Apigenin, a dietary flavonoid, induces apoptosis, DNA damage, and oxidative stress in human breast cancer MCF-7 and MDA MB-231 cells

  • Ivana Vrhovac Madunić
  • Josip Madunić
  • Maja Antunović
  • Mladen Paradžik
  • Vera Garaj-Vrhovac
  • Davorka Breljak
  • Inga Marijanović
  • Goran GajskiEmail author
Original Article


Apigenin is found in several dietary plant foods such as vegetables and fruits. To investigate potential anticancer properties of apigenin on human breast cancer, ER-positive MCF-7 and triple-negative MDA MB-231 cells were used. Moreover, toxicological safety of apigenin towards normal cells was evaluated in human lymphocytes. Cytotoxicity of apigenin towards cancer cells was evaluated by MTT assay whereas further genotoxic and oxidative stress parameters were measured by comet and lipid peroxidation assays, respectively. In order to examine the type of cell death induced by apigenin, several biomarkers were used. Toxicological safety towards normal cells was evaluated by cell viability and comet assays. After the treatment with apigenin, we observed changes in cell morphology in a dose- (10 to 100 μM) and time-dependent manner. Moreover, apigenin caused cell death in both cell lines leading to significant toxicity and dominantly to apoptosis. Furthermore, apigenin proved to be genotoxic towards the selected cancer cells with a potential to induce oxidative damage to lipids. Of great importance is that no significant cytogenotoxic effects were detected in normal cells. The observed cytogenotoxic and pro-cell death activities of apigenin coupled with its low toxicity towards normal cells indicate that this natural product could be used as a future anticancer modality. Therefore, further analysis to determine the exact mechanism of action and in vivo studies on animal models are warranted.


Apigenin Breast cancer cells Human lymphocytes Cytogenotoxicity Apoptosis Anticancer effect 



This work was supported by the funds and equipment from the University of Zagreb, Faculty of Science and Faculty of Pharmacy and Biochemistry, Ruđer Bošković Institute, and the Institute for Medical Research and Occupational Health. The authors would like to thank Prof. Dr. Ana-Marija Domijan for HPLC analysis support, Prof. Dr. Maja Matulić for providing necessary cells and chemicals, and Ms. Željana Pavlaković for manuscript language editing.

Compliance with ethical standards

The study was approved by the Institutional Ethics committee and observed the ethical principles of the Declaration of Helsinki.

Conflict of interests

The authors declare that they have no conflicts of interest.


  1. Abdal Dayem A, Choi HY, Yang G-M, Kim K, Saha S, Cho SG (2016) The anti-cancer effect of polyphenols against breast cancer and cancer stem cells: molecular mechanisms. Nutrients 8:581. CrossRefPubMedCentralGoogle Scholar
  2. Abdull Razis AF, Noor NM (2013) Cruciferous vegetables: dietary phytochemicals for cancer prevention. Asian Pac J Cancer Prev 14:1565–1570CrossRefPubMedGoogle Scholar
  3. Agrawal A, Yang J, Murphy RF, Agrawal DK (2006) Regulation of the p14ARF-Mdm2-p53 pathway: an overview in breast cancer. Exp Mol Pathol 81:115–122. CrossRefPubMedGoogle Scholar
