Natural Inhibitors of Carcinogenesis

Abstract

Previous collaborative work by our group has led to the discovery of several plant isolates and derivatives with activities in in vivo models of cancer chemoprevention, including deguelin, resveratrol, bruceantin, brassinin, 4′-bromoflavone, and oxomate. Using a panel of in vitro bioassays to monitor chromatographic fractionation, a diverse group of plant secondary metabolites has been identified as potential cancer chemopreventive agents from mainly edible plants. Nearly 50 new compounds have been isolated as bioactive principles in one or more in vitro bioassays in work performed over the last five years. Included among these new active compounds are alkaloids, flavonoids, stilbenoids, and withanolides, as well as a novel stilbenolignan and the first representatives of the norwithanolides, which have a 27-carbon atom skeleton. In addition, over 100 active compounds of previously known structure have been obtained. Based on this large pool of potential cancer chemopreventive compounds, structure-activity relationships are discussed in terms of the quinone reductase induction ability of flavonoids and withanolides and the cyclooxygenase-1 and -2 inhibitory activities of flavanones, flavones and stilbenoids. Several of the bioactive compounds were found to be active when evaluated in a mouse mammary organ culture assay, when used as a secondary discriminator in our work. The compounds (2S)-abyssinone II, (2S)-2′,4′-dihydroxy-2″-(1-hydroxy-1-methylethyl)dihydrofuro[2,3-h]-flavanone, 3′-[γ-hydroxymethyl-(E)-γ-methylallyl]-2,4,2′,4′-tetrahydroxychalcone 11′-O-coumarate, isolicoflavonol, isoliquiritigenin, and ixocarpalactone A are regarded as promising leads as potential cancer chemopreventive agents.

Key words

Edible plants - in vitro bioassays - mouse mammary organ culture - potential cancer chemopreventive agents - plant secondary metabolites - flavonoids - stilbenoids - withanolides - structure-activity relationships

References

• 1 Stewart B W, Kleihues P. World Cancer Report. Lyon; IACR Press 2003: pp 9-19
• 2 Jemal A, Murray T, Samuels A, Ghafoor A, Ward E, Thun M J. Cancer statistics. 2003.  CA - Cancer J Clin. 2003;  53 5-26
• 3 Alberts A S, Colvin O M, Conney A H, Emster V L, Garber J E, Grenwald P. et al . Prevention of cancer in the next millennium: Report of the Chemoprevention Working Group to the American Association for Cancer Research.  Cancer Res. 1999;  59 4743-58
• 4 Kelloff G J. Perspectives on cancer chemoprevention research and drug development.  In: Advances in Cancer Research. Vande Woude GF, Klein G, editors San Diego; Academic Press 1999: p 199-334
• 5 Sporn M B. The war on cancer.  Lancet. 1996;  347 1377-81
• 6 Greenwald P, Kelloff G J, Burch-Whitman C, Kramer B S. Chemoprevention.  CA - Cancer J Clin. 1995;  45 31-49
• 7 Wattenberg L W. Chemoprevention of cancer.  Cancer Res. 1985;  45 1-8
• 8 Sporn M B, Dunlop N M, Newton D L, Smith J M. Prevention of chemical carcinogenesis by vitamin A and its synthetic analogs (retinoids).  Fed Proc. 1976;  35 1332-8
• 9 Kelloff G J, Hawk E T, Karp J E, Crowell J A, Boone C W, Steele V E. et al . Progress in clinical chemoprevention.  Sem Oncol. 1997;  24 241-52
