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Sandra Murphy, Robert Ellis-Hutchings, Lavorgie Finch, Stefanie Welz, Karin Wiench
Skin tumors have been observed in C3H/HeJ mice following treatment with high and strongly irritating concentrations of 2-ethylhexyl acrylate (2-EHA). Dermal carcinogenicity studies performed with 2-EHA are reviewed, contrasting the results in two mouse strains (C3H/HeJ and NMRI) under different dosing regimens. Application of contemporary evaluation criteria to the existing dermal carcinogenicity dataset demonstrates that 2-EHA induces skin tumors only at concentrations exceeding an maximum tolerated dose (MTD) and in the immune-dysregulated C3H/HeJ mouse model...
May 15, 2018: Toxicology Letters
Alf Claesson, Alexander Minidis
Reactive metabolites are widely accepted as playing a pivotal role in causing idiosyncratic adverse drug reactions (IDR). However, much is unknown about the biological mechanisms of IDR although the initiating event in most cases is an attachment of a reactive intermediate to macromolecules leading to immune mediated responses. Reactive metabolites are also involved in many mutagenesis/ carcinogenesis events by reacting with DNA. Drug designers thus have all reasons to make large efforts to avoid making test compounds having a liability to generate reactive metabolites...
May 10, 2018: Chemical Research in Toxicology
Wei Chen, Kyung L Kang, Abdullah Alshaikh, Saaket Varma, Yi-Ling Lin, Ki-Hyuk Shin, Reuben Kim, Cun-Yu Wang, No-Hee Park, Katharina Walentin, Kai M Schmidt-Ott, Mo K Kang
Grainyhead-Like 2 (GRHL2) is an epithelial-specific transcription factor that regulates epithelial morphogenesis and differentiation. Prior studies suggested inverse regulation between GRHL2 and TGF-β in epithelial plasticity and potential carcinogenesis. Here, we report the role of GRHL2 in oral carcinogenesis in vivo using a novel Grhl2 knockout (KO) mouse model and the underlying mechanism involving its functional interaction with TGF-β signaling. We developed epithelial-specific Grhl2 conditional KO mice by crossing Grhl2 floxed mice with those expressing CreER driven by the K14 promoter...
May 8, 2018: Oncogenesis
Alberto Diaz-Ruiz, Andrea Di Francesco, Bethany A Carboneau, Sophia R Levan, Kevin J Pearson, Nathan L Price, Theresa M Ward, Michel Bernier, Rafael de Cabo, Evi M Mercken
Caloric restriction (CR) is the most potent nonpharmacological intervention known to both protect against carcinogenesis and delay aging in laboratory animals. There is a growing number of anticarcinogens and CR mimetics that activate NAD(P)H:quinone oxidoreductase 1 (NQO1). We have previously shown that NQO1, an antioxidant enzyme that acts as an energy sensor through modulation of intracellular redox and metabolic state, is upregulated by CR. Here, we used NQO1-knockout (KO) mice to investigate the role of NQO1 in both the aging process and tumor susceptibility, specifically in the context of CR...
May 4, 2018: Journals of Gerontology. Series A, Biological Sciences and Medical Sciences
Evangelina López de Maturana, Marta Rava, Chiaka Anumudu, Olga Sáez, Dolores Alonso, Núria Malats
Background: The variant/gene candidate approach to explore bladder cancer (BC) genetic susceptibility has been applied in many studies with significant findings reported. However, results are not always conclusive due to the lack of replication by subsequent studies. Objectives: To identify all epidemiological investigations on the genetic associations with BC risk, to quantify the likely magnitude of the associations by applying metaanalysis methodology and to assess whether there is a potential for publication/reporting bias...
April 26, 2018: Bladder Cancer
Jiaqiu Li, Ping Song, Tingting Jiang, Dongjun Dai, Hanying Wang, Jie Sun, Liyuan Zhu, Wenxia Xu, Lifeng Feng, Vivian Y Shin, Helen Morrison, Xian Wang, Hongchuan Jin
Heat shock factor 1 (HSF1) generally exhibits its properties under stress conditions. In tumors, HSF1 has a pleiotropic feature in regulating growth, survival, and aggressiveness of cancer cells. In this study, we found HSF1 was increased in colorectal cancer (CRC) and had a positive correlation with shorter disease-free survival (DFS). Knockdown of HSF1 in CRC cells attenuated their growth while inhibiting mTOR activation and glutamine metabolism. HSF1 inhibited the expression of microRNA137 (MIR137), which targeted GLS1 (glutaminase 1), thus stimulating GLS1 protein expression to promote glutaminolysis and mTOR activation...