  4. Anand P, Kunnumakkara AB, Sundaram C, Harikumar KB, Tharakan ST, Lai OS, Sung B, Aggarwal BB (2008) Cancer is a preventable disease that requires major lifestyle changes. Pharm Res 25:2097–2116. CrossRefPubMedPubMedCentralGoogle Scholar
  5. Anders CK, Carey LA (2009) Biology, metastatic patterns, and treatment of patients with triple-negative breast cancer. Clin Breast Cancer 9:S73–S81. CrossRefPubMedPubMedCentralGoogle Scholar
  6. Arango D, Parihar A, Villamena FA, Wang L, Freitas MA, Grotewold E, Doseff AI (2012) Apigenin induces DNA damage through the PKCδ-dependent activation of ATM and H2AX causing down-regulation of genes involved in cell cycle control and DNA repair. Biochem Pharmacol 84:1571–1580. CrossRefPubMedPubMedCentralGoogle Scholar
  7. Arango D, Morohashi K, Yilmaz A, Kuramochi K, Parihar A, Brahimaj B, Grotewold E, Doseff AI (2013) Molecular basis for the action of a dietary flavonoid revealed by the comprehensive identification of apigenin human targets. Proc Natl Acad Sci 110:E2153–E2162. CrossRefPubMedPubMedCentralGoogle Scholar
  8. Bai H, Jin H, Yang F, Zhu H, Cai J (2014) Apigenin induced MCF-7 cell apoptosis-associated reactive oxygen species. Scanning 36:622–631. CrossRefPubMedGoogle Scholar
  9. Bak MJ, Das Gupta S, Wahler J, Suh N (2016) Role of dietary bioactive natural products in estrogen receptor-positive breast cancer. Semin Cancer Biol 40-41:170–191. CrossRefPubMedPubMedCentralGoogle Scholar
  10. Begum N, Prasad NR, Kanimozhi G, Hasan AQ (2012) Apigenin ameliorates gamma radiation-induced cytogenetic alterations in cultured human blood lymphocytes. Mutat Res 747:71–76. CrossRefPubMedGoogle Scholar
  11. Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254CrossRefPubMedGoogle Scholar
  12. Budhraja A, Gao N, Zhang Z, Son YO, Cheng S, Wang X, Ding S, Hitron A, Chen G, Luo J, Shi X (2012) Apigenin induces apoptosis in human leukemia cells and exhibits anti-leukemic activity in vivo. Mol Cancer Ther 11:132–142. CrossRefPubMedGoogle Scholar
  13. Caltagirone S, Rossi C, Poggi A, Ranelletti FO, Natali PG, Brunetti M, Aiello FB, Piantelli M (2000) Flavonoids apigenin and quercetin inhibit melanoma growth and metastatic potential. Int J Cancer 87:595–600.<595::AID-IJC21>3.0.CO;2-5 CrossRefPubMedGoogle Scholar
  14. Cao X, Liu B, Cao W, Zhang W, Zhang F, Zhao H, Meng R, Zhang L, Niu R, Hao X, Zhang B (2013) Autophagy inhibition enhances apigenin-induced apoptosis in human breast cancer cells. Chin J Cancer Res 25:212–222. PubMedPubMedCentralGoogle Scholar
  15. Carruba G, Cocciadiferro L, Di Cristina A, Granata OM, Dolcemascolo C, Campisi I, Zarcone M, Cinquegrani M, Traina A (2016) Nutrition, aging and cancer: lessons from dietary intervention studies. Immun Ageing 13:13. CrossRefPubMedPubMedCentralGoogle Scholar
  16. Chacón RD, Costanzo MV (2010) Triple-negative breast cancer. Breast Cancer Res 12:S3. CrossRefPubMedPubMedCentralGoogle Scholar
  17. Chen W-Y, Hsieh Y-A, Tsai C-I, Kang YF, Chang FR, Wu YC, Wu CC (2011) Protoapigenone, a natural derivative of apigenin, induces mitogen-activated protein kinase-dependent apoptosis in human breast cancer cells associated with induction of oxidative stress and inhibition of glutathione S-transferase π. Investig New Drugs 29:1347–1359. CrossRefGoogle Scholar
