A computational method for the identification of new candidate carcinogenic and non-carcinogenic chemicals.

Cancer is one of the leading causes of human death. Based on current knowledge, one of the causes of cancer is exposure to toxic chemical compounds, including radioactive compounds, dioxin, and arsenic. The identification of new carcinogenic chemicals may warn us of potential danger and help to identify new ways to prevent cancer. In this study, a computational method was proposed to identify potential carcinogenic chemicals, as well as non-carcinogenic chemicals. According to the current validated carcinogenic and non-carcinogenic chemicals from the CPDB (Carcinogenic Potency Database), the candidate chemicals were searched in a weighted chemical network constructed according to chemical-chemical interactions. Then, the obtained candidate chemicals were further selected by a randomization test and information on chemical interactions and structures. The analyses identified several candidate carcinogenic chemicals, while those candidates identified as non-carcinogenic were supported by a literature search. In addition, several candidate carcinogenic/non-carcinogenic chemicals exhibit structural dissimilarity with validated carcinogenic/non-carcinogenic chemicals.

[1]  Lei Chen,et al.  Predicting Metabolic Pathways of Small Molecules and Enzymes Based on Interaction Information of Chemicals and Proteins , 2012, PloS one.

[2]  G. Probst,et al.  Comparison of three in vitro assays for carcinogen-induced DNA damage. , 1980, Journal of toxicology and environmental health.

[3]  Yu-Dong Cai,et al.  Prediction of Deleterious Non-Synonymous SNPs Based on Protein Interaction Network and Hybrid Properties , 2010, PloS one.

[4]  J. Kazius,et al.  Derivation and validation of toxicophores for mutagenicity prediction. , 2005, Journal of medicinal chemistry.

[5]  K. Hamase,et al.  Changes in D-aspartic acid and D-glutamic acid levels in the tissues and physiological fluids of mice with various D-aspartate oxidase activities. , 2015, Journal of pharmaceutical and biomedical analysis.

[6]  P. Schwartzkroin,et al.  Flurothyl seizure susceptibility in rats following prenatal methylazoxymethanol treatment , 1996, Epilepsy Research.

[7]  M. Miller,et al.  Mechanism of mouse skin tumor promotion by n-dodecane. , 1987, Carcinogenesis.

[8]  K. Chou,et al.  Predicting Anatomical Therapeutic Chemical (ATC) Classification of Drugs by Integrating Chemical-Chemical Interactions and Similarities , 2012, PloS one.

[9]  J. Mavri,et al.  Reactivity of bisphenol A-3,4-quinone with DNA. A quantum chemical study. , 2012, Toxicology in vitro : an international journal published in association with BIBRA.

[10]  S. Husain,et al.  Oxidants, antioxidants and carcinogenesis. , 2002, Indian journal of experimental biology.

[11]  G. Jennings,et al.  Regional homovanillic acid production in humans. , 1993, Life sciences.

[12]  S. Kawanishi,et al.  Oxidative DNA damage by a metabolite of carcinogenic and reproductive toxic nitrobenzene in the presence of NADH and Cu(II). , 1999, Biochemical and biophysical research communications.

[13]  Elkind Mm.  Enhanced risks of cancer from protracted exposures to X- or gamma-rays: a radiobiological model of radiation-induced breast cancer. , 1996 .

[14]  O. Iversen.  Hydroxyurea enhances methylnitrosourea skin tumorigenesis when given shortly before, but not after, the carcinogen. , 1982, Carcinogenesis.

[15]  S. Oikawa,et al.  Carcinogenic semicarbazide induces sequence-specific DNA damage through the generation of reactive oxygen species and the derived organic radicals. , 2003, Mutation research.

[16]  L. Sternson,et al.  Oxidation of phenylhydroxylamine in aqueous solution: a model for study of the carcinogenic effect of primary aromatic amines. , 1981, Proceedings of the National Academy of Sciences of the United States of America.

[17]  C A Jones,et al.  Animal models of schizophrenia , 2011, British journal of pharmacology.

[18]  B. Tóth.  Synthetic and naturally occurring hydrazines as possible cancer causative agents. , 1975, Cancer research.