April 14, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
Tomomi Fujii, Keiji Shimada, Tokiko Nakai, Chiho Ohbayashi
Long-term heavy cigarette smoking is a well-known high-risk factor for carcinogenesis in various organs such as the head and neck, lungs, and urinary bladder. Furthermore, cigarette smoking can systemically accelerate aging, and as the result, promoting carcinogenesis via changing the host microenvironment. Various inflammatory factors, hormones, and chemical mediators induced by smoking mediate carcinoma-related molecules and induce carcinogenesis. MicroRNAs (miRNAs) are a family of short noncoding RNA molecules that bind to mRNAs and inhibit their expression...
May 1, 2018: Journal of Clinical Medicine
Hui Zhou, Guanqing Wu, Xueyou Ma, Jun Xiao, Gan Yu, Chunguang Yang, Nan Xu, Bao Zhang, Jun Zhou, Zhangqun Ye, Zhihua Wang
BACKGROUND: Dysregulation of transforming growth factor β (TGF-β) signaling and hypoxic microenvironment have respectively been reported to be involved in disease progression in malignancies of prostate. Emerging evidence indicates that downregulation of TGFBR2, a pivotal regulator of TGF-β signaling, may contribute to carcinogenesis and progression of prostate cancer (PCa). However, the biological function and regulatory mechanism of TGFBR2 in PCa remain poorly understood. In this study, we propose to investigate the crosstalk of hypoxia and TGF-β signaling and provide insight into the molecular mechanism underlying the regulatory pathways in PCa...
April 27, 2018: Journal of Experimental & Clinical Cancer Research: CR
Igor Koturbash
In addition to the generally accepted potential of ionizing radiation to cause DNA damage, its capability to target the cellular epigenome has become increasingly evident. Epigenetics unifies the chemical marks and molecules that collectively facilitate the proper reading of genetic material. Among the epigenetic mechanisms of regulation, methylation of DNA is known to be the key player in the postirradiation response by controlling the expression of genetic information and activity of transposable elements...
April 26, 2018: Radiation Research
Norio Kudo, Akihiro Ito, Mayumi Arata, Akiko Nakata, Minoru Yoshida
SIRT2 is a member of the human sirtuin family of proteins and possesses NAD+ -dependent lysine deacetylase/deacylase activity. SIRT2 has been implicated in carcinogenesis in various cancers including leukaemia and is considered an attractive target for cancer therapy. Here, we identified NPD11033, a selective small-molecule SIRT2 inhibitor, by a high-throughput screen using the RIKEN NPDepo chemical library. NPD11033 was largely inactive against other sirtuins and zinc-dependent deacetylases. Crystallographic analysis revealed a unique mode of action, in which NPD11033 creates a hydrophobic cavity behind the substrate-binding pocket after a conformational change of the Zn-binding small domain of SIRT2...
June 5, 2018: Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences
Zahra Noorimotlagh, Seyyed Abbas Mirzaee, Mehdi Ahmadi, Neemat Jaafarzadeh, Fakher Rahim
Human impact on the environment leads to the release of many pollutants that produce artificial compounds, which can have harmful effects on the body's endocrine system; these are known as endocrine disruptors (EDs). Nonylphenol (NP) is a chemical compound with a nonyl group that is attached to a phenol ring. NP-induced H2 AX is a sensitive genotoxic biomarker for detecting possible DNA damage; it also causes male infertility and carcinogenesis. We attempt to comprehensively review all the available evidence about the different ways with descriptive mechanisms for explaining the possible DNA damage that is induced by NP...
April 20, 2018: Ecotoxicology and Environmental Safety
Hamid E Daaboul, Carole Dagher, Robin I Taleb, Kikki Bodman-Smith, Wassim N Shebaby, Mirvat El-Sibai, Mohamad A Mroueh, Costantine F Daher
β-2-himachalen-6-ol (HC), a novel sesquiterpene derived from Lebanese wild carrot, was shown to possess a remarkable anticancer activity. The present study investigates the in vitro anticancer activity of HC and its effect on papillomas induced using a DMBA/TPA skin carcinogenesis mouse model. HaCaT-ras II-4 epidermal squamous cell viability was assessed using WST-1 kit. Cell cycle was analyzed by flow cytometry, and pro/anti-apoptotic proteins were measured using western blot. Mice papillomas were induced by DMBA and promoted with TPA for 18 weeks...
April 16, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Lei Zhou, Yanyan Du, Lingqun Kong, Xingyuan Zhang, Qiangpu Chen
Background and aim: Hepatocellular carcinoma (HCC) is a major cause of cancer mortality and is increasing incidence worldwide. The aim of this study was to identify the key genes and microRNAs in HCC and explore their potential mechanisms. Methods: The gene expression profiles of GSE76427, GSE64041, GSE57957, and the microRNA dataset GSE67882 were downloaded from the Gene Expression Omnibus database. The online tool GEO2R was used to obtain differentially expressed genes (DEGs) and miRNAs (DEMs)...
