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

Vrhovac Madunić, Ivana; Madunić, Josip; Antunović, Maja; Paradžik, Mladen; Garaj-Vrhovac, Vera; Breljak, Davorka; Marijanović, Inga; Gajski, Goran

doi:10.1007/s00210-018-1486-4

Original Article
Published: 14 March 2018

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

Ivana Vrhovac Madunić¹,
Josip Madunić²,
Maja Antunović²,
Mladen Paradžik³,
Vera Garaj-Vrhovac⁴,
Davorka Breljak¹,
Inga Marijanović² &
Goran Gajski ORCID: orcid.org/0000-0002-1886-1453⁴

Naunyn-Schmiedeberg's Archives of Pharmacology volume 391, pages 537–550 (2018)Cite this article

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Abstract

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.

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References

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. https://doi.org/10.3390/nu8090581
Article PubMed Central Google Scholar
Abdull Razis AF, Noor NM (2013) Cruciferous vegetables: dietary phytochemicals for cancer prevention. Asian Pac J Cancer Prev 14:1565–1570
Article PubMed Google Scholar
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. https://doi.org/10.1016/j.yexmp.2006.07.001
CAS Article PubMed Google Scholar
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. https://doi.org/10.1007/s11095-008-9661-9
CAS Article PubMed PubMed Central Google Scholar
Anders CK, Carey LA (2009) Biology, metastatic patterns, and treatment of patients with triple-negative breast cancer. Clin Breast Cancer 9:S73–S81. https://doi.org/10.3816/CBC.2009.s.008
CAS Article PubMed PubMed Central Google Scholar
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. https://doi.org/10.1016/j.bcp.2012.09.005
CAS Article PubMed PubMed Central Google Scholar
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. https://doi.org/10.1073/pnas.1303726110
CAS Article PubMed PubMed Central Google Scholar
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. https://doi.org/10.1002/sca.21170
CAS Article PubMed Google Scholar
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. https://doi.org/10.1016/j.semcancer.2016.03.001
CAS Article PubMed PubMed Central Google Scholar
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. https://doi.org/10.1016/j.mrgentox.2012.04.001
CAS Article PubMed Google Scholar
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 72:248–254
CAS Article PubMed Google Scholar
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. https://doi.org/10.1158/1535-7163.MCT-11-0343
CAS Article PubMed Google Scholar
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. https://doi.org/10.1002/1097-0215(20000815)87:4<595::AID-IJC21>3.0.CO;2-5
CAS Article PubMed Google Scholar
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. https://doi.org/10.3978/j.issn.1000-9604.2013.04.01
PubMed PubMed Central Google Scholar
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. https://doi.org/10.1186/s12979-016-0069-9
Article PubMed PubMed Central Google Scholar
Chacón RD, Costanzo MV (2010) Triple-negative breast cancer. Breast Cancer Res 12:S3. https://doi.org/10.1186/bcr2574
Article PubMed PubMed Central Google Scholar
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. https://doi.org/10.1007/s10637-010-9497-0
CAS Article Google Scholar
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. https://doi.org/10.1038/srep35468
CAS Article PubMed PubMed Central Google Scholar
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. https://doi.org/10.3892/or_00000598
CAS Article PubMed Google Scholar
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. https://doi.org/10.1016/j.jnutbio.2008.03.005
CAS Article PubMed Google Scholar
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. https://doi.org/10.1016/j.biochi.2013.02.010
CAS Article PubMed Google Scholar
Cleator S, Heller W, Coombes RC (2007) Triple-negative breast cancer: therapeutic options. Lancet Oncol 8:235–244. https://doi.org/10.1016/S1470-2045(07)70074-8
Article PubMed Google Scholar
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. https://doi.org/10.1002/bmc.3361
CAS Article PubMed Google Scholar
Donepudi MS, Kondapalli K, Amos SJ, Venkanteshan P (2014) Breast cancer statistics and markers. J Cancer Res Ther 10:506–511. https://doi.org/10.4103/0973-1482.137927
PubMed Google Scholar
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 1–3
Google Scholar
Eastman A (1990) Activation of programmed cell death by anticancer agents: cisplatin as a model system. Cancer Cells 2:275–280
CAS PubMed Google Scholar
Efferth T, Li PCH, Konkimalla VSB, Kaina B (2007) From traditional Chinese medicine to rational cancer therapy. Trends Mol Med 13:353–361. https://doi.org/10.1016/j.molmed.2007.07.001
CAS Article PubMed Google Scholar
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. https://doi.org/10.1158/1535-7163.MCT-07-0073
CAS Article PubMed Google Scholar
Ferrini K, Ghelfi F, Mannucci R, Titta L (2015) Lifestyle, nutrition and breast cancer: facts and presumptions for consideration. Ecancermedicalscience 9:557. https://doi.org/10.3332/ecancer.2015.557
Article PubMed PubMed Central Google Scholar
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. https://doi.org/10.1016/j.bbagen.2013.10.015
CAS Article Google Scholar
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. https://doi.org/10.2478/10004-1254-60-2009-1896
Article PubMed Google Scholar
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. https://doi.org/10.1038/sj.cdd.4400851
CAS Article PubMed Google Scholar
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. https://doi.org/10.1006/bbrc.2001.5672
CAS Article PubMed Google Scholar
Halliwell B, Gutteridge JMC (1989) Free radicals in biology and medicine. Clarendon Press, Oxford
Google Scholar
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. https://doi.org/10.1016/j.yexmp.2014.07.006
CAS Article PubMed Google Scholar
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. https://doi.org/10.1016/j.phrs.2007.01.009
CAS Article PubMed PubMed Central Google Scholar
Hudis CA, Gianni L (2011) Triple-negative breast cancer: an unmet medical need. Oncologist 16(Suppl 1):1–11. https://doi.org/10.1634/theoncologist.2011-S1-01
Article PubMed Google Scholar
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. https://doi.org/10.1055/s-0033-1350899
CAS Article PubMed Google Scholar
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. https://doi.org/10.1186/bcr2445
Article Google Scholar
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. https://doi.org/10.4137/CMO.s18006
CAS Article PubMed PubMed Central Google Scholar
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. https://doi.org/10.1186/s12935-014-0126-4
Article PubMed PubMed Central Google Scholar
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. https://doi.org/10.1101/pdb.prot4493
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. https://doi.org/10.2174/138945012804545560
CAS Article PubMed Google Scholar