• 10 Willett W C, MacMahon B. Diet and cancer - an overview (second of two parts).  N Engl J Med. 1984;  310 697-703
• 11 Harris C C. Chemical and physical carcinogenesis: advances and perspectives for the 1990s.  Cancer Res. 1991;  51 (Suppl) 5023-44
• 12 De Flora S. Mechanisms of inhibitors of mutagenesis and carcinogenesis.  Mutat Res. 1998;  402 151-8
• 13 Sporn M B. Carcinogenesis and cancer: Different perspectives on the same disease.  Cancer Res. 1991;  51 6215-8
• 14 Kelloff G J, Crowell J A, Steele V E, Lubet R A, Boone C W, Malone W A. et al . Progress in cancer chemoprevention.  Ann New York Acad Sci. 1999;  889 1-13
• 15 Morse M A, Stoner G D. Cancer chemoprevention: Principles and prospects.  Carcinogenesis. 1993;  14 1737-46
• 16 Surh Y -J. Molecular mechanisms of chemopreventive effects of selected dietary and medicinal phenolic substances.  Mutat Res. 1999;  428 305-27
• 17 Reddy L, Odhav B, Bhoola K D. Natural products for cancer prevention: A global perspective.  Pharmacol Ther. 2003;  99 1-13
• 18 Fujiki H, Suganuma M, Imai K, Nakachi K. Green tea: cancer preventive beverage and/or drug.  Cancer Lett. 2002;  188 9-13
• 19 Surh Y -J. Cancer chemoprevention with dietary phytochemicals.  Nature Rev Cancer. 2003;  3 768-80
• 20 http://clinicaltrials.gov/ct/search?term=cancer+chemoprevention& submit. 
• 21 Chow H -HS, Cai Y, Hakim I A, Crowell J A, Shahi F, Brooks C , Dorr R T, Hara Y, Alberts D S. Pharmacokinetics and safety of green tea polyphenols after multiple-dose administration of epigallocatechin gallate and polyphenon E in healthy individuals.  Clin Cancer Res. 2003;  9 3312-9
• 22 Fujiki H. Two stages of cancer prevention with green tea.  J Cancer Res Clin. 1999;  125 589-97
• 23 Ren W, Qiao Z, Wang H, Zhu L, Zhang L. Flavonoids: Promising anticancer agents.  Med Res Rev. 2003;  23 519-34
• 24 Pezzuto J M. Natural product cancer chemopreventive agents.  In: Recent Advances in Phytochemistry, Vol. 29. Phytochemistry of Medicinal Plants. Arnason JT, Mata R, Romeo JT, editors New York; Plenum Press 1995: pp 19-45
• 25 Pezzuto J M, Song L L, Lee S K, Shamon L A, Mata-Greenwood E, Jang M. et al .Bioassay methods useful for activity-guided isolation of natural product cancer chemopreventive agents. In: Chemistry, Biological and Pharmacological Properties of Medicinal Plants from the Americas. Hostettmann K, Gupta MP, Marston A, editors Amsterdam; Harwood Academic Publishers 1999: pp 81-110
• 26 Kinghorn A D, Su B -N, Lee D, Gu J -Q, Pezzuto J M. Cancer chemopreventive agents discovered by activity-guided fractionation: An update.  Curr Org Chem. 2003;  7 213-26
• 27 Loub W D, Farnsworth N R, Soejarto D D, Quinn M L. NAPRALERT: computer handling of natural product research data.  J Chem Inf Computer Sci. 1985;  25 99-103
• 28 Kosmeder II J W, Pezzuto J M. Intermediate biomarkers.  Cancer Treat Res. 2001;  106 31-61
• 29 Crowell J A, Holmes C J. Agent identification and preclinical testing.  Cancer Treat Res. 2001;  106 1-30
• 30 Mehta R G, Moon R C. Characterization of effective chemopreventive agents in mammary gland in vitro using an initiation-promotion protocol.  Anticancer Res. 1991;  11 593-6
