Apigenin: A Promising Molecule for Cancer Prevention

Sanjeev Shukla1, Sanjay Gupta1
1Departments of Urology & Nutrition, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio, 44106, USA

Tóm tắt

Từ khóa


Tài liệu tham khảo

Hahn WC, Weinberg RA. Modelling the molecular circuitry of cancer. Nat Rev Cancer. 2002;2:331–41.

Austoker J. Cancer prevention in primary care. Current trends and some prospects for the future. BMJ. 1994;309:517–20.

Hajjar RR. Cancer in the elderly: is it preventable? Clin Geriatr Med. 2004;20:293–316.

Mackey S. Promoting lifestyle modification for cancer prevention. J Am Diet Assoc. 2004;104:1568–9.

Kris-Etherton PM, Hecker KD, Bonanome A, Coval SM, Binkoski AE, Hilpert KF, et al. Bioactive compounds in foods: their role in the prevention of cardiovascular disease and cancer. Am J Med. 2002;113:71S–88.

Lippman SM, Hong WK. Cancer prevention science and practice. Cancer Res. 2002;62:5119–25.

Gupta S. Prostate cancer chemoprevention: current status and future prospects. Toxicol Appl Pharmacol. 2007;224:369–76.

Heederik D, Kromhout H, Burema J, Biersteker K, Kromhout D. Occupational exposure and 25-year incidence rate of non-specific lung disease: the Zutphen Study. Int J Epidemiol. 1990;19:945–52.

Knekt P, Järvinen R, Seppänen R, Hellövaara M, Teppo L, Pukkala E, et al. Dietary flavonoids and the risk of lung cancer and other malignant neoplasms. Am J Epidemiol. 1997;146:223–30.

Hertog MG, Feskens EJ, Hollman PC, Katan MB, Kromhout D. Dietary flavonoids and cancer risk in the Zutphen Elderly Study. Nutr Cancer. 1994;22:175–84.

Rossi M, Negri E, Lagiou P, Talamini R, Dal Maso L, Montella M, et al. Flavonoids and ovarian cancer risk: a case-control study in Italy. Int J Cancer. 2008;123:895–8.

Bosetti C, Spertini L, Parpinel M, Gnagnarella P, Lagiou P, Negri E, et al. Flavonoids and breast cancer risk in Italy. Cancer Epidemiol Biomarkers Prev. 2005;14:805–8.

Hoensch H, Groh B, Edler L, Kirch W. Prospective cohort comparison of flavonoid treatment in patients with resected colorectal cancer to prevent recurrence. World J Gastroenterol. 2008;14:2187–93.

Patel D, Shukla S, Gupta S. Apigenin and cancer chemoprevention: progress, potential and promise. Int J Oncol. 2007;30:233–45.

Hertog MG, Kromhout D, Aravanis C, et al. Flavonoid intake and long-term risk of coronary heart disease and cancer in the seven countries study. Arch Intern Med. 1995;155:381–6.

Aherne SA, O’Brien NM. Dietary flavonols: chemistry, food content, and metabolism. Nutrition. 2002;18:75–81.

Johannot L, Somerset SM. Age-related variations in flavonoid intake and sources in the Australian population. Public Health Nutr. 2006;9:1045–54.

Cheung ZH, Leung MC, Yip HK, Wu W, Siu FK, So KF. A neuroprotective herbal mixture inhibits caspase-3-independent apoptosis in retinal ganglion cells. Cell Mol Neurobiol. 2008;28:137–55.

McKay DL, Blumberg JB. A review of the bioactivity and potential health benefits of chamomile tea (Matricaria recutita L.). Phytother Res. 2006;20:519–30.

Bevilacqua L, Buiarelli F, Coccioli F, Jasionowska R. Identification of compounds in wine by HPLC-tandem mass spectrometry. Ann Chim. 2004;94:679–89.

Gerhauser C. Beer constituents as potential cancer chemopreventive agents. European J Cancer. 2005;41:1941–54.

Svehlikova V, Bennett RN, Mellon FA, Needs PW, Piacente S, Kroon PA, et al. Isolation, identification and stability of acylated derivatives of apigenin 7-O-glucoside from chamomile (Chamomilla recutita [L.] Rauschert). Phytochemistry. 2004;65:2323–32.

Gupta S, Afaq F, Mukhtar H. Selective growth-inhibitory, cell-cycle deregulatory and apoptotic response of apigenin in normal versus human prostate carcinoma cells. Biochem Biophys Res Commun. 2001;287:914–20.