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. https://doi.org/10.1016/j.bbamcr.2011.12.008
CAS Article Google Scholar
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. https://doi.org/10.1016/j.taap.2007.09.013
CAS Article PubMed Google Scholar
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. https://doi.org/10.1371/journal.pone.0092007
Google Scholar
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. https://doi.org/10.1186/s12885-015-1965-7
Article PubMed PubMed Central Google Scholar
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. https://doi.org/10.1207/S15327914nc391_19
CAS Article PubMed Google Scholar
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. https://doi.org/10.1158/1535-7163.MCT-07-2350
CAS Article PubMed PubMed Central Google Scholar
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 36:1477–1484
CAS Article PubMed Google Scholar
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. https://doi.org/10.1177/0960327110386258
CAS Article PubMed Google Scholar
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. https://doi.org/10.1016/j.canlet.2017.10.041
Article PubMed Google Scholar
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. https://doi.org/10.1080/01635581.2013.833637
CAS Article PubMed Google Scholar
Marnett LJ (1999) Chemistry and biology of DNA damage by malondialdehyde. IARC Sci Publ 150:17–27
CAS Google Scholar
Matsuo M, Sasaki N, Saga K, Kaneko T (2005) Cytotoxicity of flavonoids toward cultured normal human cells. Biol Pharm Bull 28:253–259. https://doi.org/10.1248/bpb.28.253
CAS Article PubMed Google Scholar
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. https://doi.org/10.1200/JCO.2012.46.1574
CAS Article PubMed PubMed Central Google Scholar
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 18:131–136
CAS Article PubMed Google Scholar
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. https://doi.org/10.1002/pros.20167
CAS Article PubMed Google Scholar
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. https://doi.org/10.1146/annurev.nutr.21.1.381
CAS PubMed Google Scholar
Nabavi SM, Habtemariam S, Daglia M, Nabavi SF (2015) Apigenin and breast cancers: from chemistry to medicine. Anti Cancer Agents Med Chem 15:728–735
CAS Article Google Scholar
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. https://doi.org/10.1016/j.ccr.2006.10.008
CAS Article PubMed PubMed Central Google Scholar
Noel S, Kasinathan M, Rath SK (2006) Evaluation of apigenin using in vitro cytochalasin blocked micronucleus assay. Toxicol Vitro 20:1168–1172. https://doi.org/10.1016/j.tiv.2006.03.007
CAS Article Google Scholar
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 66:2075–2088
Article PubMed Google Scholar
Patel D, Shukla S, Gupta S (2007) Apigenin and cancer chemoprevention: progress, potential and promise (review). Int J Oncol 30:233–245
CAS PubMed Google Scholar
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. https://doi.org/10.1038/35021093
CAS Article PubMed Google Scholar
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. https://doi.org/10.1016/j.biocel.2013.10.004
CAS Article PubMed Google Scholar
Romagnolo DF, Selmin OI (2012) Flavonoids and cancer prevention: a review of the evidence. J Nutr Gerontol Geriatr 31:206–238. https://doi.org/10.1080/21551197.2012.702534
Article PubMed Google Scholar
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. https://doi.org/10.1016/j.cbi.2010.07.008
CAS Article PubMed Google Scholar
Sak K (2014) Cytotoxicity of dietary flavonoids on different human cancer types. Pharmacogn Rev 8:122–146. https://doi.org/10.4103/0973-7847.134247
CAS Article PubMed PubMed Central Google Scholar
Scherbakov AM, Andreeva OE (2015) Apigenin inhibits growth of breast cancer cells: the role of ERalpha and HER2/neu. Acta Nat 7:133–139
CAS Google Scholar
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. https://doi.org/10.3346/jkms.2011.26.11.1489
CAS Article PubMed PubMed Central Google Scholar
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. https://doi.org/10.3892/mmr.2015.3698
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. https://doi.org/10.1042/BSR20150165
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. https://doi.org/10.1093/jrr/rrs117
CAS Article PubMed PubMed Central Google Scholar
Sharma N, Dobhal M, Joshi Y, Chahar M (2011) Flavonoids: a versatile source of anticancer drugs. Pharmacogn Rev 5:1–12. https://doi.org/10.4103/0973-7847.79093
Article PubMed PubMed Central Google Scholar
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. https://doi.org/10.1016/j.freeradbiomed.2008.02.007
CAS Article PubMed PubMed Central Google Scholar
Shukla S, Gupta S (2010) Apigenin: a promising molecule for cancer prevention. Pharm Res 27:962–978. https://doi.org/10.1007/s11095-010-0089-7
CAS Article PubMed PubMed Central Google Scholar
Siddique YH, Ara G, Beg T, Afzal M (2010) Anticlastogenic effect of apigenin in human lymphocytes treated with ethinylestradiol. Fitoterapia 81:590–594. https://doi.org/10.1016/j.fitote.2010.02.003
CAS Article PubMed Google Scholar
Simon HU, Haj-Yehia A, Levi-Schaffer F (2000) Role of reactive oxygen species (ROS) in apoptosis induction. Apoptosis 5:415–418
CAS Article PubMed Google Scholar
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. https://doi.org/10.1016/0014-4827(88)90265-0
CAS Article PubMed Google Scholar
Singh S, Sharma B, Kanwar SS, Kumar A (2016) Lead phytochemicals for anticancer drug development. Front Plant Sci 7:1–13. https://doi.org/10.3389/fpls.2016.01667
CAS Google Scholar
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. https://doi.org/10.1073/pnas.1732912100
CAS Article PubMed PubMed Central Google Scholar
Sun S-Y, Hail N, Lotan R (2004) Apoptosis as a novel target for cancer chemoprevention. J Natl Cancer Inst 96:662–672. https://doi.org/10.1093/jnci/djh123
CAS Article PubMed Google Scholar
Sung B, Chung HY, Kim ND (2016) Role of apigenin in cancer prevention via the induction of apoptosis and autophagy. J Cancer Prev 21:216–226
Article PubMed PubMed Central Google Scholar
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. https://doi.org/10.1016/j.ejca.2005.06.005
CAS Article PubMed Google Scholar
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. https://doi.org/10.1002/tox.22247
CAS Article PubMed Google Scholar
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 64:64–71
CAS Article PubMed Google Scholar
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. https://doi.org/10.1016/j.fct.2017.10.051
CAS Article PubMed Google Scholar
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. https://doi.org/10.3892/or.2017.5450
CAS Article PubMed Google Scholar
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. https://doi.org/10.3390/nu8080515
Article PubMed Central Google Scholar
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. https://doi.org/10.1002/sca.21273
CAS Article PubMed Google Scholar

