Induction of Cancer Cell Death by Apigenin: A Review on Different Cell
Death Pathways

Peyman      Amini; Reza      Moazamiyanfar; Mohammad   Sedigh   Dakkali; Emad      Jafarzadeh; Maryam      Ganjizadeh; Nima      Rastegar-Pouyani; Kave      Moloudi; Ehsan      Khodamoradi; Shahram      Taeb; Masoud      Najafi
doi:10.2174/1389557523666230119110744
Abstract

Induction of cell death and inhibition of cell proliferation in cancer have been set as some of the main goals in anti-tumor therapy. Cancer cell resistance leads to less efficient cancer therapy, and consequently, to higher doses of anticancer drugs, which may eventually increase the risk of serious side effects in normal tissues. Apigenin, a nature-derived and herbal agent, which has shown anticancer properties in several types of cancer, can induce cell death directly and/or amplify the induction of cell death through other anti-tumor modalities. Although the main mechanism of apigenin in order to induce cell death is apoptosis, other cell death pathways, such as autophagic cell death, senescence, anoikis, necroptosis, and ferroptosis, have been reported to be induced by apigenin. It seems that apigenin enhances apoptosis by inducing anticancer immunity and tumor suppressor genes, like p53 and PTEN, and also by inhibiting STAT3 and NF-κB signaling pathways. Furthermore, it may induce autophagic cell death and ferroptosis by inducing endogenous ROS generation. Stimulation of ROS production and tumor suppressor genes, as well as downregulation of drug-resistance mediators, may induce other mechanisms of cell death, such as senescence, anoikis, and necroptosis. It seems that the induction of each type of cell death is highly dependent on the type of cancer. These modulatory actions of apigenin have been shown to enhance anticancer effects by other agents, such as ionizing radiation and chemotherapy drugs. This review explains how cancer cell death may be induced by apigenin at the cellular and molecular levels.
« Previous Next »
Graphical Abstract

[1]
khodamoradi, E.; Hoseini-Ghahfarokhi, M.; Amini, P.; Motevaseli, E.; Shabeeb, D.; Musa, A.E.; Najafi, M.; Farhood, B. Targets for pro-tection and mitigation of radiation injury. Cell. Mol. Life Sci.,  2020, 77(16), 3129-3159.
 [http://dx.doi.org/10.1007/s00018-020-03479-x] [PMID: 32072238]

[2]
Goldstein, M.; Kastan, M.B. The DNA damage response: Implications for tumor responses to radiation and chemotherapy. Annu. Rev. Med.,  2015, 66(1), 129-143.
 [http://dx.doi.org/10.1146/annurev-med-081313-121208] [PMID: 25423595]

[3]
Yu, C.; Yang, B.; Najafi, M. Targeting of cancer cell death mechanisms by curcumin: Implications to cancer therapy. Basic Clin. Pharmacol. Toxicol.,  2021, 129(6), 397-415.
 [http://dx.doi.org/10.1111/bcpt.13648] [PMID: 34473898]

[4]
Fu, X.; He, Y.; Li, M.; Huang, Z.; Najafi, M. Targeting of the tumor microenvironment by curcumin. Biofactors,  2021, 47(6), 914-932.
 [http://dx.doi.org/10.1002/biof.1776] [PMID: 34375483]

[5]
Cao, W.; Gu, Y.; Meineck, M.; Xu, H. The combination of chemotherapy and radiotherapy towards more efficient drug delivery. Chem. Asian J.,  2014, 9(1), 48-57.
 [http://dx.doi.org/10.1002/asia.201301294] [PMID: 24347066]

[6]
Wirsdörfer, F.; de Leve, S.; Jendrossek, V. Combining radiotherapy and immunotherapy in lung cancer: Can we expect limitations due to altered normal tissue toxicity? Int. J. Mol. Sci.,  2018, 20(1), 24.
 [http://dx.doi.org/10.3390/ijms20010024] [PMID: 30577587]

[7]
Nodooshan, S.J.; Amini, P.; Ashrafizadeh, M.; Tavakoli, S.; Aryafar, T.; Khalafi, L.; Musa, A.E.; Mahdavi, S.R.; Najafi, M.; Ahmadi, A.; Farhood, B. Suberosin attenuates the proliferation of MCF-7 breast cancer cells in combination with radiotherapy or hyperthermi. Curr. Drug Res. Rev.,  2020, 13(2), 148-153.
 [PMID: 33371865]

[8]
De Ruysscher, D.; Niedermann, G.; Burnet, N.G.; Siva, S.; Lee, A.W.; Hegi-Johnson, F. Radiotherapy toxicity. Nat. Rev. Dis. Primers,  2019, 5(1), 1-20.
 [PMID: 30617281]

[9]
Citrin, D.; Cotrim, A.P.; Hyodo, F.; Baum, B.J.; Krishna, M.C.; Mitchell, J.B. Radioprotectors and mitigators of radiation-induced normal tissue injury. Oncologist,  2010, 15(4), 360-371.
 [http://dx.doi.org/10.1634/theoncologist.2009-S104] [PMID: 20413641]

[10]
Ashrafizadeh, M.; Zarrabi, A.; Hashemi, F.; Moghadam, E.R.; Hashemi, F.; Entezari, M.; Hushmandi, K.; Mohammadinejad, R.; Najafi, M. Curcumin in cancer therapy: A novel adjunct for combination chemotherapy with paclitaxel and alleviation of its adverse effects. Life Sci.,  2020, 256, 117984.
 [http://dx.doi.org/10.1016/j.lfs.2020.117984] [PMID: 32593707]

[11]
Yang, A.K.; He, S.M.; Liu, L.; Liu, J.P.; Qian Wei, M.; Zhou, S.F. Herbal interactions with anticancer drugs: Mechanistic and clinical con-siderations. Curr. Med. Chem.,  2010, 17(16), 1635-1678.
 [http://dx.doi.org/10.2174/092986710791111279] [PMID: 20345351]

[12]
Ye, L.; Jia, Y.; Ji, K.; Sanders, A.J.; Xue, K.; Ji, J.; Mason, M.D.; Jiang, W.G. Traditional Chinese medicine in the prevention and treatment of cancer and cancer metastasis. Oncol. Lett.,  2015, 10(3), 1240-1250.
 [http://dx.doi.org/10.3892/ol.2015.3459] [PMID: 26622657]

[13]
Moslehi, M.; Rezaei, S.; Talebzadeh, P.; Ansari, M.J.; Jawad, M.A.; Jalil, A.T.; Rastegar-Pouyani, N.; Jafarzadeh, E.; Taeb, S.; Najafi, M. Apigenin in cancer therapy: Prevention of genomic instability and anticancer mechanisms. Clin. Exp. Pharmacol. Physiol.,  2022, 1440-1681.13725.
 [http://dx.doi.org/10.1111/1440-1681.13725] [PMID: 36111951]

[14]
Wang, M.; Firrman, J.; Liu, L.; Yam, K. A review on flavonoid apigenin: Dietary intake, ADME, antimicrobial effects, and interactions with human gut microbiota. BioMed Res. Int.,  2019, 2019, 1-18.
 [http://dx.doi.org/10.1155/2019/7010467] [PMID: 31737673]

[15]
Bhagwat, S.; Haytowitz, D.B.; Holden, J.M. USDA database for the flavonoid content of selected foods, release 3; US Department of Agriculture: Beltsville, MD, USA, 2011, p. 159.