• 31 Mehta R G, Bhat K PL, Hawthorne M E, Kopelovich L, Mehta R R, Christov K. et al . Induction of atypical ductal hyperplasia in mouse mammary gland organ culture.  J Natl Cancer Inst. 2001;  93 1103-6
• 32 Shamon L A, Pezzuto J M. Assessment of antimutagenic activity with Salmonella typhimurium strain TM677.  Methods Cell Sci. 1997;  19 57-62
• 33 Lee S K, Mbwambo Z H, Chung H, Luyengi L, Gamez E JC, Mehta R G. et al . Evaluation of the antioxidant potential of natural products.  Comb Chem High-Throughput Screening. 1998;  1 35-46
• 34 Song L L, Kosmeder II J W, Lee S K, Gerhäuser C, Lantvit D, Moon R C. et al . Cancer chemopreventive activity mediated by 4’-bromoflavone, a potent inducer of phase II detoxification enzymes.  Cancer Res. 1999;  59 578-85
• 35 Gerhäuser C, Mar W, Lee S K, Suh N, Luo Y, Kosmeder II J W. et al . Rotenoids mediate potent cancer chemopreventive activity through transcriptional regulation of ornithine decarboxylase.  Nature Med. 1995;  1 260-6
• 36 Mbwambo Z H, Lee S K, Mshiu E N, Pezzuto J M, Kinghorn A D. Constituents from the stem wood of Euphorbia quinquecostata with phorbol dibutyrate receptor-binding inhibitory activity.  J Nat Prod. 1996;  59 1051-5
• 37 Jang M, Cai L, Udeani G O, Slowing K V, Thomas C F, Beecher C WW. et al . Cancer chemopreventive activity of resveratrol, a natural product derived from grapes.  Science. 1997;  275 218-20
• 38 El-Sayed K A, Hamann M T, Waddling C A, Jensen C, Lee S K, Dunstan C A, Pezzuto J M. Structurally novel bioconversion products of the marine natural product sarcophine effectively inhibit JB6 cell transformation.  J Org Chem. 1998;  63 7449-55
• 39 Suh N, Luyengi L, Fong H HS, Kinghorn A D, Pezzuto J M. Discovery of natural product chemopreventive agents utilizing HL-60 cell differentiation as a model.  Anticancer Res. 1995;  15 233-40
• 40 Pisha E, Pezzuto J M. Cell-based assay for the determination of estrogenic and anti-estrogenic activities.  Methods Cell Sci. 1997;  19 37-43
• 41 Jeong H -J, Shin Y G, Kim I -H, Pezzuto J M. Inhibition of aromatase activity by flavonoids.  Arch Pharm Res. 1999;  22 309-12
• 42 Chang L C, Gills J J, Bhat K PL, Luyengi L, Farnsworth N R, Pezzuto J M, Kinghorn A D. Activity-guided isolation of constituents of Cerbera manghas with antiproliferative and antiestrogenic activities.  Bioorg Med Chem Lett. 2000;  10 2431-4
• 43 Gamez E JC, Luyengi L, Lee S K, Zhu L -F, Zhou B -N, Fong H HS. et al . Antioxidant flavonoid glycosides from Daphniphyllum calycinum .  J Nat Prod. 1998;  61 706-8
• 44 Su B -N, Park E J, Nikolic D, Santarsiero B D, Mesecar A D, Schunke Vigo J. et al . Activity-guided isolation of novel norwithanolides from Deprea subtriflora with potential cancer chemopreventive activity.  J Org Chem. 2003;  68 2350-61
• 45 Gu J Q, Park E J, Luyengi L, Hawthorne M E, Mehta R G, Farnsworth N R. et al . Constituents of Eugenia sandwicensis with potential cancer chemopreventive activity.  Phytochemistry. 2001;  58 121-7
• 46 Chang L C, Bhat K PL, Fong H HS, Pezzuto J M, Kinghorn A D. Novel bioactive steroidal alkaloids from Pachysandra procumbens .  Tetrahedron. 2000;  56 3133-8