Kim HY, Kim OH, Sung MK. Effects of phenol-depleted and phenol-rich diets on blood markers of oxidative stress, and urinary excretion of quercetin and kaempferol in healthy volunteers. J Am Coll Nutr. 2003;22:217–23.

Yang CS, Landau JM, Huang MT, Newmark HL. Inhibition of carcinogenesis by dietary polyphenolic compounds. Annu Rev Nutr. 2001;21:381–406.

O’Prey J, Brown J, Fleming J, Harrison PR. Effects of dietary flavonoids on major signal transduction pathways in human epithelial cells. Biochem Pharmacol. 2003;66:2075–88.

Thiery-Vuillemin A, Nguyen T, Pivot X, Spano JP, Dufresnne A, Soria JC. Molecularly targeted agents: their promise as cancer chemopreventive interventions. Eur J Cancer. 2005;41:2003–15.

Nielsen SE, Young JF, Daneshvar B, Lauridsen ST, Knuthsen P, Sandstrom B, et al. Effect of parsley (Petroselinum crispum) intake on urinary apigenin excretion, blood antioxidant enzymes and biomarkers for oxidative stress in human subjects. Br J Nutr. 1999;81:447–55.

Surh YJ. Cancer chemoprevention with dietary phytochemicals. Nat Rev Cancer. 2003;3:768–80.

Arai Y, Watanabe S, Kimira M, Shimoi K, Mochizuki R, Kinae N. Dietary intakes of flavonols, flavones and isoflavones by Japanese women and the inverse correlation between quercetin intake and plasma LDL cholesterol concentration. J Nutr. 2000;130:2243–50.

Janssen K, Mensink RP, Cox FJ, Harryvan JL, Hovenier R, Hollman PC, et al. Effects of the flavonoids quercetin and apigenin on hemostasis in healthy volunteers: results from an in vitro and a dietary supplement study. Am J Clin Nutr. 1998;67:255–62.

Kuo ML, Lin JK. Genotoxicities of nitropyrenes and their modulation by apigenin, tannic acid, ellagic acid and indole-3-carbinol in the Salmonella and CHO systems. Mutat Res. 1992;270:87–95.

Middleton JR E, Kandaswami C, Theoharides TC. The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease, and cancer. Pharmacol Rev. 2000;52:673–751.

Birt DF, Mitchell D, Gold B, Pour P, Pinch HC. Inhibition of ultraviolet light induced skin carcinogenesis in SKH-1 mice by apigenin, a plant flavonoid. Anticancer Res. 1997;17:85–91.

Van Dross R, Xue Y, Knudson A, Pelling JC. The chemopreventive bioflavonoid apigenin modulates signal transduction pathways in keratinocyte and colon carcinoma cell lines. J Nutr. 2003;133:3800S–4.

Wei H, Tye L, Bresnick E, Birt DF. Inhibitory effect of apigenin, a plant flavonoid, on epidermal ornithine decarboxylase and skin tumor promotion in mice. Cancer Res. 1990;50:499–502.

Myhrstad MC, Carlsen H, Nordstrom O, Blomhoff R, Moskaug JO. Flavonoids increase the intracellular glutathione level by transactivation of the gamma-glutamylcysteine synthetase catalytical subunit promoter. Free Radic Biol Med. 2002;32:386–93.

Liang YC, Huang YT, Tsai SH, Lin-Shiau SY, Chen CF, Lin JK. Suppression of inducible cyclooxygenase and inducible nitric oxide synthase by apigenin and related flavonoids in mouse macrophages. Carcinogenesis. 1999;20:1945–52.

Kawai M, Hirano T, Higa S, Arimitsu J, Maruta M, Kuwahara Y, et al. Favonoids and related compounds as anti-allergic substances. Allergol Int. 2007;56:113–23.

Yano S, Umeda D, Yamashita T, Ninomiya Y, Sumida M, Fujimura Y, et al. Dietary flavones suppress IgE and Th2 cytokines in OVA-immunized BALB/c mice. Eur J Nutr. 2007;46:257–63.

Choi JS, Choi YJ, Park SH, Kang JS, Kang YH. Flavones mitigate tumor necrosis factor-alpha-induced adhesion molecule upregulation in cultured human endothelial cells: role of nuclear factor-kappa B. J Nutr. 2004;4:1013–9.

Williams RJ, Spencer JP, Rice-Evans C. Flavonoids: antioxidants or signalling molecules? Free Radic Biol Med. 2004;36:838–49.