[16]
Ali, F.; Rahul; Naz, F.; Jyoti, S.; Siddique, Y.H. Health functionality of apigenin: A review. Int. J. Food Prop.,  2017, 20(6), 1197-1238.
 [http://dx.doi.org/10.1080/10942912.2016.1207188]

[17]
McKay, D.L.; Blumberg, J.B. A Review of the bioactivity and potential health benefits of chamomile tea (Matricaria recutita L.). Phytother. Res.,  2006, 20(7), 519-530.
 [http://dx.doi.org/10.1002/ptr.1900] [PMID: 16628544]

[18]
Hostetler, G.L.; Ralston, R.A.; Schwartz, S.J. Flavones: Food sources, bioavailability, metabolism, and bioactivity. Adv. Nutr.,  2017, 8(3), 423-435.
 [http://dx.doi.org/10.3945/an.116.012948] [PMID: 28507008]

[19]
Hostetler, G.L.; Riedl, K.M.; Schwartz, S.J. Effects of food formulation and thermal processing on flavones in celery and chamomile. Food Chem.,  2013, 141(2), 1406-1411.
 [http://dx.doi.org/10.1016/j.foodchem.2013.04.051] [PMID: 23790931]

[20]
DeRango-Adem, E.F.; Blay, J. Does oral apigenin have real potential for a therapeutic effect in the context of human gastrointestinal and other cancers? Front. Pharmacol.,  2021, 12(1196), 681477.
 [http://dx.doi.org/10.3389/fphar.2021.681477] [PMID: 34084146]

[21]
Zhang, J.; Liu, D.; Huang, Y.; Gao, Y.; Qian, S. Biopharmaceutics classification and intestinal absorption study of apigenin. Int. J. Pharm.,  2012, 436(1-2), 311-317.
 [http://dx.doi.org/10.1016/j.ijpharm.2012.07.002] [PMID: 22796171]

[22]
Kim, B.K.; Cho, A.R.; Park, D.J. Enhancing oral bioavailability using preparations of apigenin-loaded W/O/W emulsions: In vitro and in vivo evaluations. Food Chem.,  2016, 206, 85-91.
 [http://dx.doi.org/10.1016/j.foodchem.2016.03.052] [PMID: 27041302]

[23]
Shukla, R.; Kashaw, S.K.; Jain, A.P.; Lodhi, S. Fabrication of Apigenin loaded gellan gum–chitosan hydrogels (GGCH-HGs) for effective diabetic wound healing. Int. J. Biol. Macromol.,  2016, 91, 1110-1119.
 [http://dx.doi.org/10.1016/j.ijbiomac.2016.06.075] [PMID: 27344952]

[24]
Wu, W.; Zu, Y.; Wang, L.; Wang, L.; Wang, H.; Li, Y.; Wu, M.; Zhao, X.; Fu, Y. Preparation, characterization and antitumor activity evaluation of apigenin nanoparticles by the liquid antisolvent precipitation technique. Drug Deliv.,  2017, 24(1), 1713-1720.
 [http://dx.doi.org/10.1080/10717544.2017.1399302] [PMID: 29115900]

[25]
Ding, S.; Zhang, Z.; Song, J.; Cheng, X.; Jiang, J.; Jia, X. Enhanced bioavailability of apigenin via preparation of a carbon nanopowder solid dispersion. Int. J. Nanomedicine,  2014, 9, 2327-2333.
 [http://dx.doi.org/10.2147/IJN.S60938] [PMID: 24872695]

[26]
Huang, Y.; Zhao, X.; Zu, Y.; Wang, L.; Deng, Y.; Wu, M.; Wang, H. Enhanced solubility and bioavailability of apigenin via preparation of solid dispersions of mesoporous silica nanoparticles. Iran. J. Pharm. Res.,  2019, 18(1), 168-182.
 [PMID: 31089353]

[27]
Rajendran, I.; Dhandapani, H.; Anantanarayanan, R.; Rajaram, R. Apigenin mediated gold nanoparticle synthesis and their anti-cancer effect on human epidermoid carcinoma (A431) cells. RSC Advances,  2015, 5(63), 51055-51066.
 [http://dx.doi.org/10.1039/C5RA04303D]

[28]
Gurunathan, S.; Jeyaraj, M.; Kang, M.H.; Kim, J.H. The effects of apigenin-biosynthesized ultra-small platinum nanoparticles on the hu-man monocytic THP-1 cell line. Cells,  2019, 8(5), 444.
 [http://dx.doi.org/10.3390/cells8050444] [PMID: 31083475]

[29]
Bhattacharya, S.; Mondal, L.; Mukherjee, B.; Dutta, L.; Ehsan, I.; Debnath, M.C.; Gaonkar, R.H.; Pal, M.M.; Majumdar, S. Apigenin loaded nanoparticle delayed development of hepatocellular carcinoma in rats. Nanomedicine,  2018, 14(6), 1905-1917.
 [http://dx.doi.org/10.1016/j.nano.2018.05.011] [PMID: 29802937]

[30]
Zhang, J.; Huang, Y.; Liu, D.; Gao, Y.; Qian, S. Preparation of apigenin nanocrystals using supercritical antisolvent process for dissolution and bioavailability enhancement. Eur. J. Pharm. Sci.,  2013, 48(4-5), 740-747.
 [http://dx.doi.org/10.1016/j.ejps.2012.12.026] [PMID: 23305994]

[31]
Li, P.; Bukhari, S.N.A.; Khan, T.; Chitti, R.; Bevoor, D.B.; Hiremath, A.R.; SreeHarsha, N.; Singh, Y.; Gubbiyappa, K.S. Apigenin-loaded solid lipid nanoparticle attenuates diabetic nephropathy induced by streptozotocin nicotinamide through Nrf2/HO-1/NF-kB signalling pathway. Int. J. Nanomedicine,  2020, 15, 9115-9124.
 [http://dx.doi.org/10.2147/IJN.S256494] [PMID: 33244230]

[32]
Zafar, A.; Alruwaili, N.K.; Imam, S.S.; Hadal Alotaibi, N.; Alharbi, K.S.; Afzal, M.; Ali, R.; Alshehri, S.; Alzarea, S.I.; Elmowafy, M.; Al-hakamy, N.A.; Ibrahim, M.F. Bioactive Apigenin loaded oral nano bilosomes: Formulation optimization to preclinical assessment. Saudi Pharm. J.,  2021, 29(3), 269-279.
 [http://dx.doi.org/10.1016/j.jsps.2021.02.003] [PMID: 33981176]

[33]
Zhang, Z.; Cui, C.; Wei, F.; Lv, H. Improved solubility and oral bioavailability of apigenin via Soluplus/Pluronic F127 binary mixed micelles system. Drug Dev. Ind. Pharm.,  2017, 43(8), 1276-1282.
 [http://dx.doi.org/10.1080/03639045.2017.1313857] [PMID: 28358225]

[34]
Banerjee, K.; Banerjee, S.; Mandal, M. Enhanced chemotherapeutic efficacy of apigenin liposomes in colorectal cancer based on flavone-membrane interactions. J. Colloid Interface Sci.,  2017, 491, 98-110.
 [http://dx.doi.org/10.1016/j.jcis.2016.12.025] [PMID: 28012918]

[35]
Sen, K.; Banerjee, S.; Mandal, M. Dual drug loaded liposome bearing apigenin and 5-Fluorouracil for synergistic therapeutic efficacy in colorectal cancer. Colloids Surf. B Biointerfaces,  2019, 180, 9-22.
 [http://dx.doi.org/10.1016/j.colsurfb.2019.04.035] [PMID: 31015105]

[36]
Jin, X.; Yang, Q.; Zhang, Y. Synergistic apoptotic effects of apigenin TPGS liposomes and tyroservatide: Implications for effective treat-ment of lung cancer. Int. J. Nanomedicine,  2017, 12, 5109-5118.
 [http://dx.doi.org/10.2147/IJN.S140096] [PMID: 28761344]

[37]
Mishra, A.P.; Salehi, B.; Sharifi-Rad, M.; Pezzani, R.; Kobarfard, F.; Sharifi-Rad, J.; Nigam, M. Programmed cell death, from a cancer perspective: An overview. Mol. Diagn. Ther.,  2018, 22(3), 281-295.
 [http://dx.doi.org/10.1007/s40291-018-0329-9] [PMID: 29560608]

[38]
Fu, X.; Li, M.; Tang, C.; Huang, Z.; Najafi, M. Targeting of cancer cell death mechanisms by resveratrol: A review. Apoptosis,  2021, 26(11-12), 561-573.
 [http://dx.doi.org/10.1007/s10495-021-01689-7] [PMID: 34561763]

[39]
Cho, H.D.; Lee, J.H.; Moon, K.D.; Park, K.H.; Lee, M.K.; Seo, K.I. Auriculasin-induced ROS causes prostate cancer cell death via induction of apoptosis. Food Chem. Toxicol.,  2018, 111, 660-669.
 [http://dx.doi.org/10.1016/j.fct.2017.12.007] [PMID: 29217266]

[40]
Jiang, Q. Natural forms of vitamin E and metabolites-regulation of cancer cell death and underlying mechanisms. IUBMB Life,  2019, 71(4), 495-506.
 [PMID: 30548200]

