{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T05:20:01Z","timestamp":1791264001688,"version":"4.1.0"},"reference-count":61,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2013,12,12]],"date-time":"2013-12-12T00:00:00Z","timestamp":1386806400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Cancer is commonly diagnosed in dogs over the age of 10 and is a leading cause of death due to the lack of effective drugs. Flavonoids possess antioxidant, anti-inflammatory and anticarcinogenic properties and have been studied as chemopreventive agents in human cancer therapy. However, the literature on dogs is sparse. In this study, we analyzed the effect of nine flavonoids on cell viability, DNA damage and topoisomerase IIa\/IIb gene expression in a canine tumor cell line (DH82). Apigenin, luteolin, trans-chalcone and  4-methoxychalcone showed the highest degree of cytotoxicity in the absence of considerable DNA damage, whereas genistein exhibited low cytotoxicity but induced a high level of DNA damage. These five flavonoids inhibited topoisomerase IIa and IIb gene expression to variable extents and with variable specificity. Genistein exerted a lower inhibitory effect on the two topoisomerases than luteolin and apigenin. trans-Chalcone and 4-methoxychalcone exerted greater inhibition of topoisomerase IIa expression than topoisomerase IIb. The differences in the effects between genistein and luteolin and apigenin might be explained by the position of ring B, whereas the more specific effect of chalcones on topoisomerase IIa might be due to their open chain structure.<\/jats:p>","DOI":"10.3390\/molecules181215448","type":"journal-article","created":{"date-parts":[[2013,12,12]],"date-time":"2013-12-12T13:35:11Z","timestamp":1386855311000},"page":"15448-15463","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["In Vitro Action of Flavonoids in the Canine Malignant Histiocytic Cell Line DH82"],"prefix":"10.3390","volume":"18","author":[{"given":"Gabriel","family":"Silva","sequence":"first","affiliation":[{"name":"Biotechnology Unit, University of Ribeir\u00e3o Preto, Ribeir\u00e3o Preto 14096-900, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Fachin","sequence":"additional","affiliation":[{"name":"Biotechnology Unit, University of Ribeir\u00e3o Preto, Ribeir\u00e3o Preto 14096-900, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ren\u00ea","family":"Beleboni","sequence":"additional","affiliation":[{"name":"Biotechnology Unit, University of Ribeir\u00e3o Preto, Ribeir\u00e3o Preto 14096-900, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suzelei","family":"Fran\u00e7a","sequence":"additional","affiliation":[{"name":"Biotechnology Unit, University of Ribeir\u00e3o Preto, Ribeir\u00e3o Preto 14096-900, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mozart","family":"Marins","sequence":"additional","affiliation":[{"name":"Biotechnology Unit, University of Ribeir\u00e3o Preto, Ribeir\u00e3o Preto 14096-900, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2013,12,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1354\/vp.08-VP-0238-B-REV","article-title":"Review paper: Cancer chemopreventive compounds and canine cancer","volume":"46","author":"Baek","year":"2009","journal-title":"Vet. Pathol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1111\/j.1748-5827.2002.tb00066.x","article-title":"Canine neoplasia in the UK: Estimates of incidence rates from a population of insured dogs","volume":"43","author":"Dobson","year":"2002","journal-title":"J. Small Anim. Pract."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"976","DOI":"10.1111\/j.1939-1676.2008.0133.x","article-title":"Cancer incidence in pet dogs: Findings of the animal tumor registry of genoa, italy","volume":"22","author":"Merlo","year":"2008","journal-title":"J. Vet. Intern. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1373\/clinchem.2012.185389","article-title":"Cancer chemoprevention: Successes and failures","volume":"59","author":"Patterson","year":"2013","journal-title":"Clin. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3248S","DOI":"10.1093\/jn\/133.10.3248S","article-title":"Overview of dietary flavonoids: Nomenclature, occurrence and intake","volume":"133","author":"Beecher","year":"2003","journal-title":"J. Nutr."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1002\/mnfr.200900288","article-title":"Antioxidative and antigenotoxic properties of vegetables and dietary phytochemicals: The value of genomics biomarkers in molecular epidemiology","volume":"54","author":"Wilms","year":"2010","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"320","DOI":"10.2533\/chimia.2012.320","article-title":"Plants as a source of therapeutic and health products","volume":"66","author":"Christen","year":"2012","journal-title":"Chimia"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"517","DOI":"10.3390\/toxins2040517","article-title":"Phytochemicals in cancer prevention and therapy: Truth or dare?","volume":"2","author":"Russo","year":"2010","journal-title":"Toxins"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1016\/j.fitote.2011.01.018","article-title":"Antioxidant and prooxidant properties of flavonoids","volume":"82","year":"2011","journal-title":"Fitoterapia"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1021\/np9904509","article-title":"Flavonoids as antioxidants","volume":"63","author":"Pietta","year":"2000","journal-title":"J. Nat. Prod."