Lee SF, Lin JK. Inhibitory effects of phytopolyphenols on TPA-induced transformation, PKC activation, and c-jun expression in mouse fibroblast cells. Nutr Cancer. 1997;28:177–83.

Lin JK, Chen YC, Huang YT, Lin-Shiau SY. Suppression of protein kinase C and nuclear oncogene expression as possible molecular mechanisms of cancer chemoprevention by apigenin and curcumin. J Cell Biochem Suppl. 1997;28–29:39–48.

Mounho BJ, Thrall BD. The extracellular signal-regulated kinase pathway contributes to mitogenic and antiapoptotic effects of peroxisome proliferators in vitro. Toxicol Appl Pharmacol. 1999;159:125–33.

Shukla S, Gupta S. Apigenin-induced cell cycle arrest is mediated by modulation of MAPK, PI3K-Akt, and loss of cyclin D1 associated retinoblastoma dephosphorylation in human prostate cancer cells. Cell Cycle. 2007;6:1102–14.

Carrillo C, Cafferatam EG, Genovese J, O’Reilly M, Roberts AB, Santa-Coloma TA. TGF-beta1 up-regulates the mRNA for the Na+/Ca2+ exchanger in neonatal rat cardiac myocytes. Cell Mol Biol. 1998;44:543–51.

Yin F, Giuliano AE, Van Herle AJ. Signal pathways involved in apigenin inhibition of growth and induction of apoptosis of human anaplastic thyroid cancer cells (ARO). Anticancer Res. 1999;19:4297–303.

Hessenauer A, Montenarh M, Gotz C. Inhibition of CK2 activity provokes different responses in hormone-sensitive and hormone-refractory prostate cancer cells. Int J Oncol. 2003;22:1263–70.

Landesman-Bollag E, Song DH, Romieu-Mourez R, Sussman DJ, Cardiff RD, Sonenshein GE, et al. Protein kinase CK2: signaling and tumorigenesis in the mammary gland. Mol Cell Biochem. 2001;227:153–65.

Plaumann B, Fritsche M, Rimpler H, Brandner G, Hess RD. Flavonoids activate wild-type p53. Oncogene. 1996;13:1605–14.

Lepley DM, Pelling JC. Induction of p21/WAF1 and G1 cell-cycle arrest by the chemopreventive agent apigenin. Mol Carcinog. 1997;19:74–82.

Gupta S, Afaq F, Mukhtar H. Involvement of nuclear factor-kappa B, Bax and Bcl-2 in induction of cell cycle arrest and apoptosis by apigenin in human prostate carcinoma cells. Oncogene. 2002;21:3727–38.

Shukla S, Gupta S. Molecular mechanisms for apigenin-induced cell-cycle arrest and apoptosis of hormone refractory human prostate carcinoma DU145 cells. Mol Carcinog. 2004;39:114–26.

Wang IK, Lin-Shiau SY, Lin JK. Induction of apoptosis by apigenin and related flavonoids through cytochrome c release and activation of caspase-9 and caspase-3 in leukaemia HL-60 cells. Eur J Cancer. 1999;35:1517–25.

Iwashita K, Kobori M, Yamaki K, Tsushida T. Flavonoids inhibit cell growth and induce apoptosis in B16 melanoma 4A5 cells. Biosci Biotechnol Biochem. 2000;64:1813–20.

Hirano T, Oka K, Akiba M. Antiproliferative effects of synthetic and naturally occurring flavonoids on tumor cells of the human breast carcinoma cell line, ZR-75-1. Res Commun Chem Pathol Pharmacol. 1989;64:69–78.

Lindenmeyer F, Li H, Menashi S, Soria C, Lu H. Apigenin acts on the tumor cell invasion process and regulates protease production. Nutr Cancer. 2001;39:139–47.

Panes J, Gerritsen ME, Anderson DC, Miyasaka M, Granger DN. Apigenin inhibits tumor necrosis factor-induced intercellular adhesion molecule-1 upregulation in vivo. Microcirculation. 1996;3:279–86.

Piantelli M, Rossi C, Iezzi M, La Sorda R, Iacobelli S, Alberti S, et al. Flavonoids inhibit melanoma lung metastasis by impairing tumor cells endothelium interactions. J Cell Physiol. 2006;207:23–9.

Osada M, Imaoka S, Funae Y. Apigenin suppresses the expression of VEGF, an important factor for angiogenesis, in endothelial cells via degradation of HIF-1alpha protein. FEBS Lett. 2004;575:59–63.