[41]
Ashrafizadeh, M.; Farhood, B.; Eleojo Musa, A.; Taeb, S.; Najafi, M. The interactions and communications in tumor resistance to radiotherapy: Therapy perspectives. Int. Immunopharmacol.,  2020, 87, 106807.
 [http://dx.doi.org/10.1016/j.intimp.2020.106807] [PMID: 32683299]

[42]
Ashrafizadeh, M.; Zarrabi, A.; Orouei, S.; Kiavash, Hushmandi; Hakimi, A.; Amirhossein, Zabolian; Daneshi, S.; Samarghandian, S.; Baradaran, B.; Najafi, M. MicroRNA-mediated autophagy regulation in cancer therapy: The role in chemoresistance/chemosensitivity. Eur. J. Pharmacol.,  2021, 892, 173660.
 [http://dx.doi.org/10.1016/j.ejphar.2020.173660] [PMID: 33310181]

[43]
Towers, C.G.; Wodetzki, D.; Thorburn, A. Autophagy and cancer: Modulation of cell death pathways and cancer cell adaptations. J. Cell Biol.,  2020, 219(1), e201909033.
 [PMID: 31753861]

[44]
Carneiro, B.A.; El-Deiry, W.S. Targeting apoptosis in cancer therapy. Nat. Rev. Clin. Oncol.,  2020, 17(7), 395-417.
 [http://dx.doi.org/10.1038/s41571-020-0341-y] [PMID: 32203277]

[45]
Jan, R.; Chaudhry, G.S. Understanding apoptosis and apoptotic pathways targeted cancer therapeutics. Adv. Pharm. Bull.,  2019, 9(2), 205-218.
 [http://dx.doi.org/10.15171/apb.2019.024] [PMID: 31380246]

[46]
Shankar, E.; Goel, A.; Gupta, K.; Gupta, S. Plant flavone apigenin: An emerging anticancer agent. Curr. Pharmacol. Rep.,  2017, 3(6), 423-446.
 [http://dx.doi.org/10.1007/s40495-017-0113-2] [PMID: 29399439]

[47]
Lee, Y.J.; Park, K.S.; Nam, H.S.; Cho, M.K.; Lee, S.H. Apigenin causes necroptosis by inducing ROS accumulation, mitochondrial dys-function, and ATP depletion in malignant mesothelioma cells. Korean J. Physiol. Pharmacol.,  2020, 24(6), 493-502.
 [http://dx.doi.org/10.4196/kjpp.2020.24.6.493] [PMID: 33093271]

[48]
Xu, L.; Zaky, M.Y.; Yousuf, W.; Ullah, A.; Abdelbaset, G.R.; Zhang, Y.; Ahmed, O.M.; Liu, S.; Liu, H. The anticancer potential of apigenin via immunoregulation. Curr. Pharm. Des.,  2021, 27(4), 479-489.
 [http://dx.doi.org/10.2174/1381612826666200713171137] [PMID: 32660399]

[49]
Fu, X.; Tang, J.; Wen, P.; Huang, Z.; Najafi, M. Redox interactions-induced cardiac toxicity in cancer therapy. Arch. Biochem. Biophys.,  2021, 708, 108952.
 [http://dx.doi.org/10.1016/j.abb.2021.108952] [PMID: 34097901]

[50]
Farhood, B.; Ashrafizadeh, M.; Khodamoradi, E.; Hoseini-Ghahfarokhi, M.; Afrashi, S.; Musa, A.E.; Najafi, M. Targeting of cellular redox metabolism for mitigation of radiation injury. Life Sci.,  2020, 250, 117570.

[51]
Ashrafizadeh, M.; Bakhoda, M.R.; Bahmanpour, Z.; Ilkhani, K.; Zarrabi, A.; Makvandi, P.; Khan, H.; Mazaheri, S.; Darvish, M.; Mirzaei, H. Apigenin as tumor suppressor in cancers: biotherapeutic activity, nanodelivery, and mechanisms with emphasis on pancreatic cancer. Front Chem.,  2020, 8, 829-829.
 [http://dx.doi.org/10.3389/fchem.2020.00829] [PMID: 33195038]

[52]
Souza, R.P.; Bonfim-Mendonça, P.S.; Gimenes, F.; Ratti, B.A.; Kaplum, V.; Bruschi, M.L.; Nakamura, C.V.; Silva, S.O.; Maria-Engler, S.S.; Consolaro, M.E.L. oxidative stress triggered by apigenin induces apoptosis in a comprehensive panel of human cervical cancer-derived cell lines. Oxid. Med. Cell. Longev.,  2017, 2017, 1-18.
 [http://dx.doi.org/10.1155/2017/1512745] [PMID: 28191273]

[53]
Sawayama, H.; Ogata, Y.; Ishimoto, T.; Mima, K.; Hiyoshi, Y.; Iwatsuki, M.; Baba, Y.; Miyamoto, Y.; Yoshida, N.; Baba, H. Glucose transporter 1 regulates the proliferation and cisplatin sensitivity of esophageal cancer. Cancer Sci.,  2019, 110(5), 1705-1714.
 [http://dx.doi.org/10.1111/cas.13995] [PMID: 30861255]

[54]
Brito, A.; Pereira, P.M.R.; Soares da Costa, D.; Reis, R.L.; Ulijn, R.V.; Lewis, J.S.; Pires, R.A.; Pashkuleva, I. Inhibiting cancer metabolism by aromatic carbohydrate amphiphiles that act as antagonists of the glucose transporter GLUT1. Chem. Sci. (Camb.),  2020, 11(14), 3737-3744.
 [http://dx.doi.org/10.1039/D0SC00954G] [PMID: 34094062]

[55]
Lee, Y.M.; Lee, G.; Oh, T.I.; Kim, B.M.; Shim, D.W.; Lee, K.H.; Kim, Y.J.; Lim, B.O.; Lim, J.H. Inhibition of glutamine utilization sensi-tizes lung cancer cells to apigenin-induced apoptosis resulting from metabolic and oxidative stress. Int. J. Oncol.,  2016, 48(1), 399-408.
 [http://dx.doi.org/10.3892/ijo.2015.3243] [PMID: 26573871]

[56]
Jung, W.W. Protective effect of apigenin against oxidative stressinduced damage in osteoblastic cells. Int. J. Mol. Med.,  2014, 33(5), 1327-1334.
 [http://dx.doi.org/10.3892/ijmm.2014.1666] [PMID: 24573323]

[57]
Prasad, N.R.; Thayalan, K.; Begum, N. Apigenin protects gamma-radiation induced oxidative stress, hematological changes and animal survival in whole body irradiated Swiss albino mice. Int. J. Nutr. Pharmacol. Neurol. Dis.,  2012, 2(1), 45.
 [http://dx.doi.org/10.4103/2231-0738.93134]

[58]
Xu, Y.; Xin, Y.; Diao, Y.; Lu, C.; Fu, J.; Luo, L.; Yin, Z. Synergistic effects of apigenin and paclitaxel on apoptosis of cancer cells. PLoS One,  2011, 6(12), e29169.
 [http://dx.doi.org/10.1371/journal.pone.0029169] [PMID: 22216199]

[59]
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(10), 1833-1845.
 [http://dx.doi.org/10.1016/j.freeradbiomed.2008.02.007] [PMID: 18342637]

[60]
Chen, W.Y.; Hsieh, Y.A.; Tsai, C.I.; Kang, Y.F.; Chang, F.R.; Wu, Y.C.; Wu, C.C. 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. Invest. New Drugs,  2011, 29(6), 1347-1359.
 [http://dx.doi.org/10.1007/s10637-010-9497-0] [PMID: 20686818]

[61]
Shen, H.M.; Pervaiz, S. TNF receptor superfamilyinduced cell death: redox‐dependent execution. FASEB J.,  2006, 20(10), 1589-1598.
 [http://dx.doi.org/10.1096/fj.05-5603rev] [PMID: 16873882]

[62]
Mu, Q.; Najafi, M. Resveratrol for targeting the tumor microenvironment and its interactions with cancer cells. Int. Immunopharmacol.,  2021, 98, 107895.
 [http://dx.doi.org/10.1016/j.intimp.2021.107895] [PMID: 34171623]

[63]
Mu, Q.; Najafi, M. Modulation of the tumor microenvironment (TME) by melatonin. Eur. J. Pharmacol.,  2021, 907, 174365.
 [http://dx.doi.org/10.1016/j.ejphar.2021.174365] [PMID: 34302814]