  18. Chen M, Wang X, Zha D, Cai F, Zhang W, He Y, Huang Q, Zhuang H, Hua ZC (2016) Apigenin potentiates TRAIL therapy of non-small cell lung cancer via upregulating DR4/DR5 expression in a p53-dependent manner. Sci Rep 6:35468. CrossRefPubMedPubMedCentralGoogle Scholar
  19. Choi EJ, Kim GH (2009a) 5-Fluorouracil combined with apigenin enhances anticancer activity through induction of apoptosis in human breast cancer MDA-MB-453 cells. Oncol Rep 22:1533–1537. CrossRefPubMedGoogle Scholar
  20. Choi EJ, Kim GH (2009b) Apigenin causes G2/M arrest associated with the modulation of p21Cip1 and Cdc2 and activates p53-dependent apoptosis pathway in human breast cancer SK-BR-3 cells. J Nutr Biochem 20:285–290. CrossRefPubMedGoogle Scholar
  21. Choudhury D, Ganguli A, Dastidar DG, Acharya BR, Das A, Chakrabarti G (2013) Apigenin shows synergistic anticancer activity with curcumin by binding at different sites of tubulin. Biochimie 95:1297–1309. CrossRefPubMedGoogle Scholar
  22. Cleator S, Heller W, Coombes RC (2007) Triple-negative breast cancer: therapeutic options. Lancet Oncol 8:235–244. CrossRefPubMedGoogle Scholar
  23. Domijan A-M, Ralić J, Radić Brkanac S, Rumora L, Žanić-Grubišić T (2015) Quantification of malondialdehyde by HPLC-FL - application to various biological samples. Biomed Chromatogr 29:41–46. CrossRefPubMedGoogle Scholar
  24. Donepudi MS, Kondapalli K, Amos SJ, Venkanteshan P (2014) Breast cancer statistics and markers. J Cancer Res Ther 10:506–511. PubMedGoogle Scholar
  25. Duke RC, Cohen JJ (1992) Morphological and biochemical assays of apoptosis. In: Coligan JE, Kruis Beaal AM (eds) Current protocols in immunology. John Willey & Sons, New York, pp 1–3Google Scholar
  26. Eastman A (1990) Activation of programmed cell death by anticancer agents: cisplatin as a model system. Cancer Cells 2:275–280PubMedGoogle Scholar
  27. Efferth T, Li PCH, Konkimalla VSB, Kaina B (2007) From traditional Chinese medicine to rational cancer therapy. Trends Mol Med 13:353–361. CrossRefPubMedGoogle Scholar
  28. Efferth T, Kahl S, Paulus K, Adams M, Rauh R, Boechzelt H, Hao X, Kaina B, Bauer R (2008) Phytochemistry and pharmacogenomics of natural products derived from traditional Chinese medicine and Chinese materia medica with activity against tumor cells. Mol Cancer Ther 7:152–161. CrossRefPubMedGoogle Scholar
  29. Ferrini K, Ghelfi F, Mannucci R, Titta L (2015) Lifestyle, nutrition and breast cancer: facts and presumptions for consideration. Ecancermedicalscience 9:557. CrossRefPubMedPubMedCentralGoogle Scholar
  30. Gajski G, Jelčić Ž, Oreščanin V, Gerić M, Kollar R, Garaj-Vrhovac V (2014) Physico-chemical characterization and the in vitro genotoxicity of medical implants metal alloy (TiAlV and CoCrMo) and polyethylene particles in human lymphocytes. Biochim Biophys Acta Gen Subj 1840:565–576. CrossRefGoogle Scholar
  31. Garaj-Vrhovac V, Gajski G (2009) Evaluation of the cytogenetic status of human lymphocytes after exposure to a high concentration of bee venom in vitro. Arh Hig Rada Toksikol 60:27–34. CrossRefPubMedGoogle Scholar
  32. Gobeil S, Boucher CC, Nadeau D, Poirier GG (2001) Characterization of the necrotic cleavage of poly(ADP-ribose) polymerase (PARP-1): implication of lysosomal proteases. Cell Death Differ 8:588–594. CrossRefPubMedGoogle Scholar