Fang J, Xia C, Cao Z, Zheng JZ, Reed E, Jiang BH. Apigenin inhibits VEGF and HIF-1 expression via PI3K/AKT/p70S6K1 and HDM2/p53 pathways. FASEB J. 2005;19:342–53.

Le Bail JC, Laroche T, Marre-Fournier F, Habrioux G. Aromatase and 17 beta-hydroxysteroid dehydrogenase inhibition by flavonoids. Cancer Lett. 1998;133:101–6.

Hiremath SP, Badami S, Hunasagatta SK, Patil SB. Antifertility and hormonal properties of flavones of Striga orobanchioides. Eur J Pharmacol. 2000;391:193–7.

Mak P, Leung YK, Tang WY, Harwood C, Ho SM. Apigenin suppresses cancer cell growth through ERbeta. Neoplasia. 2006;8:896–904.

Shukla S, Mishra A, Fu P, MacLennan GT, Resnick MI, Gupta S. Up-regulation of insulin-like growth factor binding protein-3 by apigenin leads to growth inhibition and apoptosis of 22Rv1 xenograft in athymic nude mice. FASEB J. 2005;19:2042–4.

Shukla S, MacLennan GT, Flask CA, Fu P, Mishra A, Resnick MI, et al. Blockade of beta-catenin signaling by plant flavonoid apigenin suppresses prostate carcinogenesis in TRAMP mice. Cancer Research. 2007;67:6925–35.

Menichincheri M, Ballinari D, Bargiotti A, Bonomini L, Ceccarelli W, D’Alessio R, et al. Catecholic flavonoids acting as telomerase inhibitors. J Med Chem. 2004;47:6466–75.

Brusselmans K, Vrolix R, Verhoeven G, Swinnen JV. Induction of cancer cell apoptosis by flavonoids is associated with their ability to inhibit fatty acid synthase activity. J Biol Chem. 2005;280:5636–45.

Kim MH. Flavonoids inhibit VEGF/bFGF-induced angiogenesis in vitro by inhibiting the matrix-degrading proteases. J Cell Biochem. 2003;89:529–38.

Reiners Jr JJ, Clift R, Mathieu P. Suppression of cell cycle progression by flavonoids: dependence on the aryl hydrocarbon receptor. Carcinogenesis. 1999;20:1561–6.

Way TD, Kao MC, Lin JK. Apigenin induces apoptosis through proteasomal degradation of HER2/neu in HER2/neu-overexpressing breast cancer cells via the phosphatidylinositol 3-kinase/Akt-dependent pathway. J Biol Chem. 2004;279:4479–89.

Kim JS, Eom JI, Cheong JW, Choi AJ, Lee JK, Yang WI, et al. Protein kinase CK2alpha as an unfavorable prognostic marker and novel therapeutic target in acute myeloid leukemia. Clin Cancer Res. 2007;13:1019–28.

Yang CS, Landau JM, Huang MT, Newmark HL. Inhibition of carcinogenesis by dietary polyphenolic compounds. Annu Rev Nutr. 2001;21:381–406.

O’Prey J, Brown J, Fleming J, Harrison PR. Effects of dietary flavonoids on major signal transduction pathways in human epithelial cells. Biochem Pharmacol. 2003;66:2075–88.

Thiery-Vuillemin A, Nguyen T, Pivot X, Spano JP, Dufresnne A, Soria JC. Molecularly targeted agents: Their promise as cancer chemopreventive interventions. Eur J Cancer. 2005;41:2003–15.

Nielsen SE, Young JF, Daneshvar B, Lauridsen ST, Knuthsen P, Sandstrom B, et al. Effect of parsley (Petroselinum crispum) intake on urinary apigenin excretion, blood antioxidant enzymes and biomarkers for oxidative stress in human subjects. Br J Nutr. 1999;81:447–55.

Scott EN, Gescher AJ, Steward WP, Brown K. Development of dietary phytochemical chemopreventive agents: biomarkers and choice of dose for early clinical trials. Cancer Prev Res (Phila Pa). 2009;2:525–30.

Arai Y, Watanabe S, Kimira M, Shimoi K, Mochizuki R, Kinae N. Dietary intakes of flavonols, flavones and isoflavones by Japanese women and the inverse correlation between quercetin intake and plasma LDL cholesterol concentration. J Nutr. 2000;130:2243–50.