• 47 Lee D, Bhat K PL, Fong H HS, Farnsworth N R, Pezzuto J M, Kinghorn A D. Aromatase inhibitors from Broussonetia papyrifera .  J Nat Prod. 2001;  64 1286-93
• 48 Jang D S, Park E J, Kang Y -H, Vigo J S, Graham J G, Cabieses F. et al . Phenolic compounds obtained from stems of Couepia ulei with the potential to induce quinone reductase.  Arch Pharm Res. 2004;  27 169-72
• 49 Su B -N, Cuendet M, Hawthorne M E, Kardono L BS, Riswan S, Fong H HS. et al . Constituents of the bark and twigs of Artocarpus dadah with cyclooxygenase inhibitory activity.  J Nat Prod. 2002;  65 163-9
• 50 Su B -N, Misico R, Park E J, Santarsiero B D, Mesecar A D, Fong H HS. et al . Isolation and characterization of bioactive principles of the leaves and stems of Physalis philadelphica .  Tetrahedron. 2002;  58 3453-66
• 51 Jang D S, Park E J, Hawthorne M E, Vigo J S, Graham J G, Cabieses F. et al . Constituents of Musa x paradisiaca cultivar with the potential to induce the phase II enzyme, quinone reductase.  J Agric Food Chem. 2002;  50 6330-4
• 52 Chang L C, Song L L, Park E J, Luyengi L, Lee K J, Farnsworth N R. Bioactive constituents of Thuja occidentalis .  J Nat Prod. 2000;  63 1235-8
• 53 Lee D. Bioactive constituents of Broussonetia papyrifera and Antirhea acutata . Ph. D. Dissertation University of Illinois at Chicago: Chicago, IL, USA;
• 54 Lee D, Park E J, Cuendet M, Axelrod F, Chavez P I, Fong H HS. et al . Cyclooxygenase-inhibitory and antioxidant constituents of the aerial parts of Antirhea acutata .  Bioorg Med Chem Lett. 2001;  11 1565-8
• 55 Carcache-Blanco E J, Kang Y -H, Park E J, Su B -N, Kardono L BS, Riswan S. et al . Constituents of the stem bark of Pongamia pinnata with the potential to induce quinone reductase.  J Nat Prod. 2003;  66 1197-202
• 56 Westenburg H E, Lee K -J, Lee S K, Fong H HS, van Breemen R B, Pezzuto J M, Kinghorn A D. Activity-guided isolation of antioxidative constituents of Cotinus coggygria .  J Nat Prod. 2000;  63 1696-8
• 57 Jang D S, Park E J, Kang Y -H, Hawthorne M E, Vigo J S, Graham J G. et al . Potential cancer chemopreventive flavonoids from the stems of Tephrosia toxicaria .  J Nat Prod. 2003;  66 1166-70
• 58 Su B -N, Park E J, Vigo J S, Graham J G, Cabieses F, Fong H HS. et al . Activity-guided isolation of the chemical constituents of Muntingia calabura using a quinone reductase induction assay.  Phytochemistry. 2003;  63 335-41
• 59 Chang L C, Chavez D, Song L L, Farnsworth N R, Pezzuto J M, Kinghorn A D. Absolute configuration of novel bioactive flavonoids from Tephrosia purpurea .  Org Lett. 2000;  2 515-8
• 60 Gu J -Q, Park E J, Totura S, Riswan S, Fong H HS, Pezzuto J M, Kinghorn A D. Constituents of the twigs of Hernandia ovigera that inhibit the transformation of JB6 murine epidermal cells.  J Nat Prod. 2002;  65 1065-8
• 61 Su B -N, Park E J, Nikolic D, Schunke Vigo J, Graham J G, Cabieses F. et al . Isolation and characterization of miscellaneous secondary metabolites of Deprea subtriflora .  J Nat Prod. 2003;  66 1089-93
• 62 Gu J -Q, Gills J J, Park E J, Mata-Greenwood E, Hawthorne M E, Axelrod F. et al . Sesquiterpenoids from Tithonia diversifolia with potential cancer chemopreventive activity.  J Nat Prod. 2002;  65 532-6