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Acknowledgments

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.

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Ivana Vrhovac Madunić and Josip Madunić contributed equally to this work.

Authors and Affiliations

Molecular Toxicology Unit, Institute for Medical Research and Occupational Health, Ksaverska cesta 2, 10000, Zagreb, Croatia
Ivana Vrhovac Madunić & Davorka Breljak
Department of Molecular Biology, Faculty of Science, University of Zagreb, Horvatovac 102a/2, 10000, Zagreb, Croatia
Josip Madunić, Maja Antunović & Inga Marijanović
Laboratory for Cell Biology and Signalling, Division of Molecular Biology, Ruđer Bošković Institute, Bijenička cesta 54, 10000, Zagreb, Croatia
Mladen Paradžik
Mutagenesis Unit, Institute for Medical Research and Occupational Health, Ksaverska cesta 2, 10000, Zagreb, Croatia
Vera Garaj-Vrhovac & Goran Gajski

Authors

Ivana Vrhovac Madunić
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Josip Madunić
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Maja Antunović
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Mladen Paradžik
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Vera Garaj-Vrhovac
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Davorka Breljak
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Inga Marijanović
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Goran Gajski
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Corresponding author

Correspondence to Goran Gajski.

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

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The authors declare that they have no conflicts of interest.

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Vrhovac Madunić, I., Madunić, J., Antunović, M. et al. Apigenin, a dietary flavonoid, induces apoptosis, DNA damage, and oxidative stress in human breast cancer MCF-7 and MDA MB-231 cells. Naunyn-Schmiedeberg's Arch Pharmacol 391, 537–550 (2018). https://doi.org/10.1007/s00210-018-1486-4

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Received: 27 September 2017
Accepted: 06 March 2018
Published: 14 March 2018
Issue Date: May 2018
DOI: https://doi.org/10.1007/s00210-018-1486-4

Keywords

Apigenin
Breast cancer cells
Human lymphocytes
Cytogenotoxicity
Apoptosis
Anticancer effect