[64]
Bauer, D.; Redmon, N.; Mazzio, E.; Soliman, K.F. Apigenin inhibits TNFα/IL-1α-induced CCL2 release through IKBK-epsilon signaling in MDA-MB-231 human breast cancer cells. PLoS One,  2017, 12(4), e0175558.
 [http://dx.doi.org/10.1371/journal.pone.0175558] [PMID: 28441391]

[65]
Villalobos-Ayala, K.; Ortiz Rivera, I.; Alvarez, C.; Husain, K.; DeLoach, D.; Krystal, G.; Hibbs, M.L.; Jiang, K.; Ghansah, T. Apigenin increases SHIP-1 expression, promotes tumoricidal macrophages and anti-tumor immune responses in murine pancreatic cancer. Cancers,  2020, 12(12), 3631.
 [http://dx.doi.org/10.3390/cancers12123631] [PMID: 33291556]

[66]
Bauer, D.; Mazzio, E.; Soliman, K.F.A. Whole transcriptomic analysis of apigenin on TNFα immuno-activated MDA-MB-231 breast cancer cells. Cancer Genomics Proteomics,  2019, 16(6), 421-431.
 [http://dx.doi.org/10.21873/cgp.20146] [PMID: 31659097]

[67]
Mortezaee, K.; Najafi, M. Immune system in cancer radiotherapy: Resistance mechanisms and therapy perspectives. Crit. Rev. Oncol. Hematol.,  2021, 157, 103180.
 [http://dx.doi.org/10.1016/j.critrevonc.2020.103180] [PMID: 33264717]

[68]
Lee, D.Y.; Im, E.; Yoon, D.; Lee, Y-S.; Kim, G-S.; Kim, D.; Kim, S-H. Pivotal role of PD-1/PD-L1 immune checkpoints in immune escape and cancer progression: Their interplay with platelets and FOXP3+Tregs related molecules, clinical implications and combinational potential with phytochemicals. Semin. Cancer Biol.,  2020, 86(3), 1033-1057.

[69]
Oishi, M.; Iizumi, Y.; Taniguchi, T.; Goi, W.; Miki, T.; Sakai, T. Apigenin sensitizes prostate cancer cells to Apo2L/TRAIL by targeting adenine nucleotide translocase-2. PLoS One,  2013, 8(2), e55922.
 [http://dx.doi.org/10.1371/journal.pone.0055922] [PMID: 23431365]

[70]
Kang, C.H.; Molagoda, I.M.N.; Choi, Y.H.; Park, C.; Moon, D.O.; Kim, G.Y. Apigenin promotes TRAIL-mediated apoptosis regardless of ROS generation. Food Chem. Toxicol.,  2018, 111, 623-630.
 [http://dx.doi.org/10.1016/j.fct.2017.12.018] [PMID: 29247770]

[71]
Horinaka, M.; Yoshida, T.; Shiraishi, T.; Nakata, S.; Wakada, M.; Sakai, T. The dietary flavonoid apigenin sensitizes malignant tumor cells to tumor necrosis factor–related apoptosis-inducing ligand. Mol. Cancer Ther.,  2006, 5(4), 945-951.
 [http://dx.doi.org/10.1158/1535-7163.MCT-05-0431] [PMID: 16648565]

[72]
Chan, L-P.; Chou, T-H.; Ding, H-Y.; Chen, P-R.; Chiang, F-Y.; Kuo, P-L.; Liang, C-H. Apigenin induces apoptosis via tumor necrosis factor receptor-and Bcl-2-mediated pathway and enhances susceptibility of head and neck squamous cell carcinoma to 5-fluorouracil and cisplatin. Biochim Biophys Acta Gen Subjects,  2012, 1820(7), 1081-1091.
 [http://dx.doi.org/10.1016/j.bbagen.2012.04.013] [PMID: 22554915]

[73]
Wang, Q.R.; Yao, X.Q.; Wen, G.; Fan, Q.; Li, Y.J.; Fu, X.Q.; Li, C.K.; Sun, X.G. Apigenin suppresses the growth of colorectal cancer xenografts via phosphorylation and up-regulated FADD expression. Oncol. Lett.,  2011, 2(1), 43-47.
 [http://dx.doi.org/10.3892/ol.2010.215] [PMID: 22870126]

[74]
Hou, H.; Sun, D.; Zhang, X. The role of MDM2 amplification and overexpression in therapeutic resistance of malignant tumors. Cancer Cell Int.,  2019, 19(1), 216.
 [http://dx.doi.org/10.1186/s12935-019-0937-4] [PMID: 31440117]

[75]
King, J.C.; Lu, Q.Y.; Li, G.; Moro, A.; Takahashi, H.; Chen, M.; Go, V.L.W.; Reber, H.A.; Eibl, G.; Hines, O.J. Evidence for activation of mutated p53 by apigenin in human pancreatic cancer. Biochim. Biophys. Acta Mol. Cell Res.,  2012, 1823(2), 593-604.
 [http://dx.doi.org/10.1016/j.bbamcr.2011.12.008] [PMID: 22227579]

[76]
Torkin, R.; Lavoie, J.F.; Kaplan, D.R.; Yeger, H. Induction of caspase-dependent, p53-mediated apoptosis by apigenin in human neuro-blastoma. Mol. Cancer Ther.,  2005, 4(1), 1-11.
 [http://dx.doi.org/10.1158/1535-7163.1.4.1] [PMID: 15657348]

[77]
Chen, M.; Wang, X.; Zha, D.; Cai, F.; Zhang, W.; He, Y.; Huang, Q.; Zhuang, H.; Hua, Z.C. Apigenin potentiates TRAIL therapy of non-small cell lung cancer via upregulating DR4/DR5 expression in a p53-dependent manner. Sci. Rep.,  2016, 6(1), 35468.
 [http://dx.doi.org/10.1038/srep35468] [PMID: 27752089]

[78]
Zheng, P.W.; Chiang, L.C.; Lin, C.C. Apigenin induced apoptosis through p53-dependent pathway in human cervical carcinoma cells. Life Sci.,  2005, 76(12), 1367-1379.
 [http://dx.doi.org/10.1016/j.lfs.2004.08.023] [PMID: 15670616]

[79]
Choi, E.J.; Kim, G.H. 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.,  2009, 20(4), 285-290.
 [http://dx.doi.org/10.1016/j.jnutbio.2008.03.005] [PMID: 18656338]

[80]
Seo, H.S.; Choi, H.S.; Kim, S.R.; Choi, Y.K.; Woo, S.M.; Shin, I.; Woo, J.K.; Park, S.Y.; Shin, Y.C.; Ko, S.K. Apigenin induces apoptosis via extrinsic pathway, inducing p53 and inhibiting STAT3 and NFκB signaling in HER2-overexpressing breast cancer cells. Mol. Cell. Biochem.,  2012, 366(1-2), 319-334.
 [http://dx.doi.org/10.1007/s11010-012-1310-2] [PMID: 22527937]

[81]
Granato, M.; Gilardini Montani, M.S.; Santarelli, R.; D’Orazi, G.; Faggioni, A.; Cirone, M. Apigenin, by activating p53 and inhibiting STAT3, modulates the balance between pro-apoptotic and prosurvival pathways to induce PEL cell death. J. Exp. Clin. Cancer Res.,  2017, 36(1), 167.
 [http://dx.doi.org/10.1186/s13046-017-0632-z] [PMID: 29179721]

[82]
Liu, R.; Ji, P.; Liu, B.; Qiao, H.; Wang, X.; Zhou, L.; Deng, T.; Ba, Y. Apigenin enhances the cisplatin cytotoxic effect through p53-modulated apoptosis. Oncol. Lett.,  2017, 13(2), 1024-1030.
 [http://dx.doi.org/10.3892/ol.2016.5495] [PMID: 28356995]

[83]
Zhao, S.; Tang, Y.; Wang, R.; Najafi, M. Mechanisms of cancer cell death induction by paclitaxel: An updated review. Apoptosis,  2022, 27(9-10), 647-667.
 [http://dx.doi.org/10.1007/s10495-022-01750-z] [PMID: 35849264]

[84]
Yang, J.; Nie, J.; Ma, X.; Wei, Y.; Peng, Y.; Wei, X. Targeting PI3K in cancer: Mechanisms and advances in clinical trials. Mol. Cancer,  2019, 18(1), 26.
 [http://dx.doi.org/10.1186/s12943-019-0954-x] [PMID: 30782187]