• 63 Waffo-Téguo P, Lee D, Cuendet M, Mérillon J -M, Pezzuto J M, Kinghorn A D. Two new stilbene dimer glucosides from grape (Vitis vinifera) cell cultures.  J Nat Prod. 2001;  64 136-8
• 64 Lee D, Cuendet M, Schunke Vigo J, Graham J G, Cabieses F, Fong H HS. et al . A novel cyclooxygenase-inhibitory stilbenolignan from the seeds of Aiphanes aculeata .  Org Lett. 2001;  3 2169-71
• 65 Gu J -Q, Li W, Kang Y -H, Su B -N, Fong H HS, van Breemen R B. et al . Minor withanolides from Physalis philadelphica: Structures, quinone reductase induction activities, and liquid chromatography (LC)-MS-MS investigation as artifacts.  Chem Pharm Bull. 2003;  51 530-9
• 66 Jang D S, Park E J, Kang Y -H, Su B -N, Hawthorne M E, Schunke Vigo J. et al . Compounds obtained from Sida acuta with the potential to induce quinone reductase and to inhibit 7,12-dimethylbenz[a]anthracene-induced preneoplastic lesions in a mouse mammary organ culture model.  Arch Pharm Res. 2003;  26 585-90
• 67 Pawlus A D, Choi J K, Chai K H, Kang Y -H, Farnsworth N R, Pezzuto J M. et al .Potential cancer chemopreventive agents from Aglaia ponapensis . 44th Annual Meeting of the American Society of Pharmacognosy Chapel Hill, NC; July 12 - 16, 2003: (Abstract P-196)
• 68 Su B -N, Park E J, Mbwambo Z H, Santarsiero B D, Mesecar A D, Fong H HS. et al . New chemical constituents of Euphorbia quinquecostata and absolute configuration assignment by a convenient Mosher ester procedure carried out in NMR tubes.  J Nat Prod. 2002;  65 1278-82
• 69 Jang D S, Cuendet M, Fong H HS, Pezzuto J M, Kinghorn A D. Constituents of Asparagus officinalis (Asparagus) with inhibitory activity against cyclooxygenase-2.  J Agric Food Chem. 2004;  52 2218-22
• 70 Jang D S, Park E J, Hawthorne M E, Schunke Vigo J, Graham J G, Cabieses F. et al . Potential cancer chemopreventive constituents of the seeds of Dipteryx odorata (tonka bean).  J Nat Prod. 2003;  66 583-7
• 71 Jang D S, Cuendet M, Pawlus A D, Kardono L BS, Kawanishi K, Farnsworth N R. et al . Potential cancer chemopreventive constituents of the leaves of Macaranga triloba .  Phytochemistry. 2004;  65 345-50
• 72 Gu J -Q, Park E J, Vigo J S, Graham J G, Fong H HS, Pezzuto J M, Kinghorn A D. Activity-guided isolation of constituents of Renealmia nicolaioides with the potential to induce the phase II enzyme quinone reductase.  J Nat Prod. 2002;  65 1616-20
• 73 Jang D S, Cuendet M, Hawthorne M E, Kardono L BS, Kawanishi K, Fong H HS. et al . Prenylated flavonoids of the leaves of Macaranga conifera with inhibitory activity against cyclooxygenase-2.  Phytochemistry. 2002;  61 867-72
• 74 Su B -N, Chang L C, Park E J, Cuendet M, Santarsiero B D, Mesecar A D. et al . Bioactive constituents of the seeds of Brucea javanica .  Planta Medica. 2002;  68 730-3
• 75 Su B N, Jones W P, Cuendet M, Kardono L BS, Ismail R, Riswan S. et al .Constituents of the stems of Macrococculus pomiferus and their inhibitory activities against cyclooxygenases-1 and -2. Phytochemistry 2004: in press
• 76 Chang L C, Chavez D, Gills J J, Fong H HS, Pezzuto J M, Kinghorn A D. Rubiasins A - C, new anthracene derivatives from the roots and stems of Rubia cordifolia .  Tetrahedron Lett. 2000;  41 7157-62