  33. Gupta S, Afaq F, Mukhtar H (2001) Selective growth-inhibitory, cell-cycle deregulatory and apoptotic response of apigenin in normal versus human prostate carcinoma cells. Biochem Biophys Res Commun 287:914–920. CrossRefPubMedGoogle Scholar
  34. Halliwell B, Gutteridge JMC (1989) Free radicals in biology and medicine. Clarendon Press, OxfordGoogle Scholar
  35. Harrison ME, Power Coombs MR, Delaney LM, Hoskin DW (2014) Exposure of breast cancer cells to a subcytotoxic dose of apigenin causes growth inhibition, oxidative stress, and hypophosphorylation of Akt. Exp Mol Pathol 97:211–217. CrossRefPubMedGoogle Scholar
  36. Higdon JV, Delage B, Williams DE, Dashwood RH (2007) Cruciferous vegetables and human cancer risk: epidemiologic evidence and mechanistic basis. Pharmacol Res 55:224–236. CrossRefPubMedPubMedCentralGoogle Scholar
  37. Hudis CA, Gianni L (2011) Triple-negative breast cancer: an unmet medical need. Oncologist 16(Suppl 1):1–11. CrossRefPubMedGoogle Scholar
  38. Hyuga S, Hyuga M, Yoshimura M, Amakura Y, Goda Y, Hanawa T (2013) Herbacetin, a constituent of ephedrae herba, suppresses the HGF-induced motility of human breast cancer MDA-MB-231 cells by inhibiting c-met and akt phosphorylation. Planta Med 79:1525–1530. CrossRefPubMedGoogle Scholar
  39. Inbar-Rozensal D, Castiel A, Visochek L, Castel D, Dantzer F, Izraeli S, Cohen-Armon M (2009) A selective eradication of human nonhereditary breast cancer cells by phenanthridine-derived polyADP-ribose polymerase inhibitors. Breast Cancer Res 11:1–11. CrossRefGoogle Scholar
  40. Inic Z, Zegarac M, Inic M, Markovic I, Kozomara Z, Djurisic I, Inic I, Pupic G, Jancic S (2014) Difference between luminal a and luminal B subtypes according to Ki-67, tumor size, and progesterone receptor negativity providing prognostic information. Clin Med Insights Oncol 8:107–111. CrossRefPubMedPubMedCentralGoogle Scholar
  41. Jia T, Zhang L, Duan Y, Zhang M, Wang G, Zhang J, Zhao Z (2014) The differential susceptibilities of MCF-7 and MDA-MB-231 cells to the cytotoxic effects of curcumin are associated with the PI3K/Akt-SKP2- Cip/Kips pathway. Cancer Cell Int 14:126. CrossRefPubMedPubMedCentralGoogle Scholar
  42. Kasibhatla S, Amarante-Mendes GP, Finucane D, Brunner T, Bossy-Wetzel E, Green DR (2006) Acridine Orange/Ethidium Bromide (AO/EB) staining to detect apoptosis. CSH Protocol.
  43. Khan HY, Zubair H, Ullah MF, Ahmad A, Hadi SM (2012) A prooxidant mechanism for the anticancer and chemopreventive properties of plant polyphenols. Curr Drug Targets 13:1738–1749. CrossRefPubMedGoogle Scholar
  44. King JC, Lu QY, Li G, Moro A, Takahashi H, Chen M, Go VLW, Reber HA, Eibl G, Hines OJ (2012) Evidence for activation of mutated p53 by apigenin in human pancreatic cancer. Biochim Biophys Acta Mol Cell Res 1823:593–604. CrossRefGoogle Scholar
  45. Lee W-J, Chen W-K, Wang C-J, Lin WL, Tseng TH (2008) Apigenin inhibits HGF-promoted invasive growth and metastasis involving blocking PI3K/Akt pathway and β4 integrin function in MDA-MB-231 breast cancer cells. Toxicol Appl Pharmacol 226:178–191. CrossRefPubMedGoogle Scholar
  46. Liao Y, Shen W, Kong G, Lv H, Tao W, Bo P (2014) Apigenin induces the apoptosis and regulates MAPK signaling pathways in mouse macrophage ANA-1 cells. PLoS One 9:1–8. Google Scholar