[85]
Cheng, H.; Shcherba, M.; Pendurti, G.; Liang, Y.; Piperdi, B.; Perez-Soler, R. Targeting the PI3K/AKT/mTOR pathway: Potential for lung cancer treatment. Lung Cancer Manag.,  2014, 3(1), 67-75.
 [http://dx.doi.org/10.2217/lmt.13.72] [PMID: 25342981]

[86]
Davis, N.M.; Sokolosky, M.; Stadelman, K.; Abrams, S.L.; Libra, M.; Candido, S.; Nicoletti, F.; Polesel, J.; Maestro, R.; D’Assoro, A.; Drobot, L.; Rakus, D.; Gizak, A.; Laidler, P.; Dulińska-Litewka, J.; Basecke, J.; Mijatovic, S.; Maksimovic-Ivanic, D.; Montalto, G.; Cervello, M.; Fitzgerald, T.L.; Demidenko, Z.N.; Martelli, A.M.; Cocco, L.; Steelman, L.S.; McCubrey, J.A. Deregulation of the EGFR/PI3K/PTEN/Akt/mTORC1 pathway in breast cancer: Possibilities for therapeutic intervention. Oncotarget,  2014, 5(13), 4603-4650.
 [http://dx.doi.org/10.18632/oncotarget.2209] [PMID: 25051360]

[87]
Tong, X.; Pelling, J. Targeting the PI3K/Akt/mTOR axis by apigenin for cancer prevention. Anticancer Agents Med. Chem.,  2013, 13(7), 971-978.
 [http://dx.doi.org/10.2174/18715206113139990119] [PMID: 23272913]

[88]
Liu, M.M.; Ma, R.H.; Ni, Z.J.; Thakur, K.; Cespedes-Acuña, C.L.; Jiang, L.; Wei, Z.J. Apigenin 7-O-glucoside promotes cell apoptosis through the PTEN/PI3K/AKT pathway and inhibits cell migration in cervical cancer HeLa cells. Food Chem. Toxicol.,  2020, 146, 111843.
 [http://dx.doi.org/10.1016/j.fct.2020.111843] [PMID: 33152472]

[89]
Shukla, S.; Bhaskaran, N.; Babcook, M.A.; Fu, P.; MacLennan, G.T.; Gupta, S. Apigenin inhibits prostate cancer progression in TRAMP mice via targeting PI3K/Akt/FoxO pathway. Carcinogenesis,  2014, 35(2), 452-460.
 [http://dx.doi.org/10.1093/carcin/bgt316] [PMID: 24067903]

[90]
Yang, L.; Xie, S.; Jamaluddin, M.S.; Altuwaijri, S.; Ni, J.; Kim, E.; Chen, Y.T.; Hu, Y.C.; Wang, L.; Chuang, K.H.; Wu, C.T.; Chang, C. Induction of androgen receptor expression by phosphatidylinositol 3-kinase/Akt downstream substrate, FOXO3a, and their roles in apop-tosis of LNCaP prostate cancer cells. J. Biol. Chem.,  2005, 280(39), 33558-33565.
 [http://dx.doi.org/10.1074/jbc.M504461200] [PMID: 16061480]

[91]
Liu, J.W.; Chandra, D.; Rudd, M.D.; Butler, A.P.; Pallotta, V.; Brown, D.; Coffer, P.J.; Tang, D.G. Induction of prosurvival molecules by apoptotic stimuli: Involvement of FOXO3a and ROS. Oncogene,  2005, 24(12), 2020-2031.
 [http://dx.doi.org/10.1038/sj.onc.1208385] [PMID: 15674333]

[92]
Ayyildiz, A.; Koc, H.; Turkekul, K.; Erdogan, S. Co-administration of apigenin with doxorubicin enhances anti-migration and antiproliferative effects via PI3K/PTEN/AKT pathway in prostate cancer cells. Exp. Oncol.,  2021, 43(2), 125-134.
 [PMID: 34190523]

[93]
Erdogan, S.; Turkekul, K.; Serttas, R.; Erdogan, Z. The natural flavonoid apigenin sensitizes human CD44 + prostate cancer stem cells to cisplatin therapy. Biomed. Pharmacother.,  2017, 88, 210-217.
 [http://dx.doi.org/10.1016/j.biopha.2017.01.056] [PMID: 28107698]

[94]
Erdogan, S.; Turkekul, K.; Dibirdik, I.; Doganlar, Z.B.; Doganlar, O.; Bilir, A. Midkine silencing enhances the anti–prostate cancer stem cell activity of the flavone apigenin: Cooperation on signaling pathways regulated by ERK, p38, PTEN, PARP, and NF-κB. Invest. New Drugs,  2020, 38(2), 246-263.
 [http://dx.doi.org/10.1007/s10637-019-00774-8] [PMID: 30993586]

[95]
Choi, E.J.; Kim, G-H. 5-Fluorouracil combined with apigenin enhances anticancer activity through induction of apoptosis in human breast cancer MDA-MB-453 cells. Oncol. Rep.,  2009, 22(6), 1533-1537.
 [http://dx.doi.org/10.3892/or_00000598] [PMID: 19885610]

[96]
Taniguchi, K.; Karin, M. NF-κB, inflammation, immunity and cancer: coming of age. Nat. Rev. Immunol.,  2018, 18(5), 309-324.
 [http://dx.doi.org/10.1038/nri.2017.142] [PMID: 29379212]

[97]
Zhou, P.; Wang, C.; Hu, Z.; Chen, W.; Qi, W.; Li, A. Genistein induces apoptosis of colon cancer cells by reversal of epithelial-tomesenchymal via a Notch1/NF-κB/slug/E-cadherin pathway. BMC Cancer,  2017, 17(1), 813.
 [http://dx.doi.org/10.1186/s12885-017-3829-9] [PMID: 28049525]

[98]
Xia, L.; Tan, S.; Zhou, Y.; Lin, J.; Wang, H.; Oyang, L.; Tian, Y.; Liu, L.; Su, M.; Wang, H.; Cao, D.; Liao, Q. Role of the NFκB-signaling pathway in cancer. OncoTargets Ther.,  2018, 11, 2063-2073.
 [http://dx.doi.org/10.2147/OTT.S161109] [PMID: 29695914]

[99]
Mortezaee, K.; Najafi, M.; Farhood, B.; Ahmadi, A.; Shabeeb, D.; Musa, A.E. NF‐κB targeting for overcoming tumor resistance and nor-mal tissues toxicity. J. Cell. Physiol.,  2019, 234(10), 17187-17204.
 [http://dx.doi.org/10.1002/jcp.28504] [PMID: 30912132]

[100]
Kim, H.S.; Sharma, A.; Ren, W.X.; Han, J.; Kim, J.S. COX-2 Inhibition mediated anti-angiogenic activatable prodrug potentiates cancer therapy in preclinical models. Biomaterials,  2018, 185, 63-72.
 [http://dx.doi.org/10.1016/j.biomaterials.2018.09.006] [PMID: 30223141]

[101]
Hu, H.; Han, T.; Zhuo, M.; Wu, L.; Yuan, C.; Wu, L.; Lei, W.; Jiao, F.; Wang, L.W. Elevated COX-2 expression promotes angiogenesis through EGFR/p38-MAPK/Sp1-dependent signalling in pancreatic cancer. Sci. Rep.,  2017, 7(1), 470.
 [http://dx.doi.org/10.1038/s41598-017-00288-4] [PMID: 28352075]

[102]
Karpisheh, V.; Nikkhoo, A.; Hojjat-Farsangi, M.; Namdar, A.; Azizi, G.; Ghalamfarsa, G.; Sabz, G.; Yousefi, M.; Yousefi, B.; Jadidi-Niaragh, F. Prostaglandin E2 as a potent therapeutic target for treatment of colon cancer. Prostaglandins Other Lipid Mediat.,  2019, 144, 106338.
 [http://dx.doi.org/10.1016/j.prostaglandins.2019.106338] [PMID: 31100474]

[103]
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(2), 114-126.
 [http://dx.doi.org/10.1002/mc.10168] [PMID: 14750216]

[104]
Tong, J.; Shen, Y.; Zhang, Z.; Hu, Y.; Zhang, X.; Han, L. Apigenin inhibits epithelial-mesenchymal transition of human colon cancer cells through NF-κB/Snail signaling pathway. Biosci. Rep.,  2019, 39(5), BSR20190452.
 [http://dx.doi.org/10.1042/BSR20190452] [PMID: 30967496]