• 77 Waffo-Téguo P, Hawthorne M E, Cuendet M, Mérillon J -M, Kinghorn A D, Pezzuto J M, Mehta R G. Potential cancer-chemopreventive activities of wine stilbenoids and flavans extracted from grape (Vitis vinifera) cell cultures.  Nutr Cancer. 2001;  40 173-9
• 78 Su B -N, Cuendet M, Farnsworth N R, Fong H HS, Pezzuto J M, Kinghorn A D. Activity-guided fractionation of the seeds of Ziziphus jujuba using a cyclooxygenase-2 inhibitory assay.  Planta Medica. 2002;  68 1125-8
• 79 Dinkova-Kostova A T, Talalay P. Persuasive evidence that quinone reductase type 1 (DT diaphorase) protects cells against the toxicity of electrophiles and reactive forms of oxygen.  Free Radic Biol Med. 2000;  29 231-40
• 80 Prochaska H J, Santamaria A B. Direct measurement of NAD(P)H:quinone reductase from cells cultured in microtiter wells: A screening assay for anticarcinogenic enzyme inducers.  Anal Biochem. 1988;  169 328-36
• 81 Miranda C L, Aponso G LM, Stevens J F, Deinzer M L, Buhler D R. Prenylated chalcones and flavanones as inducers of quinone reductase in mouse hepa 1c1c7 cells.  Cancer Lett. 2000;  149 21-9
• 82 Uda Y, Price K R, Williamson G, Rhodes M JC. Induction of the anticarcinogenic marker enzyme, quinone reductase, in murine hepatoma cells in vitro by flavonoids.  Cancer Lett. 1997;  120 313-6
• 83 Wang W, Liu L Q, Higuchi C M, Chen H. Induction of NADPH:quinone reductase by dietary phytoestrogens in colonic colo205 cells.  Biochem Pharmacol. 1998;  56 189-95
• 84 Gerhäuser C, Klimo K, Heiss E, Neumann I, Gamal-Eldeen A, Knauft J. et al . Mechanism-based in vitro screening of potential cancer chemopreventive agents.  Mutation Res. 2003;  523 - 524 163-72
• 85 Zhang Y, Kensler T W, Cho C -G, Posner G H, Talalay P. Anticarcinogenic activities of sulforaphane and structurally related synthetic norbornyl isothiocyanates.  Proc Natl Acad Sci USA. 1994;  91 3147-50
• 86 Hayes J D, McMahon M. Molecular basis for the contribution of the antioxidant responsive element to cancer chemoprevention.  Cancer Lett. 2001;  174 103-13
• 87 De Flora S, Izzotti A, D’Agostini F, Balansky R M, Noonan D, Albini A. Multiple points of intervention in the prevention of cancer and other mutation-related diseases.  Mutation Res. 2001;  480 - 481 9-22
• 88 Middleton E J, Kandaswami C, Theoharides T C. The effects of plant flavonoids on mammalian cells: Implications for inflammation, heart disease, and cancer.  Pharmacol Rev. 2000;  52 673-751
• 89 Talalay P, De Long M J, Prochaska H J. Identification of a common chemical signal regulating the induction of enzymes that protect against chemical carcinogenesis.  Proc Natl Acad Sci USA. 1988;  85 8261-5
• 90 Yannai S, Day A J, Williamson G, Rhodes M JC. Characterization of flavonoids as monofunctional or bifunctional inducers of quinone reductase in murine hepatoma cell lines.  Food Chem Toxicol. 1998;  36 623-30
• 91 Fahey J W, Stephenson K K. Pinostrobin from honey and Thai ginger (Boesenbergia pandurata): A potent flavonoid inducer of mammalian phase 2 chemoprotective and antioxidant enzymes.  J Agric Food Chem. 2002;  50 7472-6