  47. Lin C-H, Chang C-Y, Lee K-R, Lin HJ, Chen TH, Wan L (2015) Flavones inhibit breast cancer proliferation through the Akt/FOXO3a signaling pathway. BMC Cancer 15:958. CrossRefPubMedPubMedCentralGoogle Scholar
  48. Lindenmeyer F, Li H, Menashi S, Soria C, Lu H (2001) Apigenin acts on the tumor cell invasion process and regulates protease production. Nutr Cancer 39:139–147. CrossRefPubMedGoogle Scholar
  49. Long X, Fan M, Bigsby RM, Nephew KP (2008) Apigenin inhibits Antiestrogen-resistant breast cancer cell growth through estrogen receptor-α-dependent and - independent mechanisms. Mol Cancer Ther 7:2096–2108. CrossRefPubMedPubMedCentralGoogle Scholar
  50. Lu H-F, Chie Y-J, Yang M-S, Lee CS, Fu JJ, Yang JS, Tan TW, Wu SH, Ma YS, Ip SW, Chung JG (2010) Apigenin induces caspase-dependent apoptosis in human lung cancer A549 cells through Bax- and Bcl-2-triggered mitochondrial pathway. Int J Oncol 36:1477–1484CrossRefPubMedGoogle Scholar
  51. Lu H-F, Chie Y-J, Yang M-S, Lu KW, Fu JJ, Yang JS, Chen HY, Hsia TC, Ma CY, Ip SW, Chung JG (2011) Apigenin induces apoptosis in human lung cancer H460 cells through caspase- and mitochondria-dependent pathways. Hum Exp Toxicol 30:1053–1061. CrossRefPubMedGoogle Scholar
  52. Madunić J, Vrhovac Madunić I, Gajski G, Popić J, Garaj-Vrhovac V (2018) Apigenin: a dietary flavonoid with diverse anticancer properties. Cancer Lett 413:11–22. CrossRefPubMedGoogle Scholar
  53. Mafuvadze B, Cook M, Xu Z, Besch-Williford CL, Hyder SM (2013) Effects of dietary apigenin on tumor latency, incidence and multiplicity in a medroxyprogesterone acetate-accelerated 7,12-dimethylbenz(a)anthracene-induced breast cancer model. Nutr Cancer 65:1184–1191. CrossRefPubMedGoogle Scholar
  54. Marnett LJ (1999) Chemistry and biology of DNA damage by malondialdehyde. IARC Sci Publ 150:17–27Google Scholar
  55. Matsuo M, Sasaki N, Saga K, Kaneko T (2005) Cytotoxicity of flavonoids toward cultured normal human cells. Biol Pharm Bull 28:253–259. CrossRefPubMedGoogle Scholar
  56. Metzger-Filho O, Sun Z, Viale G, Price KN, Crivellari D, Snyder RD, Gelber RD, Castiglione-Gertsch M, Coates AS, Goldhirsch A, Cardoso F (2013) Patterns of recurrence and outcome according to breast cancer subtypes in lymph node-negative disease: results from International Breast Cancer Study Group Trials VIII and IX. J Clin Oncol 31:3083–3090. CrossRefPubMedPubMedCentralGoogle Scholar
  57. Mickisch G, Fajta S, Keilhauer G, Schlick E, Tschada R, Alken P (1990) Chemosensitivity testing of primary human renal cell carcinoma by a tetrazolium based microculture assay (MTT). Urol Res 18:131–136CrossRefPubMedGoogle Scholar
  58. Morrissey C, O’Neill A, Spengler B, Christoffel V, Fitzpatrick JM, Watson RW (2005) Apigenin drives the production of reactive oxygen species and initiates a mitochondrial mediated cell death pathway in prostate epithelial cells. Prostate 63:131–142. CrossRefPubMedGoogle Scholar
  59. Naasani I, Oh-Hashi F, Oh-Hara T, Feng WY, Johnston J, Chan K, Tsuruo T (2003) Blocking telomerase by dietary polyphenols is a major mechanism for limiting the growth of human cancer cells in vitro and in vivo. Cancer Res 63:824–830. PubMedGoogle Scholar