[19]  R. Tennant,et al.  Chemical structure, Salmonella mutagenicity and extent of carcinogenicity as indicators of genotoxic carcinogenesis among 222 chemicals tested in rodents by the U.S. NCI/NTP. , 1988, Mutation research.

[20]  S. Sternberg,et al.  Differences in the acute response of the various segments ofrat intestine to treatment with the intestinal carcinogen, methylazoxymethanol acetate. , 1977, Cancer research.

[21]  David Rogers,et al.  Extended-Connectivity Fingerprints , 2010, J. Chem. Inf. Model..

[22]  J. Mavri,et al.  Guanine alkylation by ethylene oxide: calculation of chemical reactivity. , 2006, The journal of physical chemistry. A.

[23]  D. Kaushik,et al.  Hydroxyurea: a key player in cancer chemotherapy , 2012, Expert review of anticancer therapy.

[24]  R Benigni,et al.  Prediction of rodent carcinogenicity of aromatic amines: a quantitative structure-activity relationships model. , 2001, Carcinogenesis.

[25]  Darren Finlay,et al.  3-Dimensional Culture Systems for Anti-Cancer Compound Profiling and High-Throughput Screening Reveal Increases in EGFR Inhibitor-Mediated Cytotoxicity Compared to Monolayer Culture Systems , 2014, PloS one.

[26]  Yong Wang,et al.  Estimation of Carcinogenicity Using Molecular Fragments Tree , 2012, J. Chem. Inf. Model..

[27]  I. Yajima,et al.  Bidirectional Functions of Arsenic as a Carcinogen and an Anti-Cancer Agent in Human Squamous Cell Carcinoma , 2014, PloS one.

[28]  Romualdo Benigni,et al.  Mechanisms of chemical carcinogenicity and mutagenicity: a review with implications for predictive toxicology. , 2011, Chemical reviews.

[29]  E C Miller,et al.  Searches for ultimate chemical carcinogens and their reactions with cellular macromolecules , 1981, Cancer.

[30]  B. Sadikovic,et al.  Benzopyrene exposure disrupts DNA methylation and growth dynamics in breast cancer cells. , 2006, Toxicology and applied pharmacology.

[31]  Patricia Rodriguez-Tomé,et al.  IARC Database of p53 gene mutations in human tumors and cell lines: updated compilation, revised formats and new visualisation tools , 1998, Nucleic Acids Res..

[33]  Kuo-Chen Chou,et al.  Predicting Biological Functions of Compounds Based on Chemical-Chemical Interactions , 2011, PloS one.

[34]  Maykel Pérez González,et al.  QSAR modeling of the rodent carcinogenicity of nitrocompounds. , 2008, Bioorganic & medicinal chemistry.

[35]  B. Gómez-González,et al.  Genome instability: a mechanistic view of its causes and consequences , 2008, Nature Reviews Genetics.

[36]  T. Lehtimäki,et al.  Homocysteine and carotid atherosclerosis in chronic renal failure--the confounding effect of renal function. , 2004, Atherosclerosis.

[37]  Emilio Benfenati,et al.  New public QSAR model for carcinogenicity , 2010, Chemistry Central journal.

[38]  I. Rosenberg,et al.  Homocysteine and cognitive function. , 2005, Seminars in vascular medicine.

[39]  Philip J. Landrigan,et al.  Occupational Exposure to Asbestos and Ovarian Cancer: A Meta-analysis , 2011, Environmental health perspectives.

[40]  Gabriela L. Borosky,et al.  A DFT Model Study of the Carbocations Formed via the Fjord- and Bay-Region Diol Epoxide Metabolites of Isomeric Dibenzopyrenes and Naphthopyrene , 2009 .

[41]  Lei Chen,et al.  Prediction of Cancer Drugs by Chemical-Chemical Interactions , 2014, PloS one.

[42]  Stefan Günther,et al.  SuperPred: drug classification and target prediction , 2008, Nucleic Acids Res..

[43]  Romualdo Benigni,et al.  Structure alerts for carcinogenicity, and the Salmonella assay system: a novel insight through the chemical relational databases technology. , 2008, Mutation research.