• 92 Kuroyanagi M, Shibata K, Umehara K. Cell differentiation inducing steroids from Withania somnifera (L.) Dun.  Chem Pharm Bull. 1999;  47 1646-9
• 93 Su B N, Gu J Q, Kang Y H, Park E J, Pezzuto J M, Kinghorn A D. Induction of the phase II enzyme, quinone reductase, by withanolides and norwithanolides from Solanaceous species.  Mini Rev Org Chem. 2004;  1 115-23
• 94 Karmali R A. Prostaglandins and cancer. Review.  Prostaglandins. 1980;  5 1-28
• 95 Marnett L J. Aspirin and the potential role of prostaglandins in colon cancer.  Cancer Res. 1992;  52 5575-89
• 96 Levy G N. Prostaglandin H synthases, nonsteroidal anti-inflammatory drugs, and colon cancer.  FASEB J. 1997;  11 234-47
• 97 Marnett L J. Prostaglandin synthase-mediated metabolism of carcinogens and a potential role for peroxyl radicals as positive intermediates.  Environ Health Persp. 1990;  88 5-12
• 98 Lupulescu A. Prostaglandins, their inhibitors and cancer.  Prostaglandins Leukotrienes Essent Fatty Acids. 1996;  54 83-94
• 99 Cho H, Yun C W, Park W Y, Kong J Y, Kim K S, Park Y. et al . Modulation of the activity of pro-inflammatory enzymes, COX-2 and iNOS, by chrysin derivatives.  Pharmacol Res. 2004;  49 37-43
• 100 Jang M, Pezzuto J M. Cancer chemopreventive activity of resveratrol.  Drugs Exptl Clin Res. 1999;  25 65-77
• 101 Jang M, Pezzuto J M. Resveratrol blocks eicosanoid production and chemical-induced cellular transformation: Implication for cancer chemoprevention.  Pharm Biol. 1998;  36(S) 28-34
• 102 Banwell M G, Bezos A, Chand S, Dannhardt G, Kiefer W, Nowe U. et al . Convergent synthesis and preliminary biological evaluations of the stilbenolignan (±)-aiphanol and various congeners.  Org Biomol Chem. 2003;  1 2427-9
• 103 Kuboki A, Yamamoto T, Ohira S. Total synthesis of (±)-aiphanol, a novel cyclooxygenase-inhibitory stilbenolignan.  Chem Lett. 2003;  32 420-1
• 104 Ringbom T, Huss U, Stenholm Å, Flock S, Skattebøl L, Perera P, Bohlin L. COX-2 inhibitory effects of naturally occurring and modified fatty acids.  J Nat Prod. 2001;  64 745-9
• 105 Henry G E, Momin R A, Nair M G, Dewitt D L. Antioxidant and cyclooxygenase activities of fatty acids found in food.  J Agric Food Chem. 2002;  50 2231-4
• 106 Pezzuto J M, Kosmeder I IJW, Park E J, Lee S K, Cuendet M, Gills J. et al .Characterization of chemopreventive agents in natural products.  In: Strategies for Cancer Chemoprevention. Kelloff GJ, Hawk ET, Sigman, CC, editors Totowa, New Jersey; The Humana Press 2005
• 107 Kang Y -H, Pezzuto J M. Induction of quinone reductase as a primary screen for natural product anticarcinogens. In: Quinones and Quinone Enzymes (A Volume of Methods in Enzymology). Sies, H, Packer, L, editors San Diego; Elsevier Science 2003: p380-414
• 108 Baba M, Asano R, Takigami I, Takahashi T, Ohmura M, Okada Y. et al . Studies on cancer chemoprevention by traditional folk medicines. XXV. Inhibitory effect of isoliquiritigenin on azomethane-induced murine colon aberrant crypt focus formation and carcinogenesis.  Biol Pharm Bull. 2002;  25 247-9
• 109 Yamazaki S, Morita T, Endo H, Hamamoto T, Baba M, Joichi Y. et al . Isoliquiritigenin suppresses pulmonary metastasis of mouse renal cell carcinoma.  Cancer Lett. 2002;  183 23-30