Janssen K, Mensink RP, Cox FJ, Harryvan JL, Hovenier R, Hollman PC, et al. Effects of the flavonoids quercetin and apigenin on hemostasis in healthy volunteers: results from an in vitro and a dietary supplement study. Am J Clin Nutr. 1998;67:255–62.

Way TD, Kao MC, Lin JK. Degradation of HER2/neu by apigenin induces apoptosis through cytochrome c release and caspase-3 activation in HER2/neu-overexpressing breast cancer cells. FEBS Lett. 2005;579:145–52.

Weldon CB, McKee A, Collins-Burow BM, Melnik LI, Scandurro AB, McLachlan JA, et al. PKC-mediated survival signaling in breast carcinoma cells: a role for MEK1-AP1 signaling. Int J Oncol. 2005;26:763–8.

Choi EJ, Kim GH. Apigenin Induces Apoptosis through a Mitochondria/Caspase-Pathway in Human Breast Cancer MDA-MB-453 Cells. J Clin Biochem Nutr. 2009;44:260–5.

Choi EJ, Kim GH. 5-Fluorouracil combined with apigenin enhances anticancer activity through induction of apoptosis in human breast cancer MDA-MB-453 cells. Oncol Rep. 2009;22:1533–7.

Yin F, Giuliano AE, Law RE, Van Herle AJ. Apigenin inhibits growth and induces G2/M arrest by modulating cyclin-CDK regulators and ERK MAP kinase activation in breast carcinoma cells. Anticancer Res. 2001;21:413–20.

Choi EJ, Kim GH. Apigenin causes G (2)/M arrest associated with the modulation of p21 (Cip1) and Cdc2 and activates p53-dependent apoptosis pathway in human breast cancer SK-BR-3 cells. J Nutr Biochem. 2009;20:285–90.

Wang C, Kurzer MS. Phytoestrogen concentration determines effects on DNA synthesis in human breast cancer cells. Nutr Cancer. 1997;28:236–47.

Wang C, Kurzer MS. Effects of phytoestrogens on DNA synthesis in MCF-7 cells in the presence of estradiol or growth factors. Nutr Cancer. 1998;31:90–100.

Collins-Burow BM, Burow ME, Duong BN, McLachlan JA. Estrogenic and antiestrogenic activities of flavonoid phytochemicals through estrogen receptor binding-dependent and-independent mechanisms. Nutr Cancer. 2000;38:229–44.

Long X, Fan M, Bigsby RM, Nephew KP. Apigenin inhibits antiestrogen-resistant breast cancer cell growth through estrogen receptor-alpha-dependent and estrogen receptor-alpha-independent mechanisms. Mol Cancer Ther. 2008;7:2096–108.

Zhang S, Yang X, Morris ME. Combined effects of multiple flavonoids on breast cancer resistance protein (ABCG2)-mediated transport. Pharm Res. 2004;21:1263–73.

Stroheker T, Picard K, Lhuguenot JC, Canivenc-Lavier MC, Chagnon MC. Steroid activities comparison of natural and food wrap compounds in human breast cancer cell lines. Food Chem Toxicol. 2004;42:887–97.

Seo HS, DeNardo DG, Jacquot Y, Laïos I, Vidal DS, Zambrana CR, et al. Stimulatory effect of genistein and apigenin on the growth of breast cancer cells correlates with their ability to activate ER alpha. Breast Cancer Res Treat. 2006;99:121–34.

Van Meeuwen JA, Korthagen N, de Jong PC, Piersma AH, Van den Berg M. (Anti) estrogenic effects of phytochemicals on human primary mammary fibroblasts, MCF-7 cells and their co-culture. Toxicol Appl Pharmacol. 2007;221:372–83.

Menendez JA, Vazquez-Martin A, Oliveras-Ferraros C, Garcia-Villalba R, Carrasco-Pancorbo A, Fernandez-Gutierrez A, et al. Analyzing effects of extra-virgin olive oil polyphenols on breast cancer-associated fatty acid synthase protein expression using reverse-phase protein microarrays. Int J Mol Med. 2008;22:433–9.

Chen T, Li LP, Lu XY, Jiang HD, Zeng S. Absorption and excretion of luteolin and apigenin in rats after oral administration of Chrysanthemum morifolium extract. J Agric Food Chem. 2007;55:273–7.

Lee SH, Ryu JK, Lee KY, Woo SM, Park JK, Yoo JW, et al. Enhanced anti-tumor effect of combination therapy with gemcitabine and apigenin in pancreatic cancer. Cancer Lett. 2008;259:39–49.