[44]  E. Pira,et al.  The carcinogenic effect of aromatic amines: an epidemiological study on the role of o-toluidine and 4,4'-methylene bis (2-methylaniline) in inducing bladder cancer in man. , 1982, Environmental research.

[45]  Christian von Mering,et al.  STITCH: interaction networks of chemicals and proteins , 2007, Nucleic Acids Res..

[46]  R. Fitzpatrick.  CPDB: Carcinogenic Potency Database , 2008, Medical Reference Services Quarterly.

[47]  B. Costall,et al.  Thyroid hormones, brain function and cognition: a brief review , 2002, Neuroscience & Biobehavioral Reviews.

[48]  Susumu Goto,et al.  KEGG: Kyoto Encyclopedia of Genes and Genomes , 2000, Nucleic Acids Res..

[49]  R. Cathcart.  Vitamin C: the nontoxic, nonrate-limited, antioxidant free radical scavenger. , 1985, Medical hypotheses.

[50]  David Weininger,et al.  SMILES, a chemical language and information system. 1. Introduction to methodology and encoding rules , 1988, J. Chem. Inf. Comput. Sci..

[51]  A. D’Aniello.  d-Aspartic acid: An endogenous amino acid with an important neuroendocrine role , 2007, Brain Research Reviews.

[52]  C. Mathers,et al.  Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008 , 2010, International journal of cancer.

[53]  J. Le Pecq,et al.  Effect of mutation, electric membrane potential, and metabolic inhibitors on the accessibility of nucleic acids to ethidium bromide in Escherichia coli cells. , 1984, Biochemistry.

[54]  D. S. Snyder,et al.  Ability of PABA to protect mammalian skin from ultraviolet light-induced skin tumors and actinic damage. , 1975, The Journal of investigative dermatology.

[55]  S. Sternberg,et al.  Biochemical and pathological effects of methylazoxymethanol acetate, a potent carcinogen. , 1970, Cancer research.

[56]  B. Halliwell,et al.  Damage to DNA by reactive oxygen and nitrogen species: role in inflammatory disease and progression to cancer. , 1996, The Biochemical journal.

[57]  S. De Flora,et al.  DNA-damaging activity in vivo and bacterial mutagenicity of sixteen hydrazine derivatives as related quantitatively to their carcinogenicity. , 1981, Cancer research.

[58]  Yu-Dong Cai,et al.  Finding Candidate Drugs for Hepatitis C Based on Chemical-Chemical and Chemical-Protein Interactions , 2014, PloS one.

[59]  R. Tackett,et al.  Cerebroventricular propranolol elevates cerebrospinal fluid norepinephrine and lowers blood pressure. , 1981, Science.

[60]  D. Paustenbach,et al.  A critical evaluation of the use of mutagenesis, carcinogenesis, and tumor promotion data in a cancer risk assessment of 2,3,7,8-tetrachlorodibenzo-p-dioxin. , 1987, Regulatory toxicology and pharmacology : RTP.

[61]  Jing Lu,et al.  A hybrid method for prediction and repositioning of drug Anatomical Therapeutic Chemical classes. , 2014, Molecular bioSystems.

[62]  S Laskin,et al.  Gaseous formaldehyde and hydrogen chloride induction of nasal cancer in the rat. , 1982, Journal of the National Cancer Institute.

[63]  Bing Niu,et al.  Prediction of small molecules' metabolic pathways based on functional group composition. , 2009, Protein and peptide letters.

[64]  A. Bast,et al.  Glutathione revisited: a better scavenger than previously thought , 2014, Front. Pharmacol..

[65]  D. Hanahan,et al.  Hallmarks of Cancer: The Next Generation , 2011, Cell.

[66]  A. Bailey,et al.  The use of structure-activity relationship analysis in the food contact notification program. , 2005, Regulatory toxicology and pharmacology : RTP.

[67]  R. Schiestl,et al.  Glutathione depletion by buthionine sulfoximine induces DNA deletions in mice. , 2006, Carcinogenesis.

[68]  Holder Jw.  Nitrobenzene carcinogenicity in animals and human hazard evaluation. , 1999 .