[105]
Gu, Y.; Mohammad, I.; Liu, Z. Overview of the STAT 3 signaling pathway in cancer and the development of specific inhibitors (Review). Oncol. Lett.,  2020, 19(4), 2585-2594.
 [http://dx.doi.org/10.3892/ol.2020.11394] [PMID: 32218808]

[106]
Ai, X.Y.; Qin, Y.; Liu, H.J.; Cui, Z.H.; Li, M.; Yang, J.H.; Zhong, W.L.; Liu, Y.R.; Chen, S.; Sun, T.; Zhou, H.G.; Yang, C. Apigenin inhi-bits colonic inflammation and tumorigenesis by suppressing STAT3-NF-κB signaling. Oncotarget,  2017, 8(59), 100216-100226.
 [http://dx.doi.org/10.18632/oncotarget.22145] [PMID: 29245972]

[107]
Seo, H.S.; Jo, J.K.; Ku, J.M.; Choi, H.S.; Choi, Y.K.; Woo, J.K.; Kim, H.; Kang, S.; Lee, K.; Nam, K.W.; Park, N.; Jang, B.H.; Shin, Y.C.; Ko, S.G. Induction of caspase-dependent extrinsic apoptosis by apigenin through inhibition of signal transducer and activator of transcription 3 (STAT3) signalling in HER2-overexpressing BT-474 breast cancer cells. Biosci. Rep.,  2015, 35(6), e00276.
 [http://dx.doi.org/10.1042/BSR20150165] [PMID: 26500281]

[108]
Seo, H.S.; Ku, J.M.; Choi, H.S.; Woo, J.K.; Jang, B.H.; Go, H.; Shin, Y.C.; Ko, S.G. 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.,  2015, 12(2), 2977-2984.
 [http://dx.doi.org/10.3892/mmr.2015.3698] [PMID: 25936427]

[109]
Seo, H.S.; Ku, J.M.; Choi, H.S.; Woo, J.K.; Lee, B.H.; Kim, D.S.; Song, H.J.; Jang, B.H.; Shin, Y.C.; Ko, S.G. Apigenin overcomes drug resistance by blocking the signal transducer and activator of transcription 3 signaling in breast cancer cells. Oncol. Rep.,  2017, 38(2), 715-724.
 [http://dx.doi.org/10.3892/or.2017.5752] [PMID: 28656316]

[110]
Suh, Y.A.; Jo, S.Y.; Lee, H.Y.; Lee, C. Inhibition of IL-6/STAT3 axis and targeting Axl and Tyro3 receptor tyrosine kinases by apigenin circumvent taxol resistance in ovarian cancer cells. Int. J. Oncol.,  2015, 46(3), 1405-1411.
 [http://dx.doi.org/10.3892/ijo.2014.2808] [PMID: 25544427]

[111]
Colhado Rodrigues, B.L.; Lallo, M.A.; Perez, E.C. The controversial role of autophagy in tumor development: A systematic review. Immunol. Invest.,  2020, 49(4), 386-396.
 [http://dx.doi.org/10.1080/08820139.2019.1682600] [PMID: 31726897]

[112]
D’Arcy, M.S. Cell death: a review of the major forms of apoptosis, necrosis and autophagy. Cell Biol. Int.,  2019, 43(6), 582-592.
 [http://dx.doi.org/10.1002/cbin.11137] [PMID: 30958602]

[113]
Onorati, A.V.; Dyczynski, M.; Ojha, R.; Amaravadi, R.K. Targeting autophagy in cancer. Cancer,  2018, 124(16), 3307-3318.
 [http://dx.doi.org/10.1002/cncr.31335] [PMID: 29671878]

[114]
Cao, X.; Liu, B.; Cao, W.; Zhang, W.; Zhang, F.; Zhao, H.; Meng, R.; Zhang, L.; Niu, R.; Hao, X.; Zhang, B. Autophagy inhibition enhances apigenin-induced apoptosis in human breast cancer cells. Chinese J. Cancer Res.,  2013, 25(2), 212-222.

[115]
Lee, Y.; Sung, B.; Kang, Y.J.; Kim, D.H.; Jang, J.Y.; Hwang, S.Y.; Kim, M.; Lim, H.S.; Yoon, J.H.; Chung, H.Y.; Kim, N.D. Apigenin-induced apoptosis is enhanced by inhibition of autophagy formation in HCT116 human colon cancer cells. Int. J. Oncol.,  2014, 44(5), 1599-1606.
 [http://dx.doi.org/10.3892/ijo.2014.2339] [PMID: 24626522]

[116]
Sung, B.; Chung, H.Y.; Kim, N.D. Role of apigenin in cancer prevention via the induction of apoptosis and autophagy. J. Cancer Prev.,  2016, 21(4), 216-226.
 [http://dx.doi.org/10.15430/JCP.2016.21.4.216] [PMID: 28053955]

[117]
Ruela-de-Sousa, R.R.; Fuhler, G.M.; Blom, N.; Ferreira, C.V.; Aoyama, H.; Peppelenbosch, M.P. Cytotoxicity of apigenin on leukemia cell lines: Implications for prevention and therapy. Cell Death Dis.,  2010, 1(1), e19.
 [http://dx.doi.org/10.1038/cddis.2009.18] [PMID: 21364620]

[118]
Sharma, V.R.; Gupta, G.K.; Sharma, A.K.; Batra, N.; Sharma, D.K.; Joshi, A.; Sharma, A.K.A.; Batra, N.; K Sharma, D.; Joshi, A.; K Sharma, A. PI3K/Akt/mTOR intracellular pathway and breast cancer: Factors, mechanism and regulation. Curr. Pharm. Des.,  2017, 23(11), 1633-1638.
 [http://dx.doi.org/10.2174/1381612823666161116125218] [PMID: 27848885]

[119]
Yang, J.; Pi, C.; Wang, G. Inhibition of PI3K/Akt/mTOR pathway by apigenin induces apoptosis and autophagy in hepatocellular carcinoma cells. Biomed. Pharmacother.,  2018, 103, 699-707.
 [http://dx.doi.org/10.1016/j.biopha.2018.04.072] [PMID: 29680738]

[120]
Umezawa, S.; Higurashi, T.; Nakajima, A. AMPK: Therapeutic target for diabetes and cancer prevention. Curr. Pharm. Des.,  2017, 23(25), 3629-3644.
 [PMID: 28714409]

[121]
Li, Y.; Chen, Y. AMPK and autophagy. Adv. Exp. Med. Biol.,  2019, 1206, 85-108.
 [http://dx.doi.org/10.1007/978-981-15-0602-4_4] [PMID: 31776981]

[122]
Herzig, S.; Shaw, R.J. AMPK: Guardian of metabolism and mitochondrial homeostasis. Nat. Rev. Mol. Cell Biol.,  2018, 19(2), 121-135.
 [http://dx.doi.org/10.1038/nrm.2017.95] [PMID: 28974774]

[123]
Tong, X.; Smith, K.A.; Pelling, J.C. Apigenin, a chemopreventive bioflavonoid, induces AMP-activated protein kinase activation in human keratinocytes. Mol. Carcinog.,  2012, 51(3), 268-279.
 [http://dx.doi.org/10.1002/mc.20793] [PMID: 21538580]

[124]
Zhan, T.; Rindtorff, N.; Boutros, M. Wnt signaling in cancer. Oncogene,  2017, 36(11), 1461-1473.
 [http://dx.doi.org/10.1038/onc.2016.304] [PMID: 27617575]

[125]
Zhang, Y.; Wang, X. Targeting the Wnt/β-catenin signaling pathway in cancer. J. Hematol. Oncol.,  2020, 13(1), 165.
 [http://dx.doi.org/10.1186/s13045-020-00990-3] [PMID: 33276800]

[126]
Lin, C.M.; Chen, H.H.; Lin, C.A.; Wu, H.C.; Sheu, J.J.C.; Chen, H.J. Apigenin-induced lysosomal degradation of β-catenin in Wnt/β-catenin signaling. Sci. Rep.,  2017, 7(1), 372.
 [http://dx.doi.org/10.1038/s41598-017-00409-z] [PMID: 28337019]