Zheng PW, Chiang LC, Lin CC. Apigenin induced apoptosis through p53-dependent pathway in human cervical carcinoma cells. Life Sci. 2005;76:1367–79.

Czyz J, Madeja Z, Irmer U, Korohoda W, Hulser DF. Flavonoid apigenin inhibits motility and invasiveness of carcinoma cells in vitro. Int J Cancer. 2005;114:12–8.

Wu C, Chen F, Rushing JW, Wang X, Kim HJ, Huang G, et al. Antiproliferative activities of parthenolide and golden feverfew extract against three human cancer cell lines. J Med Food. 2006;9:55–61.

Wang W, Heideman L, Chung CS, Pelling JC, Koehler KJ, Birt DF. Cell-cycle arrest at G2/M and growth inhibition by apigenin in human colon carcinoma cell lines. Mol Carcinog. 2000;28:102–10.

Wang W, VanAlstyne PC, Irons KA, Chen S, Stewart JW, Birt DF. Individual and interactive effects of apigenin analogs on G2/M cell-cycle arrest in human colon carcinoma cell lines. Nutr Cancer. 2004;48:106–14.

Takagaki N, Sowa Y, Oki T, Nakanishi R, Yogosawa S, Sakai T. Apigenin induces cell cycle arrest and p21/WAF1 expression in a p53-independent pathway. Int J Oncol. 2005;26:185–9.

Chung CS, Jiang Y, Cheng D, Birt DF. Impact of adenomatous polyposis coli (APC) tumor supressor gene in human colon cancer cell lines on cell cycle arrest by apigenin. Mol Carcinog. 2007;46:773–82.

Farah M, Parhar K, Moussavi M, Eivemark S, Salh B. 5, 6-Dichloro-ribifuranosylbenzimidazole- and apigenin-induced sensitization of colon cancer cells to TNF-alpha-mediated apoptosis. Am J Physiol Gastrointest Liver Physiol. 2003;285:919–28.

Au A, Li B, Wang W, Roy H, Koehler K, Birt D. Effect of dietary apigenin on colonic ornithine decarboxylase activity, aberrant crypt foci formation, and tumorigenesis in different experimental models. Nutr Cancer. 2006;54:243–51.

Svehlikova V, Bennett RN, Mellon FA, Needs PW, Piacente S, Kroon PA, et al. Isolation, identification and stability of acylated derivatives of apigenin 7-O-glucoside from chamomile (Chamomilla recutita [L.] Rauschert). Phytochemistry. 2004;65:2323–32.

Al-Fayez M, Cai H, Tunstall R, Steward WP, Gescher AJ. Differential modulation of cyclooxygenase-mediated prostaglandin production by the putative cancer chemopreventive flavonoids tricin, apigenin and quercetin. Cancer Chemother Pharmacol. 2006;58:816–25.

Vargo MA, Voss OH, Poustka F, Cardounel AJ, Grotewold E, Doseff AI. Apigenin-induced-apoptosis is mediated by the activation of PKCdelta and caspases in leukemia cells. Biochem Pharmacol. 2006;72:681–92.

Navarro-Núñez L, Lozano ML, Palomo M, Martínez C, Vicente V, Castillo J, et al. Apigenin inhibits platelet adhesion and thrombus formation and synergizes with aspirin in the suppression of the arachidonic acid pathway. J Agric Food Chem. 2008;56:2970–6.

Chen D, Daniel KG, Chen MS, Kuhn DJ, Landis-Piwowar KR, Dou QP. Dietary flavonoids as proteasome inhibitors and apoptosis inducers in human leukemia cells. Biochem Pharmacol. 2005;69:1421–32.

Abaza L, Talorete TP, Yamada P, Kurita Y, Zarrouk M, Isoda H. Induction of growth inhibition and differentiation of human leukemia HL-60 cells by a Tunisian gerboui olive leaf extract. Biosci Biotechnol Biochem. 2007;71:1306–12.

Monasterio A, Urdaci MC, Pinchuk IV, Lopez-Moratalla N, Martinez-Irujo J. Flavonoids induce apoptosis in human leukemia U937 cells through caspase- and caspase-calpain-dependent pathways. J Nutr Cancer. 2004;50:90–100.

Horvathova K, Novotny L, Vachalkova A. The free radical scavenging activity of four flavonoids determined by the comet assay. Neoplasma. 2003;50:291–5.

Strick R, Strissel PL, Borgers S, Smith SL, Rowley JD. Dietary bioflavonoids induce cleavage in the MLL gene and may contribute to infant leukemia. Proc Natl Acad Sci USA. 2000;97:4790–5.