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1379","DOI":"10.1248\/bpb.26.1379","article-title":"Specific inhibition of hypoxia-inducible factor (hif)-1 alpha activation and of vascular endothelial growth factor (vegf) production by flavonoids","volume":"26","author":"Hasebe","year":"2003","journal-title":"Biol. Pharm. Bull."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1477","DOI":"10.1093\/jn\/136.6.1477","article-title":"Flavonoids and vitamin e reduce the release of the angiogenic peptide vascular endothelial growth factor from human tumor cells","volume":"136","author":"Schindler","year":"2006","journal-title":"J. Nutr."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2873","DOI":"10.1016\/0006-2952(87)90282-6","article-title":"Inhibition of the mitochondrial nadh-oxidase (nadh-coenzyme q oxido-reductase) enzyme system by flavonoids: A structure-activity study","volume":"36","author":"Hodnick","year":"1987","journal-title":"Biochem. Pharmacol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1002\/ptr.2008","article-title":"Inhibition of angiotensin converting enzyme (ace) by flavonoids isolated from ailanthus excelsa (roxb) (simaroubaceae)","volume":"21","author":"Loizzo","year":"2007","journal-title":"Phytother. Res. PTR"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/j.jnutbio.2006.05.003","article-title":"Up-regulation of tumor suppressor carcinoembryonic antigen-related cell adhesion molecule 1 in human colon cancer caco-2 cells following repetitive exposure to dietary levels of a polyphenol-rich chokeberry juice","volume":"18","author":"Larrosa","year":"2007","journal-title":"J. Nutr. Biochem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1699","DOI":"10.1586\/14737140.6.12.1699","article-title":"Genistein and resveratrol: Mammary cancer chemoprevention and mechanisms of action in the rat","volume":"6","author":"Whitsett","year":"2006","journal-title":"Expert Rev. Anticancer Ther."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2622","DOI":"10.1093\/jn\/137.12.2622","article-title":"Annurca apple polyphenols have potent demethylating activity and can reactivate silenced tumor suppressor genes in colorectal cancer cells","volume":"137","author":"Fini","year":"2007","journal-title":"J. Nutr."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"114","DOI":"10.2174\/138161210789941856","article-title":"The anticancer properties of dietary polyphenols and its relation with apoptosis","volume":"16","author":"Fresco","year":"2010","journal-title":"Curr. Pharm. Des."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.bbrc.2010.07.043","article-title":"Genistein induces topoisomerase iibeta- and proteasome-mediated DNA sequence rearrangements: Implications in infant leukemia","volume":"399","author":"Azarova","year":"2010","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1703","DOI":"10.1093\/carcin\/bgm102","article-title":"Dietary flavonoids induce mll translocations in primary human cd34+ cells","volume":"28","author":"Janssen","year":"2007","journal-title":"Carcinogenesis"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.fitote.2007.07.008","article-title":"Flavonoids with DNA strand-scission activity from rhus javanica var. Roxburghiana","volume":"79","author":"Lin","year":"2008","journal-title":"Fitoterapia"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1002\/em.20334","article-title":"Base excision repair pathway is involved in the repair of lesions generated by flavonoid-enriched fractions of pepper tree (schinus terebinthifolius, raddi) stem bark","volume":"48","year":"2007","journal-title":"Environ. Mol. Mutagen."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1756","DOI":"10.2174\/092986710791111161","article-title":"Flavonoids influence epigenetic-modifying enzyme activity: Structure\u2014function relationships and the therapeutic potential for cancer","volume":"17","author":"Gilbert","year":"2010","journal-title":"Curr. Med. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"233","DOI":"10.2174\/1874467210801030233","article-title":"Polyphenols: Biological activities, molecular targets, and the effect of methylation","volume":"1","author":"Dou","year":"2008","journal-title":"Curr. Mol. Pharmacol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2141","DOI":"10.2174\/092986710791299966","article-title":"Impact on DNA methylation in cancer prevention and therapy by bioactive dietary components","volume":"17","author":"Li","year":"2010","journal-title":"Curr. Med. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1016\/j.semcancer.2007.04.002","article-title":"Oxidative breakage of cellular DNA by plant polyphenols: A putative mechanism for anticancer properties","volume":"17","author":"Hadi","year":"2007","journal-title":"Semin. Cancer Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"764","DOI":"10.1080\/10715760802302251","article-title":"Plant polyphenols mobilize nuclear copper in human peripheral lymphocytes leading to oxidatively generated DNA breakage: Implications for an anticancer mechanism","volume":"42","author":"Shamim","year":"2008","journal-title":"Free Radic. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1038\/nrc2607","article-title":"Targeting DNA topoisomerase ii in cancer chemotherapy","volume":"9","author":"Nitiss","year":"2009","journal-title":"Nat. Rev. Cancer"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.1158\/1078-0432.CCR-08-1610","article-title":"Soy-derived isoflavones inhibit the growth of canine lymphoid cell lines","volume":"15","author":"Papich","year":"2009","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1007\/BF02623551","article-title":"A macrophage-monocyte cell line from a dog with malignant histiocytosis","volume":"24","author":"Wellman","year":"1988","journal-title":"In Vitro Cell Dev. Biol."},{"key":"ref_31","first-page":"1041","article-title":"Canine histiocytic neoplasia: An overview","volume":"48","author":"Fulmer","year":"2007","journal-title":"Can. Vet. J. La Revue Vet. Can."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1","DOI":"10.4103\/0973-7847.79093","article-title":"Flavonoids: A versatile source of anticancer drugs","volume":"5","author":"Chahar","year":"2011","journal-title":"Pharmacogn. Rev."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/S0304-3835(01)00738-8","article-title":"Effect of flavonoids on cell cycle progression in prostate cancer cells","volume":"176","author":"Kobayashi","year":"2002","journal-title":"Cancer Lett."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1248\/bpb.28.253","article-title":"Cytotoxicity of flavonoids toward cultured normal human cells","volume":"28","author":"Matsuo","year":"2005","journal-title":"Biol. Pharm. Bull."},{"key":"ref_35","first-page":"1295","article-title":"Profiling flavonoid cytotoxicity in human breast cancer cell lines: Determination of structure-function relationships","volume":"7","author":"Yadegarynia","year":"2012","journal-title":"Nat. Prod. Commun."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.taap.2007.04.004","article-title":"The quercetin paradox","volume":"222","author":"Boots","year":"2007","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.fct.2012.09.015","article-title":"Bioconversion of quercetin and rutin and the cytotoxicity activities of the transformed products","volume":"51","author":"Araujo","year":"2013","journal-title":"Food Chem. Toxicol. Int. J. Publ. Bri. Ind. Biol. Res. Assoc."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/S0891-5849(98)00167-1","article-title":"Quercetin may act as a cytotoxic prooxidant after its metabolic activation to semiquinone and quinoidal product","volume":"26","author":"Metodiewa","year":"1999","journal-title":"Free Radic. Biol. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.abb.2007.02.003","article-title":"Structure-activity relationships of flavonoid-induced cytotoxicity on human leukemia cells","volume":"460","author":"Plochmann","year":"2007","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1271\/bbb.63.896","article-title":"Antiproliferative activity of flavonoids on several cancer cell lines","volume":"63","author":"Kawaii","year":"1999","journal-title":"Biosci. Biotechnol. Biochem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1137","DOI":"10.1007\/s12272-001-1280-8","article-title":"Structurally related cytotoxic effects of flavonoids on human cancer cells in vitro","volume":"31","author":"Chang","year":"2008","journal-title":"Arch. Pharmacal Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1593\/neo.11972","article-title":"A novel topoisomerase inhibitor, daurinol, suppresses growth of hct116 cells with low hematological toxicity compared to etoposide","volume":"13","author":"Kang","year":"2011","journal-title":"Neoplasia"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"17643","DOI":"10.1074\/jbc.273.28.17643","article-title":"Merbarone inhibits the catalytic activity of human topoisomerase iialpha by blocking DNA cleavage","volume":"273","author":"Fortune","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"11900","DOI":"10.1021\/bi800981j","article-title":"The efficacy of topoisomerase ii-targeted anticancer agents reflects the persistence of drug-induced cleavage complexes in cells","volume":"47","author":"Bandele","year":"2008","journal-title":"Biochemistry"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"6097","DOI":"10.1021\/bi7000664","article-title":"Bioflavonoids as poisons of human topoisomerase ii alpha and ii beta","volume":"46","author":"Bandele","year":"2007","journal-title":"Biochemistry"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1042\/bj20020098","article-title":"Luteolin, an emerging anti-cancer flavonoid, poisons eukaryotic DNA topoisomerase i","volume":"366","author":"Chowdhury","year":"2002","journal-title":"Biochem. J."