  60. Nabavi SM, Habtemariam S, Daglia M, Nabavi SF (2015) Apigenin and breast cancers: from chemistry to medicine. Anti Cancer Agents Med Chem 15:728–735CrossRefGoogle Scholar
  61. Neve RM, Chin K, Fridlyand J, Yeh J, Baehner FL, Fevr T, Clark L, Bayani N, Coppe JP, Tong F, Speed T, Spellman PT, DeVries S, Lapuk A, Wang NJ, Kuo WL, Stilwell JL, Pinkel D, Albertson DG, Waldman FM, McCormick F, Dickson RB, Johnson MD, Lippman M, Ethier S, Gazdar A, Gray JW (2006) A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes. Cancer Cell 10:515–527. CrossRefPubMedPubMedCentralGoogle Scholar
  62. Noel S, Kasinathan M, Rath SK (2006) Evaluation of apigenin using in vitro cytochalasin blocked micronucleus assay. Toxicol Vitro 20:1168–1172. CrossRefGoogle Scholar
  63. O’Prey J, Brown J, Fleming J, Harrison PR (2003) Effects of dietary flavonoids on major signal transduction pathways in human epithelial cells. Biochem Pharmacol 66:2075–2088CrossRefPubMedGoogle Scholar
  64. Patel D, Shukla S, Gupta S (2007) Apigenin and cancer chemoprevention: progress, potential and promise (review). Int J Oncol 30:233–245PubMedGoogle Scholar
  65. Perou CM, Sørlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA, Fluge Ø, Pergamenschikov A, Williams C, Zhu SX, Lønning PE, Børresen-Dale AL, Brown PO, Botstein D (2000) Molecular portraits of human breast tumours. Nature 406:747–752. CrossRefPubMedGoogle Scholar
  66. Ravishankar D, Rajora AK, Greco F, Osborn HMI (2013) Flavonoids as prospective compounds for anti-cancer therapy. Int J Biochem Cell Biol 45:2821–2831. CrossRefPubMedGoogle Scholar
  67. Romagnolo DF, Selmin OI (2012) Flavonoids and cancer prevention: a review of the evidence. J Nutr Gerontol Geriatr 31:206–238. CrossRefPubMedGoogle Scholar
  68. Rusak G, Piantanida I, Masić L, Kapuralin K, Durgo K, Kopjar N (2010) Spectrophotometric analysis of flavonoid-DNA interactions and DNA damaging/protecting and cytotoxic potential of flavonoids in human peripheral blood lymphocytes. Chem Biol Interact 188:181–189. CrossRefPubMedGoogle Scholar
  69. Sak K (2014) Cytotoxicity of dietary flavonoids on different human cancer types. Pharmacogn Rev 8:122–146. CrossRefPubMedPubMedCentralGoogle Scholar
  70. Scherbakov AM, Andreeva OE (2015) Apigenin inhibits growth of breast cancer cells: the role of ERalpha and HER2/neu. Acta Nat 7:133–139Google Scholar
  71. Seo YJ, Kim BS, Chun SY, Park YK, Kang KS, Kwon TG (2011) Apoptotic effects of genistein, biochanin-A and apigenin on LNCaP and PC-3 cells by p21 through transcriptional inhibition of polo-like kinase-1. J Korean Med Sci 26:1489–1494. CrossRefPubMedPubMedCentralGoogle Scholar
  72. Seo HS, Ku JM, Choi HS, Woo JK, Jang BH, Go H, Shin YC, Ko SG (2015a) Apigenin induces caspase-dependent apoptosis by inhibiting signal transducer and activator of transcription 3 signaling in HER2-overexpressing SKBR3 breast cancer cells. Mol Med Rep 12:2977–2984.
  73. Seo HS, Jo JK, Ku JM, Choi HS, Choi YK, Woo JK, Kim HI, Kang SY, Lee KM, Nam KW, Park N, Jang BH, Shin YC, Ko SG (2015b) Induction of caspase-dependent extrinsic apoptosis by apigenin through inhibition of signal transducer and activator of transcription 3 (STAT3) signaling in HER2-overexpressing BT-474 breast cancer cells. Biosci Rep 3:BSR20150165.