Li ZD, Liu LZ, Shi X, Fang J, Jiang BH. Benzo[a]pyrene-3, 6-dione inhibited VEGF expression through inducing HIF-1alpha degradation. Biochem Biophys Res Commun. 2007;357:517–23.

Watanabe N, Hirayama R, Kubota N. The chemopreventive flavonoid apigenin confers radiosensitizing effect in human tumor cells grown as monolayers and spheroids. J Radiat Res (Tokyo). 2007;48:45–50.

Lee WJ, Chen WK, Wang CJ, Lin WL, Tseng TH. Apigenin inhibits HGF-promoted invasive growth and metastasis involving blocking PI3K/Akt pathway and beta 4 integrin function in MDA-MB-231 breast cancer cells. Toxicol Appl Pharmacol. 2008;226:178–91.

Engelmann C, Blot E, Panis Y, Bauer S, Trochon V, Nagy HJ, et al. Apigenin–strong cytostatic and anti-angiogenic action in vitro contrasted by lack of efficacy in vivo. Phytomedicine. 2002;9:489–95.

Fang J, Zhou Q, Liu LZ, Xia C, Hu X, Shi X, et al. Apigenin inhibits tumor angiogenesis through decreasing HIF-1alpha and VEGF expression. Carcinogenesis. 2007;28:858–64.

Zhu F, Liu XG, Liang NC. Effect of emodin and apigenin on invasion of human ovarian carcinoma HO-8910PM cells in vitro. Ai Zheng. 2003;22:358–62.

Hu XW, Meng D, Fang J. Apigenin inhibited migration and invasion of human ovarian cancer A2780 cells through focal adhesion kinase. Carcinogenesis. 2008;29:2369–76.

Li ZD, Hu XW, Wang YT, Fang J. Apigenin inhibits proliferation of ovarian cancer A2780 cells through Id1. FEBS Lett. 2009;583:1999–2003.

Knowles LM, Zigrossi DA, Tauber RA, Hightower C, Milner JA. Flavonoids suppress androgen-independent human prostate tumor proliferation. Nutr Cancer. 2000;38:116–22.

Lee SC, Kuan CY, Yang CC, Yang SD. Bioflavonoids commonly and potently induce tyrosine dephosphorylation/inactivation of oncogenic proline-directed protein kinase FA in human prostate carcinoma cells. Anticancer Res. 1998;18:1117–21.

Morrissey C, O’Neill A, Spengler B, Christoffel V, Fitzpatrick JM, Watson RW. Apigenin drives the production of reactive oxygen species and initiates a mitochondrial mediated cell death pathway in prostate epithelial cells. Prostate. 2005;63:131–42.

Shukla S, Gupta S. Suppression of constitutive and tumor necrosis factor alpha-induced nuclear factor (NF)-kappaB activation and induction of apoptosis by apigenin in human prostate carcinoma PC-3 cells: correlation with down-regulation of NF-kappaB-responsive genes. Clin Cancer Res. 2004;10:3169–78.

Shukla S, Gupta S. Molecular targets for apigenin-induced cell cycle arrest and apoptosis in prostate cancer cell xenograft. Mol Cancer Ther. 2006;5:843–52.

Shukla S, Gupta S. Apigenin-induced prostate cancer cell death is initiated by reactive oxygen species and p53 activation. Free Radic Biol Med. 2008;44:1833–45.

Shukla S, Gupta S. Apigenin suppresses insulin-like growth factor I receptor signaling in human prostate cancer: an in vitro and in vivo study. Mol Carcinog. 2009;48:243–52.

Kaur P, Shukla S, Gupta S. Plant flavonoid apigenin inactivates Akt to trigger apoptosis in human prostate cancer: an in vitro and in vivo study. Carcinogenesis. 2008;29:2210–7.

Mirzoeva S, Kim ND, Chiu K, Franzen CA, Bergan RC, Pelling JC. Inhibition of HIF-1 alpha and VEGF expression by the chemopreventive bioflavonoid apigenin is accompanied by Akt inhibition in human prostate carcinoma PC3-M cells. Mol Carcinog. 2008;47:686–700.

Franzen CA, Amargo E, Todorović V, Desai BV, Huda S, Mirzoeva S, et al. The chemopreventive bioflavonoid apigenin inhibits prostate cancer cell motility through the focal adhesion kinase/Src signaling mechanism. Cancer Prev Res (Phila Pa). 2009;2(9):830–41.