[127]
Yan, X.; Qi, M.; Li, P.; Zhan, Y.; Shao, H. Apigenin in cancer therapy: anti-cancer effects and mechanisms of action. Cell Biosci.,  2017, 7(1), 50.
 [http://dx.doi.org/10.1186/s13578-017-0179-x] [PMID: 29034071]

[128]
Wyld, L.; Bellantuono, I.; Tchkonia, T.; Morgan, J.; Turner, O.; Foss, F.; George, J.; Danson, S.; Kirkland, J.L. senescence and cancer: A review of clinical implications of senescence and senotherapies. Cancers,  2020, 12(8), 2134.
 [http://dx.doi.org/10.3390/cancers12082134] [PMID: 32752135]

[129]
Schosserer, M.; Grillari, J.; Breitenbach, M. The dual role of cellular senescence in developing tumors and their response to cancer thera-py. Front. Oncol.,  2017, 7(278), 278.
 [http://dx.doi.org/10.3389/fonc.2017.00278] [PMID: 29218300]

[130]
Beck, J.; Turnquist, C.; Horikawa, I.; Harris, C. Targeting cellular senescence in cancer and aging: Roles of p53 and its isoforms. Carcinogenesis,  2020, 41(8), 1017-1029.
 [http://dx.doi.org/10.1093/carcin/bgaa071] [PMID: 32619002]

[131]
Provinciali, M.; Cardelli, M.; Marchegiani, F.; Pierpaoli, E. Impact of cellular senescence in aging and cancer. Curr. Pharm. Des.,  2013, 19(9), 1699-1709.
 [PMID: 23061727]

[132]
Ou, H-L.; Hoffmann, R.; González-López, C.; Doherty, G.J.; Korkola, J.E.; Muñoz-Espín, D. Cellular senescence in cancer: From mechanisms to detection. Mol. Oncol.,  2020, 15(10), 2634-2671.

[133]
Salminen, A.; Kauppinen, A.; Kaarniranta, K. Emerging role of NF-κB signaling in the induction of Senescence-Associated Secretory Phenotype (SASP). Cell. Signal.,  2012, 24(4), 835-845.
 [http://dx.doi.org/10.1016/j.cellsig.2011.12.006] [PMID: 22182507]

[134]
Wang, S.M.; Yang, P.W.; Feng, X.J.; Zhu, Y.W.; Qiu, F.J.; Hu, X.D.; Zhang, S.H. Apigenin inhibits the growth of hepatocellular carcinoma cells by affecting the expression of microRNA transcriptome. Front. Oncol.,  2021, 11(1001), 657665.
 [http://dx.doi.org/10.3389/fonc.2021.657665] [PMID: 33959508]

[135]
Zohreh, B.; Masoumeh, V.; Fakhraddin, N.; Omrani, G.H.R. Apigenin-mediated alterations in viability and senescence of SW480 colorectal cancer cells persist in the Presence of L-thyroxine. Anti Cancer. Agents Med. Chem.,  2019, 19(12), 1535-1542.

[136]
Banerjee, K.; Mandal, M. Oxidative stress triggered by naturally occurring flavone apigenin results in senescence and chemotherapeutic effect in human colorectal cancer cells. Redox Biol.,  2015, 5, 153-162.
 [http://dx.doi.org/10.1016/j.redox.2015.04.009] [PMID: 25965143]

[137]
Liu, P.; Lu, Z.; Wu, Y.; Shang, D.; Zhao, Z.; Shen, Y.; Zhang, Y.; Zhu, F.; Liu, H.; Tu, Z. Cellular senescence-inducing small molecules for cancer treatment. Curr. Cancer Drug Targets,  2019, 19(2), 109-119.
 [http://dx.doi.org/10.2174/1568009618666180530092825] [PMID: 29848278]

[138]
You, J.; Dong, R.; Ying, M.; He, Q.; Cao, J.; Yang, B. Cellular senescence and anti-cancer therapy. Curr. Drug Targets,  2019, 20(7), 705-715.
 [http://dx.doi.org/10.2174/1389450120666181217100833] [PMID: 30556499]

[139]
Perrott, K.M.; Wiley, C.D.; Desprez, P.Y.; Campisi, J. Apigenin suppresses the senescence-associated secretory phenotype and paracrine effects on breast cancer cells. Geroscience,  2017, 39(2), 161-173.
 [http://dx.doi.org/10.1007/s11357-017-9970-1] [PMID: 28378188]

[140]
Maru, D.; Hothi, A.; Bagariya, C.; Kumar, A. Targeting ferroptosis pathways: A novel strategy for cancer therapy. Curr. Cancer Drug Targets,  2022, 22(3), 234-244.
 [http://dx.doi.org/10.2174/1568009622666220211122745] [PMID: 35152865]

[141]
Wu, Y.; Yu, C.; Luo, M.; Cen, C.; Qiu, J.; Zhang, S.; Hu, K. Ferroptosis in cancer treatment: Another way to rome. Front. Oncol.,  1924, 2020, 10.
 [PMID: 33102227]

[142]
Bebber, C.M.; Müller, F.; Prieto Clemente, L.; Weber, J.; von Karstedt, S. Ferroptosis in cancer cell biology. Cancers,  2020, 12(1), 164.
 [http://dx.doi.org/10.3390/cancers12010164] [PMID: 31936571]

[143]
Xie, Y.; Zhou, X.; Li, J.; Yao, X.C.; Liu, W.L.; Kang, F.H.; Zou, Z.X.; Xu, K.P.; Xu, P.S.; Tan, G.S. Identification of a new natural biflavonoids against breast cancer cells induced ferroptosis via the mitochondrial pathway. Bioorg. Chem.,  2021, 109, 104744.
 [http://dx.doi.org/10.1016/j.bioorg.2021.104744] [PMID: 33639365]

[144]
N Adham, A.; F Hegazy, M.E.; Naqishbandi, A.M.; Efferth, T. A.; F Hegazy, M.E.; Naqishbandi, A.M.; Efferth, T. Induction of apoptosis, autophagy and ferroptosis by Thymus vulgaris and Arctium lappa extract in leukemia and multiple myeloma cell lines. Molecules,  2020, 25(21), 5016.
 [http://dx.doi.org/10.3390/molecules25215016] [PMID: 33138135]

[145]
Adham, A.N.; Abdelfatah, S.; Naqishbandi, A.M.; Mahmoud, N.; Efferth, T. Cytotoxicity of apigenin toward multiple myeloma cell lines and suppression of iNOS and COX-2 expression in STAT1-transfected HEK293 cells. Phytomedicine,  2021, 80, 153371.
 [http://dx.doi.org/10.1016/j.phymed.2020.153371] [PMID: 33070080]

[146]
Adeshakin, F.O.; Adeshakin, A.O.; Afolabi, L.O.; Yan, D.; Zhang, G.; Wan, X. Mechanisms for modulating anoikis resistance in cancer and the relevance of metabolic reprogramming. Front. Oncol.,  2021, 11(528), 626577.
 [http://dx.doi.org/10.3389/fonc.2021.626577] [PMID: 33854965]

[147]
Shang, Y.; Cai, X.; Fan, D. Roles of epithelial-mesenchymal transition in cancer drug resistance. Curr. Cancer Drug Targets,  2013, 13(9), 915-929.
 [http://dx.doi.org/10.2174/15680096113136660097] [PMID: 24168191]

[148]
Cai, Q.; Yan, L.; Xu, Y. Anoikis resistance is a critical feature of highly aggressive ovarian cancer cells. Oncogene,  2015, 34(25), 3315-3324.
 [http://dx.doi.org/10.1038/onc.2014.264] [PMID: 25132267]

[149]
Paoli, P.; Giannoni, E.; Chiarugi, P. Anoikis molecular pathways and its role in cancer progression. Biochim. Biophy. Acta (BBA) -. Molec. Cell Res.,  2013, 1833(12), 3481-3498.