  74. Sharma NK (2013) Modulation of radiation-induced and mitomycin C-induced chromosome damage by apigenin in human lymphocytes in vitro. J Radiat Res 54:789–797. CrossRefPubMedPubMedCentralGoogle Scholar
  75. Sharma N, Dobhal M, Joshi Y, Chahar M (2011) Flavonoids: a versatile source of anticancer drugs. Pharmacogn Rev 5:1–12. CrossRefPubMedPubMedCentralGoogle Scholar
  76. Shukla S, Gupta S (2008) Apigenin-induced prostate cancer cell death is initiated by reactive oxygen species and p53 activation. Free Radic Biol Med 44:1833–1845. CrossRefPubMedPubMedCentralGoogle Scholar
  77. Shukla S, Gupta S (2010) Apigenin: a promising molecule for cancer prevention. Pharm Res 27:962–978. CrossRefPubMedPubMedCentralGoogle Scholar
  78. Siddique YH, Ara G, Beg T, Afzal M (2010) Anticlastogenic effect of apigenin in human lymphocytes treated with ethinylestradiol. Fitoterapia 81:590–594. CrossRefPubMedGoogle Scholar
  79. Simon HU, Haj-Yehia A, Levi-Schaffer F (2000) Role of reactive oxygen species (ROS) in apoptosis induction. Apoptosis 5:415–418CrossRefPubMedGoogle Scholar
  80. Singh NP, McCoy MT, Tice RR, Schneider EL (1988) A simple technique for quantitation of low levels of DNA damage in individual cells. Exp Cell Res 175:184–191. CrossRefPubMedGoogle Scholar
  81. Singh S, Sharma B, Kanwar SS, Kumar A (2016) Lead phytochemicals for anticancer drug development. Front Plant Sci 7:1–13. Google Scholar
  82. Sotiriou C, Neo SY, McShane LM, Korn EL, Long PM, Jazaeri A, Martiat P, Fox SB, Harris AL, Liu ET (2003) Breast cancer classification and prognosis based on gene expression profiles from a population-based study. Proc Natl Acad Sci 100:10393–10398. CrossRefPubMedPubMedCentralGoogle Scholar
  83. Sun S-Y, Hail N, Lotan R (2004) Apoptosis as a novel target for cancer chemoprevention. J Natl Cancer Inst 96:662–672. CrossRefPubMedGoogle Scholar
  84. Sung B, Chung HY, Kim ND (2016) Role of apigenin in cancer prevention via the induction of apoptosis and autophagy. J Cancer Prev 21:216–226CrossRefPubMedPubMedCentralGoogle Scholar
  85. Thiery-Vuillemin A, Nguyen T, Pivot X, Spano JP, Dufresnne A, Soria JC (2005) Molecularly targeted agents: their promise as cancer chemopreventive interventions. Eur J Cancer 41:2003–2015. CrossRefPubMedGoogle Scholar
  86. Tseng T-H, Chien M-H, Lin W-L, Wen YC, Chow JM, Chen CK, Kuo TC, Lee WJ (2017) Inhibition of MDA-MB-231 breast cancer cell proliferation and tumor growth by apigenin through induction of G2/M arrest and histone H3 acetylation-mediated p21 WAF1/CIP1 expression. Environ Toxicol 32:434–444. CrossRefPubMedGoogle Scholar
  87. Wang ZC, Lin M, Wei L-J, Li C, Miron A, Lodeiro G, Harris L, Ramaswamy S, Tanenbaum DM, Meyerson M, Iglehart JD, Richardson A (2004) Loss of heterozygosity and its correlation with expression profiles in subclasses of invasive breast cancers. Cancer Res 64:64–71CrossRefPubMedGoogle Scholar
  88. Wilsher NE, Arroo RR, Matsoukas MT, Tsatsakis AM, Spandidos DA, Androutsopoulos VP (2017) Cytochrome P450 CYP1 metabolism of hydroxylated flavones and flavonols: selective bioactivation of luteolin in breast cancer cells. Food Chem Toxicol 110:383–394. CrossRefPubMedGoogle Scholar
  89. Zhao G, Han X, Cheng W, Ni J, Zhang Y, Lin J, Song Z (2017) Apigenin inhibits proliferation and invasion, and induces apoptosis and cell cycle arrest in human melanoma cells. Oncol Rep 37:2277–2285. CrossRefPubMedGoogle Scholar
  90. Zhou Y, Zheng J, Li Y, Xu DP, Li S, Chen YM, Li HB (2016) Natural polyphenols for prevention and treatment of cancer. Nutrients 8:515. CrossRefPubMedCentralGoogle Scholar
  91. Zhu H, Jin H, Pi J, Bai H, Yang F, Wu C, Jiang J, Cai J (2016) Apigenin induced apoptosis in esophageal carcinoma cells by destruction membrane structures. Scanning 38:322–328. CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Molecular Toxicology UnitInstitute for Medical Research and Occupational HealthZagrebCroatia
  2. 2.Department of Molecular Biology, Faculty of ScienceUniversity of ZagrebZagrebCroatia
  3. 3.Laboratory for Cell Biology and Signalling, Division of Molecular BiologyRuđer Bošković InstituteZagrebCroatia
  4. 4.Mutagenesis UnitInstitute for Medical Research and Occupational HealthZagrebCroatia

Personalised recommendations