McVean M, Xiao H, Isobe K, Pelling JC. Increase in wild-type p53 stability and transactivational activity by the chemopreventive agent apigenin in keratinocytes. Carcinogenesis. 2000;21:633–9.

Li B, Birt DF. In vivo and in vitro percutaneous absorption of cancer preventive flavonoid apigenin in different vehicles in mouse skin. Pharm Res. 1996;13:1710–5.

Li B, Pinch H, Birt DF. Influence of vehicle, distant topical delivery, and biotransformation on the chemopreventive activity of apigenin, a plant flavonoid, in mouse skin. Pharm Res. 1996;13:1530–4.

Tong X, Van Dross RT, Abu-Yousif A, Morrison AR, Pelling JC. Apigenin prevents UVB-induced cyclooxygenase 2 expression: coupled mRNA stabilization and translational inhibition. Mol Cell Biol. 2007;27:283–96.

Van Dross RT, Hong X, Essengue S, Fischer SM, Pelling JC. Modulation of UVB-induced and basal cyclooxygenase-2 (COX-2) expression by apigenin in mouse keratinocytes: role of USF transcription factors. Mol Carcinog. 2007;46:303–14.

Caltagirone S, Rossi C, Poggi A, Ranelletti FO, Natali PG, Brunetti M, et al. Flavonoids apigenin and quercetin inhibit melanoma growth and metastatic potential. Int J Cancer. 2000;87:595–600.

Schroder-van der Elst JP, van der Heide D, Romijn JA, Smit JW. Differential effects of natural flavonoids on growth and iodide content in a human Na+/I-symporter-transfected follicular thyroid carcinoma cell line. Eur J Endocrinol. 2004;150:557–64.

O’Toole SA, Sheppard BL, Sheils O, O'Leary JJ, Spengler B, Christoffel V. Analysis of DNA in endometrial cancer cells treated with phyto-estrogenic compounds using comparative genomic hybridisation microarrays. Planta Med. 2005;71:435–9.

Wu K, Yuan LH, Xia W. Inhibitory effects of apigenin on the growth of gastric carcinoma SGC-7901 cells. World J Gastroenterol. 2005;11:4461–4.

Eaton EA, Walle UK, Lewis AJ, Hudson T, Wilson AA, Walle T. Flavonoids, potent inhibitors of the human P-form phenolsulfotransferase: Potential role in drug metabolism and chemoprevention. Drug Metab Dispos. 1996;24:232–7.

Watjen W, Weber N, Lou YJ, Wang ZQ, Chovolou Y, Kampkotter A, et al. Prenylation enhances cytotoxicity of apigenin and liquiritigenin in rat H4IIE hepatoma and C6 glioma cells. Food Chem Toxicol. 2007;45:119–24.

Yee SB, Lee JH, Chung HY, Im KS, Bae SJ, Choi JS, et al. Inhibitory effects of luteolin isolated from Ixeris sonchifolia Hance on the proliferation of HepG2 human hepatocellular carcinoma cells. Arch Pharm Res. 2003;26:151–6.

Jeyabal PV, Syed MB, Venkataraman M, Sambandham JK, Sakthisekaran D. Apigenin inhibits oxidative stress-induced macromolecular damage in N-nitrosodiethylamine (NDEA)-induced hepatocellular carcinogenesis in Wistar albino rats. Mol Carcinog. 2005;44:11–20.

Sanderson JT, Hordijk J, Denison MS, Springsteel MF, Nantz MH, Van den Berg M. Induction and inhibition of aromatase (CYP19) activity by natural and synthetic flavonoid compounds in H295R human adrenocortical carcinoma cells. Toxicol Sci. 2004;82:70–9.

Ohno S, Shinoda S, Toyoshima S, Nakazawa H, Makino T, Nakajin S. Effects of flavonoid phytochemicals on cortisol production and on activities of steroidogenic enzymes in human adrenocortical H295R cells. J Steroid Biochem Mol Biol. 1999;80:355–63.

Torkin R, Lavoie JF, Kaplan DR, Yeger H. Induction of caspase-dependent, p53-mediated apoptosis by apigenin in human neuroblastoma. Mol Cancer Ther. 2005;4:1–11.

Das A, Banik NL, Ray SK. Mechanism of apoptosis with the involvement of calpain and caspase cascades in human malignant neuroblastoma SH-SY5Y cells exposed to flavonoids. Int J Cancer. 2006;119:2575–85.