流行病学研究表明摄入大豆制品可以降低罹患结直肠癌的风险,可能是大豆中含有丰富的异黄酮类物质,金雀异黄酮(genistein)是其中的主要成分。最近的研究表明,在核酸分解代谢中,催化嘌呤产生尿酸和活性氧的黄嘌呤氧化酶(xanthine oxidase, XO)可促进肿瘤的发展。同时,黄酮类物质显示出对XO抑制的巨大潜力,为了探究黄酮类抑制剂对结肠癌发展的影响。首先,该文通过HPLC方法体外筛选XO的抑制剂,其中包括12种黄酮类化合物和2种酚酸类化合物,结果显示,100 μmol/L的金雀异黄酮可以显著抑制XO的活性,并具有剂量依赖效应。其次,通过建立氧化偶氮甲烷(azoxymethane,AOM)/葡聚糖硫酸钠(dextran sulfate sodium,DSS)诱导的原发性结肠肿瘤小鼠模型,结果显示,在给与小鼠40 mg/kg金雀异黄酮时,可以显著降低小鼠结肠部位肿瘤数目;与空白组相比,模型组结肠部位的XO表达和活性,尿酸水平,以及肿瘤坏死因子(tumor necrosis factor,TNFα)的水平显著升高;与模型组相比,金雀异黄酮干预组小鼠结肠部位的XO表达和活性,尿酸水平,以及TNFα含量显著降低;金雀异黄酮同时提高了结肠部位的还原性谷胱甘肽(glutathione,GSH)含量。结果表明,金雀异黄酮通过抑制XO的活性进而延缓结肠肿瘤的发展。
Epidemiological studies have shown that the consumption of soybeans can reduce the risk of colorectal cancer (CRC). It may be that soybeans are rich in isoflavones, and genistein is the main ingredient. On the other hand, xanthine oxidase is the main enzyme that catalyzes the production of uric acid and reactive oxygen from purine in nucleic acid catabolism. Recent studies have shown that xanthine oxidase promote the development of cancer. Flavonoids have shown great potential in inhibiting xanthine oxidase. In order to explore the influence of flavonoid inhibitors on the development of colon cancer, firstly, we screened xanthine oxidase inhibitors by HPLC in vitro, including twelve flavonoids and two phenolic acid compounds. The results showed that 100 μmol/L genistein significantly inhibited the activity of xanthine oxidase and had a dose-dependent effect. Secondly, a mouse model of primary colorectal tumors induced by AOM/DSS was established, when 40 mg/kg genistein was administered to mice, the number of tumors in the colon of mice significantly reduced. Compared with the control group, the expression and activity of xanthine oxidase, the uric acid level, and the TNF-α level in the colon of the model group were significantly increased. Compared with the model group, the expression and activity of xanthine oxidase xanthine, uric acid level, and TNF-α level in the colon of the mice in the genistein group, were significantly reduced, and genistein also increased the GSH level in the colon. These results indicate that genistein can delay the development of colon tumors by inhibiting the activity of xanthine oxidase.
[1] SIEGEL R L, MILLER K D, JEMAL A.Cancer statistics, 2019 [J].CA:A Cancer Journal for Clinicians, 2019, 69(1):7-34.
[2] KANG Y P, WARD N P, DENICOLA G M.Recent advances in cancer metabolism:A technological perspective[J].Experimental & molecular medicine, 2018, 50(4):1-16.
[3] SAKITA J Y, GASPAROTTO B, GARCIA S B, et al.A critical discussion on diet, genomic mutations and repair mechanisms in colon carcinogenesis [J].Toxicology Letters, 2017, 265:106-116.
[4] JAWAD N, DIREKZE N, LEEDHAM S J.Inflammatory bowel disease and colon cancer.[J].Recent Results in Cancer Research.Fortschritte Der Krebsforschung.Progrès Dans Les Recherches Sur Le Cancer, 2011, 185:99-115.
[5] BODE A M, DONG Z G.Cancer prevention research-then and now[J].Nature Reviews Cancer, 2009,9(7):508-516.
[6] JÄNNE P A, MAYER R J.Chemoprevention of colorectal cancer[J].New England Journal of Medicine, 2000, 342(26):1 960-1 968.
[7] SOLOMON S D, MCMURRAY J J V, PFEFFER M A, et al.Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention[J].The New England Journal of Medicine.2005, 352(11):1 071-1 080.
[8] SPAGNUOLO C, RUSSO G L, ORHAN I E, et al.Genistein and cancer:Current status, challenges, and future directions[J].Advances in Nutrition, 2015, 6(4):408-419.
[9] HAINER B L, MATHESON E, WILKES R T.Diagnosis, treatment, and prevention of gout[J].American Family Physician, 2014, 90(12):831-836.
[10] KUSANO T, EHIRCHIOU D, MATSUMURA T, et al.Targeted knock-in mice expressing the oxidase-fixed form of xanthine oxidoreductase favor tumor growth [J].Nature Communications, 2019, 10(1):4 904.
[11] BORGES F, FERNANDES E, ROLEIRA F.Progress towards the discovery of xanthine oxidase inhibitors[J].Current Medicinal Chemistry, 2002, 9(2):195-217.
[12] YAN L, SPITZNAGEI E L.Soy consumption and prostate cancer risk in men:A revisit of a meta-analysis[J].The American Journal of Clinical Nutrition, 2009, 89(4):1 155-1 163.
[13] YAN L, SPITZNAGEL E L.Meta-analysis of soy food and risk of prostate cancer in men[J].International Journal of Cancer, 2005, 117(4):667-669.
[14] APPLEGATE C, ROWLES J L, RANARD K M, et al.Soy consumption and the risk of prostate cancer:An updated systematic review and meta-analysis[J].Nutrients, 2018, 10(1):40.
[15] LI D Q, ZHAO J, LI S P.High-performance liquid chromatography coupled with post-column dual-bioactivity assay for simultaneous screening of xanthine oxidase inhibitors and free radical scavengers from complex mixture[J].Journal of Chromatography A, 2014,1 345:50-56.
[16] NEUFERT C, BECKER C, NEURATH M F.An inducible mouse model of colon carcinogenesis for the analysis of sporadic and inflammation-driven tumor progression[J].Nature Protocols, 2007, 2(8):1 998-2 004.
[17] BHATTACHARYYA A, CHATTOPADHYAY R, MITRA S, et al.Oxidative stress:An essential factor in the pathogenesis of gastrointestinal mucosal diseases[J].Physiological Reviews, 2014, 94(2):329-354.
[18] GASSE P, RITEAU N, PÉTRILLI V, et al.Uric acid is a danger signal activating NALP3 inflammasome in lung injury inflammation and fibrosis[J].Revue Des Maladies Respiratoires 2008,25(9):1 191.
[19] CHIARO T R, SOTO R, STEPHENS W Z, et al.A member of the gut mycobiota modulates host purine metabolism exacerbating colitis in mice[J].Science Translational Medicine, 2017, 9(380).DOI:10.1126/scitranslmed.aaf9044.
[20] CHANG E C, CHARN T H, PARK S H, et al.Estrogen receptors α and β as determinants of gene expression:Influence of ligand, dose, and chromatin binding[J].Molecular Endocrinology, 2008,22(5):1 032-1 043.
[21] SPAGNUOLO C, RUSSO G L, ORHAN I E, et al.Genistein and cancer:Current status, challenges, and future directions [J].Advances in Nutrition, 2015, 6(4):408-419.