2018: OncoTargets and Therapy
Peter O Coe, Steve R Williams, David M Morris, Ed Parkin, Michelle Harvie, Andrew G Renehan, Derek A O'Reilly
BACKGROUND: Excess body adiposity is associated with increased risk of pancreatic cancer, and in animal models excess intra-pancreatic fat is a driver of pancreatic carcinogenesis. Within a programme to evaluate pancreatic fat and PC risk in humans, we assessed whether MR-quantified pancreatic fat fraction (PFF) was 'fit for purpose' as an imaging biomarker. METHODS: We determined PFF using MR spectroscopy (MRS) and MR chemical shift imaging (CS-MR), in two groups...
April 3, 2018: Pancreatology: Official Journal of the International Association of Pancreatology (IAP) ... [et Al.]
Marie Stiborova
Covalent DNA adducts formed by chemicals or drugs with carcinogenic potency are judged as one of the most important factors in the initiation phase of carcinogenic processes. This covalent binding, which is considered the cause of tumorigenesis, is now evaluated as a central dogma of chemical carcinogenesis. Here, methods are described employing the reactions catalyzed by cytochrome P450 and additional biotransformation enzymes to investigate the potency of chemicals or drugs for their activation to metabolites forming these DNA adducts...
March 20, 2018: Journal of Visualized Experiments: JoVE
Tarik Ghailan, Mustapha El Ftouh
BACKGROUND: The World Health Organisation places lung cancer as the leading cause of cancer mortality in the world. The fishermen are one of the most important consumers of tobacco, which remains the main risk factor for lung cancer. However, there are no epidemiological data on the role of other causes, particularly occupational ones, in genesis of this disease. The objective of our work is to expose medical and occupational data of 3 fishermen with lung cancer and discuss a possible occupational origin of their pathology...
2018: International Maritime Health
Jéssica Alessandra-Perini, Jamila Alessandra Perini, Karina Cristina Rodrigues-Baptista, Roberto Soares de Moura, Antonio Palumbo Junior, Thiago Alves Dos Santos, Pergentino José Cunha Souza, Luiz Eurico Nasciutti, Daniel Escorsim Machado
BACKGROUND: Among the processes involved in the breast tumor microenvironment, angiogenesis and inflammation play a central role, and the main factors of these processes are the vascular endothelial growth factor (VEGF), cyclooxygenase 2 (COX-2) and macrophages. Recently, the extract of Euterpe oleracea (açaí), a fruit that is widely found in the Amazon region, already showed antitumorigenic effects in vitro in human breast cancer cell lines. The present study aimed to investigate the effect of açaí on breast cancer using a chemically DMBA (7,12-dimethylbenzanthracene) experimental model...
April 2, 2018: BMC Complementary and Alternative Medicine
Vladimir G Bespalov, Valerij A Alexandrov, Galina I Vysochina, Vera A Kostikova, Alexandr L Semenov, Denis A Baranenko
BACKGROUND: The meadowsweet (Filipendula ulmaria (L.) Maxim.) may have a cancer prophylactic activity, since its extracts exhibits antioxidant, antiinflammatory and other effects. We investigated the ability of a meadowsweet decoction to inhibit mammary carcinogenesis induced by intramammary injections of methylnitrosourea (MNU) to the target organ in rats. MATERIALS AND METHODS: The chemical composition of meadowsweet extracts was studied by traditional methods...
April 2, 2018: Anti-cancer Agents in Medicinal Chemistry
Christiana Demetriou, Davide Degli Esposti, Kristi Pullen Fedinick, Federica Russo, Oliver Robinson, Paolo Vineis
Cancer is believed to arise through the perturbation of pathways and the order of pathway perturbation events can enhance understanding and evaluation of carcinogenicity. This order has not been examined so far and this paper aims to fill this gap by attempting to gather evidence on the potential temporal sequence of events in carcinogenesis. The methodology followed was to discuss first the temporal sequence of hallmarks of cancer from the point of view of pathological specimens of cancer (essentially branched mutations), and then to consider the hallmarks of cancer that one well-known carcinogen, benzo(a)pyrene, can modify...
March 31, 2018: European Journal of Clinical Investigation
Martine Chevillard-Briet, Fabrice Escaffit
Since chromatin-modifying enzymes are involved in most processes needing to access the DNA fiber such as transcription, replication or DNA repair, their involvement in the regulation of gene expression in numerous physiopathological contexts is widely studied. Most of these enzymes are essential for cell growth and survival due to their pleiotropic roles and studying their impact in vivo on organ development or tissue physiopathology is challenging. In this chapter, we describe a chemically-mediated method to induce colorectal carcinogenesis that we have used to identify in vivo the role of two chromatin modifying enzymes belonging to the same multimolecular complex, the histone acetyltransferase Tip60 and the histone variant-incorporating ATPase p400...
2018: Methods in Molecular Biology
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