oncotarget.430] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Head and neck squamous cell carcinomas (HNSCCs) are the sixth most common malignant neoplasm and more than 50% of patients succumb to this disease. HNSCCs are characterized by therapy resistance, which relies on the overexpression of anti-apoptotic proteins and on the aberrant regulation of the epidermal growth factor receptor (EGFR). As inherent and acquired resistance to therapy counteracts improvement of long-term survival, novel multi-targeting strategies triggering cancer cell death are urgently required. We investigated how induction of replicational stress by the ribonucleotide reductase inhibitor hydroxyurea (HU) combined with histone deacetylase inhibitors (HDACi) exerts anti-tumor activity. We treated HNSCC cell lines and freshly isolated tumor cells with HDACi, such as the clinically approved anti-epileptic drug valproic acid (VPA), in combination with HU. Our data demonstrate that at clinically achievable levels VPA/HU combinations efficiently block proliferation as well as clonogenic survival, and trigger apoptosis of HNSCC cells. In the presence of VPA/HU, such tumor cells increase expression of the pro-apoptotic BCL-2 family protein BIM, independent of wild-type p53 signaling and in the absence of increased expression of the p53 targets PUMA and BAX. The pro-apoptotic activity of BIM in HNSCCs was found critical for tumor cell death; ectopic overexpression of BIM induced HNSCC apoptosis and RNAi-mediated depletion of BIM protected HNSCC cells from VPA/HU. Also, significantly elevated BIM levels (p<0.01) were detectable in the apoptotic tumor centers versus proliferating tumor margins in HNSCC patients (n=31), underlining BIM's clinical relevance. Importantly, VPA/HU treatment additionally reduces expression and cell surface localization of EGFR. Accordingly, in a xenograft mouse model, VPA/HU efficiently blocked tumor growth (P<0.001) correlating with BIM induction and EGFR downregulation. We provide a molecular rationale for the potent anti-cancer activities of this drug combination. Our data suggest its exploitation as a potential strategy for the treatment of HNSCC and other tumor entities characterized by therapy resistance linked to dysregulated EGFR activation.
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Affiliation(s)
- Roland H Stauber
- Molecular and Cellular Oncology/Mainz Screening Center, University Hospital of Mainz, Germany.
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Nagatsuka H, Siar CH, Tsujigiwa H, Naomoto Y, Han PP, Gunduz M, Sugahara T, Sasaki A, Nakajima M. Heparanase and cyclooxygenase-2 gene and protein expressions during progression of oral epithelial dysplasia to carcinoma. Ann Diagn Pathol 2012; 16:354-61. [PMID: 22575501 DOI: 10.1016/j.anndiagpath.2012.02.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2012] [Accepted: 02/24/2012] [Indexed: 12/16/2022]
Abstract
Heparanase and cyclooxygenase-2 (COX-2) are 2 key enzymes that modulate diverse physiological processes during embryonic development and in adult life. Their deregulations have been implicated in the growth and progression of many cancer types. To date, comparatively little is known about the roles of these molecules during oral carcinogenesis. The aim of this study was to investigate the expression patterns of heparanase and COX-2 during progression of oral epithelial dysplasia (OED) to carcinoma. In situ hybridization and immunohistochemistry were performed on 5 cases of normal mucosa, 15 cases of OED, 5 cases of carcinoma in situ and/or microinvasive carcinoma, and 40 cases of oral squamous cell carcinoma (OSCC). Results demonstrated that heparanase and COX-2 messenger RNA and protein were absent in normal oral mucosa but were coexpressed in increasing intensity as OED progressed to OSCC. Concomitant heparanase- and COX-2-positive staining in the stromal cells suggests that OED/OSCC progression may be modulated by stromal-cancer cell interactions. Diffuse intense staining of poorly differentiated OSCC compared with staining localized to tumor nest periphery in well- and moderately differentiated OSCC suggests that heparanase and COX-2 overexpressions correlated with tumor grade. Strong expression of these enzymes in tumor cells at the advancing front suggests a role in local tumor spread. These results, taken together, suggest that heparanase and COX-2 might play complementary roles in the stepwise progression of OED to carcinoma.