[150]
Hasnat, M.; Pervin, M.; Lim, J.; Lim, B. Apigenin attenuates melanoma cell migration by inducing anoikis through integrin and focal adhe-sion kinase inhibition. Molecules,  2015, 20(12), 21157-21166.
 [http://dx.doi.org/10.3390/molecules201219752] [PMID: 26633318]

[151]
Hu, X.W.; Meng, D.; Fang, J. Apigenin inhibited migration and invasion of human ovarian cancer A2780 cells through focal adhesion kinase. Carcinogenesis,  2008, 29(12), 2369-2376.
 [http://dx.doi.org/10.1093/carcin/bgn244] [PMID: 18974065]

[152]
Lee, W.J.; Chen, W.K.; Wang, C.J.; Lin, W.L.; Tseng, T.H. 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.,  2008, 226(2), 178-191.
 [http://dx.doi.org/10.1016/j.taap.2007.09.013] [PMID: 17961621]

[153]
Christofferson, D.E.; Yuan, J. Necroptosis as an alternative form of programmed cell death. Curr. Opin. Cell Biol.,  2010, 22(2), 263-268.
 [http://dx.doi.org/10.1016/j.ceb.2009.12.003] [PMID: 20045303]

[154]
Marseglia, G.; Licari, A.; Leonardi, S.; Papale, M.; Zicari, A.M.; Schiavi, L.; Ciprandi, G. A polycentric, randomized, parallel-group, study on Lertal®, a multicomponent nutraceutical, as preventive treatment in children with allergic rhinoconjunctivitis: Phase II. Ital. J. Pediatr.,  2019, 45(1), 84.
 [http://dx.doi.org/10.1186/s13052-019-0678-y] [PMID: 31319883]

[155]
Chen, Y.H.; Wu, J.X.; Yang, S.F.; Yang, C.K.; Chen, T.H.; Hsiao, Y.H. Anticancer effects and molecular mechanisms of apigenin in cervical cancer cells. Cancers (Basel),  2022, 14(7), 1824.
 [http://dx.doi.org/10.3390/cancers14071824] [PMID: 35406599]

[156]
Salehi, B.; Venditti, A.; Sharifi-Rad, M.; Kręgiel, D.; Sharifi-Rad, J.; Durazzo, A.; Lucarini, M.; Santini, A.; Souto, E.; Novellino, E.; Anto-lak, H.; Azzini, E.; Setzer, W.; Martins, N. The therapeutic potential of apigenin. Int. J. Mol. Sci.,  2019, 20(6), 1305.
 [http://dx.doi.org/10.3390/ijms20061305] [PMID: 30875872]

[157]
Ashrafizadeh, M.; Taeb, S.; Haghi-Aminjan, H.; Afrashi, S.; Moloudi, K.; Musa, A.E.; Najafi, M.; Farhood, B. Resveratrol as an enhancer of apoptosis in cancer: A mechanistic review. Anticancer. Agents Med. Chem.,  2021, 21(17), 2327-2336.

[158]
Mortezaee, K.; Najafi, M.; Farhood, B.; Ahmadi, A.; Shabeeb, D.; Musa, A.E. Resveratrol as an adjuvant for normal tissues protection and tumor sensitization. Curr. Cancer Drug Targets,  2020, 20(2), 130-145.
 [http://dx.doi.org/10.2174/1568009619666191019143539] [PMID: 31738153]

[159]
Zhang, M.; Feng, K.; Huang, G.; Xin, Y.; Xiao, J.; Cao, Y.; Ludescher, R.; Ho, C.T.; Huang, Q. Assessment of oral bioavailability and biotransformation of emulsified nobiletin using in vitro and in vivo models. J. Agric. Food Chem.,  2020, 68(41), 11412-11420.
 [http://dx.doi.org/10.1021/acs.jafc.0c04450] [PMID: 32935545]

[160]
Singh, P.; Mishra, S.K.; Noel, S.; Sharma, S.; Rath, S.K. Acute exposure of apigenin induces hepatotoxicity in Swiss mice. PLoS One,  2012, 7(2), e31964.
 [http://dx.doi.org/10.1371/journal.pone.0031964] [PMID: 22359648]

[161]
Alshehri, S.M.; Shakeel, F.; Ibrahim, M.A.; Elzayat, E.M.; Altamimi, M.; Mohsin, K.; Almeanazel, O.T.; Alkholief, M.; Alshetaili, A.; Alsulays, B.; Alanazi, F.K.; Alsarra, I.A. Dissolution and bioavailability improvement of bioactive apigenin using solid dispersions prepa-red by different techniques. Saudi Pharm. J.,  2019, 27(2), 264-273.
 [http://dx.doi.org/10.1016/j.jsps.2018.11.008] [PMID: 30766439]

[162]
Z, A.G.; Farhood, B.; Noodeh, F.A.; Mosaed, R.; Hassanzadeh, G.; Bagheri, H.; Najafi, M. Histopathological evaluation of nanocurcumin for mitigation of radiation-induced small intestine injury. Curr. Radiopharm.,  15(1)2022, 

[163]
Mabrouk Zayed, M.M.; Sahyon, H.A.; Hanafy, N.A.N.; El-Kemary, M.A. The effect of encapsulated apigenin nanoparticles on HePG-2 Cells through regulation of P53. Pharmaceutics,  2022, 14(6), 1160.
 [http://dx.doi.org/10.3390/pharmaceutics14061160] [PMID: 35745733]

[164]
Yu, Y.; Wang, J.; Kaul, S.C.; Wadhwa, R.; Miyako, E. Folic acid receptor-mediated targeting enhances the cytotoxicity, efficacy, and selec-tivity of Withania somnifera Leaf extract: In vitro and in vivo evidence. Front. Oncol.,  2019, 9, 602.
 [http://dx.doi.org/10.3389/fonc.2019.00602] [PMID: 31334122]

[165]
Yang, R.; Tan, C.; Najafi, M. Cardiac inflammation and fibrosis following chemo/radiation therapy: Mechanisms and therapeutic agents. Inflammopharmacology,  2022, 30(1), 73-89.
 [http://dx.doi.org/10.1007/s10787-021-00894-9] [PMID: 34813027]

[166]
Qu, N.; Itoh, M.; Sakabe, K. Effects of chemotherapy and radiotherapy on spermatogenesis: The role of testicular immunology. Int. J. Mol. Sci.,  2019, 20(4), 957.
 [http://dx.doi.org/10.3390/ijms20040957] [PMID: 30813253]

[167]
Xu, C.; Najafi, M.; Shang, Z. Lung pneumonitis and fibrosis in cancer therapy;
          A review on cellular and molecular mechanisms. Curr. Drug Targets,  2022, 23(16), 1505-1525.
 [http://dx.doi.org/10.2174/1389450123666220907144131] [PMID: 36082868]

[168]
Lai, X.; Najafi, M. Redox interactions in chemo/radiation therapy-induced lung toxicity;
          mechanisms and therapy perspectives. Curr. Drug Targets,  2022, 23(13), 1261-1276.
 [http://dx.doi.org/10.2174/1389450123666220705123315] [PMID: 35792117]

[169]
Amini, P.; Moazamiyanfar, R.; Dakkali, M.S.; Khani, A.; Jafarzadeh, E.; Mouludi, K.; Khodamoradi, E.; Johari, R.; Taeb, S.; Najafi, M. Resveratrol in cancer therapy;
          from stimulation of genomic stability to adjuvant cancer therapy;
          A comprehensive review. Curr. Top. Med. Chem., 2022.
 [PMID: 36239730]

[170]
Popat, R.; Plesner, T.; Davies, F.; Cook, G.; Cook, M.; Elliott, P.; Jacobson, E.; Gumbleton, T.; Oakervee, H.; Cavenagh, J. A phase 2 study of SRT501 (resveratrol) with bortezomib for patients with relapsed and or refractory multiple myeloma. Br. J. Haematol.,  2013, 160(5), 714-717.
 [http://dx.doi.org/10.1111/bjh.12154] [PMID: 23205612]

[171]
Singh, D.; Gupta, M.; Sarwat, M.; Siddique, H.R. Apigenin in cancer prevention and therapy: A systematic review and meta-analysis of animal models. Crit. Rev. Oncol. Hematol.,  2022, 176, 103751.
 [http://dx.doi.org/10.1016/j.critrevonc.2022.103751] [PMID: 35752426]
Rights & Permissions Print Cite
Journal Information
For Authors
For Editors
For Reviewers
Explore Articles
Open Access
Open Access Articles
For Visitors
DOI https://dx.doi.org/10.2174/1389557523666230119110744	Print ISSN 1389-5575
Publisher Name Bentham Science Publisher	Online ISSN 1875-5607
Mini-Reviews in Medicinal Chemistry

Induction of Cancer Cell Death by Apigenin: A Review on Different Cell Death Pathways

Abstract Play Pause

Graphical Abstract

Related Journals

Related Books

Abstract