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1258\/ebm.2009.009184","article-title":"Dietary factors and the risk for acute infant leukemia: Evaluating the effects of cocoa-derived flavanols on DNA topoisomerase activity","volume":"235","author":"Lanoue","year":"2010","journal-title":"Exp. Biol. Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1093\/mutage\/ger006","article-title":"Green tea constituents (\u2212)-epigallocatechin-3-gallate (egcg) and gallic acid induce topoisomerase i- and topoisomerase ii-DNA complexes in cells mediated by pyrogallol-induced hydrogen peroxide","volume":"26","author":"Austin","year":"2011","journal-title":"Mutagenesis"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2075","DOI":"10.1016\/j.bcp.2003.07.007","article-title":"Effects of dietary flavonoids on major signal transduction pathways in human epithelial cells","volume":"66","author":"Brown","year":"2003","journal-title":"Biochem. Pharmacol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1002\/mnfr.200700326","article-title":"Cancer chemoprevention and chemotherapy: Dietary polyphenols and signalling pathways","volume":"52","author":"Ramos","year":"2008","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"3255","DOI":"10.3390\/ijms10073255","article-title":"Genistein inhibition of topoisomerase iialpha expression participated by sp1 and sp3 in hela cell","volume":"10","author":"Zhou","year":"2009","journal-title":"Int. J. Mol. Sci."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1093\/nar\/gkn937","article-title":"The DNA cleavage reaction of topoisomerase ii: Wolf in sheep\u2019s clothing","volume":"37","author":"Deweese","year":"2009","journal-title":"Nucleic Acids Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"11014","DOI":"10.1073\/pnas.0704002104","article-title":"Roles of DNA topoisomerase ii isozymes in chemotherapy and secondary malignancies","volume":"104","author":"Azarova","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"8839","DOI":"10.1158\/0008-5472.CAN-07-1649","article-title":"Topoisomerase iibeta mediated DNA double-strand breaks: Implications in doxorubicin cardiotoxicity and prevention by dexrazoxane","volume":"67","author":"Lyu","year":"2007","journal-title":"Cancer Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.abb.2011.10.001","article-title":"Topoisomerase iibeta associates with ku70 and parp-1 during double strand break repair of DNA in neurons","volume":"516","author":"Mandraju","year":"2011","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.abb.2007.10.017","article-title":"Distinct roles of topoisomerase ii isoforms: DNA damage accelerating alpha, double strand break repair promoting beta","volume":"470","author":"Mandraju","year":"2008","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/S0163-7258(03)00058-5","article-title":"Catalytic topoisomerase ii inhibitors in cancer therapy","volume":"99","author":"Larsen","year":"2003","journal-title":"Pharmacol. Ther."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/0022-1759(83)90303-4","article-title":"Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays","volume":"65","author":"Mosmann","year":"1983","journal-title":"J. Immunol. Methods"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/0027-5107(93)90207-V","article-title":"The single cell gel electrophoresis assay (comet assay): A european review","volume":"288","author":"Green","year":"1993","journal-title":"Mutat. Res.\/Fundam. Mol. Mech. Mutagen."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/0921-8777(94)00043-6","article-title":"The kinetics of repair of oxidative DNA damage (strand breaks and oxidised pyrimidines) in human cells","volume":"336","author":"Collins","year":"1995","journal-title":"Mutat. Res."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1590\/S0102-09352005000300004","article-title":"Altera\u00e7\u00f5es ecocardiogr\u00e1ficas em c\u00e3es sob tratamento prolongado com doxorrubicina","volume":"57","author":"Silva","year":"2005","journal-title":"Arq. Bras. Med. Vet. Zootec."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/18\/12\/15448\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T21:51:19Z","timestamp":1760219479000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/18\/12\/15448"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,12,12]]},"references-count":61,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2013,12]]}},"alternative-id":["molecules181215448"],"URL":"https:\/\/doi.org\/10.3390\/molecules181215448","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,12,12]]}}}