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Affiliation(s)
- Hitoshi Nagatsuka
- Department of Oral Pathology and Medicine, Graduate School of Medicine and Dentistry, Okayama University, Shikata-cho, Japan.
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Zhang L, He M, Zhang Y, Nilubol N, Shen M, Kebebew E. Quantitative high-throughput drug screening identifies novel classes of drugs with anticancer activity in thyroid cancer cells: opportunities for repurposing. J Clin Endocrinol Metab 2012; 97:E319-28. [PMID: 22170715 PMCID: PMC3319218 DOI: 10.1210/jc.2011-2671] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
CONTEXT Despite increased understanding of the pathogenesis and targets for thyroid cancer and other cancers, developing a new anticancer chemical agent remains an expensive and long process. An alternative approach is the exploitation of clinically used and/or bioactive compounds. OBJECTIVE Our objective was to identify agents with an anticancer effect in thyroid cancer cell lines using quantitative high-throughput screening (qHTS). DESIGN We used the newly assembled National Institutes of Health Chemical Genomic Center's pharmaceutical collection, which contains 2816 clinically approved drugs and bioactive compounds to perform qHTS. RESULTS Multiple agents, across a variety of therapeutic categories and with different modes of action, were found to have an antiproliferative effect. We found the following therapeutic categories were the most enriched categories with antiproliferative activity: cardiotonic and antiobesity agents. Sixteen agents had an efficacy of greater than 60% and a 50% inhibitory concentration (IC50) in the nanomolar range. We validated the results of the qHTS using two agents (bortezomib and ouabain) in additional cell lines representing different histological subtypes of thyroid cancer and with different mutations (BRAF V600E, RET/PTC1, p53, PTEN). Both agents induced apoptosis, and ouabain also caused cell cycle arrest. CONCLUSIONS To our knowledge, this is the first study to use qHTS of a large drug library to identify candidate drugs for anticancer therapy. Our results indicate such a screening approach can lead to the discovery of novel agents in different therapeutic categories and drugs with nonclassic chemotherapy mode of action. Our approach could lead to drug repurposing and accelerate clinical trials of compounds with well-established pharmacokinetics and toxicity profiles.
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Affiliation(s)
- Lisa Zhang
- Endocrine Oncology Section, Surgery Branch, National Cancer Institute, Clinical Research Center, Building 10-CRC, Room 3-3940, 10 Center Drive, MSC 1201, Bethesda, Maryland 20892, USA
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50
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Hearnden V, Sankar V, Hull K, Juras DV, Greenberg M, Kerr AR, Lockhart PB, Patton LL, Porter S, Thornhill MH. New developments and opportunities in oral mucosal drug delivery for local and systemic disease. Adv Drug Deliv Rev 2012; 64:16-28. [PMID: 21371513 DOI: 10.1016/j.addr.2011.02.008] [Citation(s) in RCA: 200] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2010] [Revised: 02/15/2011] [Accepted: 02/23/2011] [Indexed: 02/08/2023]
Abstract
The oral mucosa's accessibility, excellent blood supply, by-pass of hepatic first-pass metabolism, rapid repair and permeability profile make it an attractive site for local and systemic drug delivery. Technological advances in mucoadhesives, sustained drug release, permeability enhancers and drug delivery vectors are increasing the efficient delivery of drugs to treat oral and systemic diseases. When treating oral diseases, these advances result in enhanced therapeutic efficacy, reduced drug wastage and the prospect of using biological agents such as genes, peptides and antibodies. These technologies are also increasing the repertoire of drugs that can be delivered across the oral mucosa to treat systemic diseases. Trans-mucosal delivery is now a favoured route for non-parenteral administration of emergency drugs and agents where a rapid onset of action is required. Furthermore, advances in drug delivery technology are bringing forward the likelihood of transmucosal systemic delivery of biological agents.
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