Exploring the molecular targets of dietary flavonoid fisetin in cancer

Seminars in Cancer Biology

Volumn 40_41, Issue , 2016, Pages 130-140

  Syed, Deeba N ^a   Adhami, Vaqar Mustafa ^a   Khan, Naghma ^a   Khan, Mohammad Imran ^a   Mukhtar, Hasan ^a  

^a UNIVERSITY OF WISCONSIN SCHOOL OF MEDICINE AND PUBLIC HEALTH   (United States)

Author keywords

Anti oxidant; Apoptosis; Autophagy; Bioavailability; Cancer; Fisetin; Flavonoid; Invasion; Migration

Indexed keywords

FISETIN; REACTIVE OXYGEN METABOLITE; ANTINEOPLASTIC AGENT; FLAVONOID; PLANT EXTRACT;

ANTINEOPLASTIC ACTIVITY; ANTIOXIDANT ACTIVITY; APOPTOSIS; AREA UNDER THE CURVE; AUTOPHAGY; CANCER CELL LINE; CANCER INHIBITION; CELL CYCLE REGULATION; CELL INVASION; CELL MIGRATION; CELL PROLIFERATION; CHEMOSENSITIVITY; DRUG BIOAVAILABILITY; DRUG HALF LIFE; DRUG STRUCTURE; EPITHELIAL MESENCHYMAL TRANSITION; G2 PHASE CELL CYCLE CHECKPOINT; HUMAN; IN VITRO STUDY; IN VIVO STUDY; MALIGNANT NEOPLASTIC DISEASE; MAXIMUM PLASMA CONCENTRATION; MEAN ABSORPTION TIME; MEAN RESIDENCE TIME; MICROTUBULE ASSEMBLY; NONHUMAN; REVIEW; SIGNAL TRANSDUCTION; ANIMAL; DRUG SCREENING; MOLECULARLY TARGETED THERAPY; NEOPLASM;

ANIMALS; ANTINEOPLASTIC AGENTS, PHYTOGENIC; DRUG SCREENING ASSAYS, ANTITUMOR; FLAVONOIDS; HUMANS; MOLECULAR TARGETED THERAPY; NEOPLASMS; PLANT EXTRACTS;

EID: 84975450279     PISSN: 1044579X     EISSN: 10963650     Source Type: Journal    
DOI: 10.1016/j.semcancer.2016.04.003     Document Type: Review

References (91)

1. [1] Salvamani, S., Gunasekaran, B., Shaharuddin, N.A., Ahmad, S.A., Shukor, M.Y., Antiartherosclerotic effects of plant flavonoids. BioMed Res. Int., 2014, 2014, 480258.
2. [2] Arai, Y., Watanabe, S., Kimira, M., Shimoi, K., Mochizuki, R., Kinae, N., Dietary intakes of flavonols, flavones and isoflavones by Japanese women and the inverse correlation between quercetin intake and plasma LDL cholesterol concentration. J. Nutr. 130 (2000), 2243–2250.
3. [3] Khan, N., Afaq, F., Syed, D.N., Fisetin, Mukhtar H., a novel dietary flavonoid, causes apoptosis and cell cycle arrest in human prostate cancer LNCaP cells. Carcinogenesis 29 (2008), 1049–1056.
4. [4] Kim, J.A., Lee, S., Kim, D.E., Kim, M., Kwon, B.M., Fisetin, Han D.C., a dietary flavonoid, induces apoptosis of cancer cells by inhibiting HSF1 activity through blocking its binding to the hsp70 promoter. Carcinogenesis 36 (2015), 696–706.
5. [5] Syed, D.N., Lall, R.K., Chamcheu, J.C., Haidar, O., Mukhtar, H., Involvement of ER stress and activation of apoptotic pathways in fisetin induced cytotoxicity in human melanoma. Arch. Biochem. Biophys. 563 (2014), 108–117.
6. [6] Pal, H.C., Sharma, S., Elmets, C.A., Athar, M., Afaq, F., Fisetin inhibits growth, induces G(2)/M arrest and apoptosis of human epidermoid carcinoma A431 cells: role of mitochondrial membrane potential disruption and consequent caspases activation. Exp. Dermatol. 22 (2013), 470–475.
7. [7] Haddad, A.Q., Fleshner, N., Nelson, C., Saour, B., Musquera, M., Venkateswaran, V., et al. Antiproliferative mechanisms of the flavonoids 2,2′-dihydroxychalcone and fisetin in human prostate cancer cells. Nutr. Cancer 62 (2010), 668–681.
8. [8] Khan, N., Syed, D.N., Ahmad, N., Mukhtar, H., Fisetin: a dietary antioxidant for health promotion. Antioxid. Redox Signaling 19 (2013), 151–162.
9. [9] Shia, C.S., Tsai, S.Y., Kuo, S.C., Hou, Y.C., Chao, P.D., Metabolism and pharmacokinetics of 3,3’,4’,7-tetrahydroxyflavone (fisetin), 5-hydroxyflavone, and 7-hydroxyflavone and antihemolysis effects of fisetin and its serum metabolites. J. Agric. Food Chem. 57 (2009), 83–89.
10. [10] Touil, Y.S., Auzeil, N., Boulinguez, F., Saighi, H., Regazzetti, A., Scherman, D., et al. Fisetin disposition and metabolism in mice: identification of geraldol as an active metabolite. Biochem. Pharmacol. 82 (2011), 1731–1739.
11. [11] Guzzo, M.R., Uemi, M., Donate, P.M., Nikolaou, S., Machado, A.E., Okano, L.T., Study of the complexation of fisetin with cyclodextrins. J. Phys. Chem. A 110 (2006), 10545–10551.
12. [12] Bothiraja, C., Yojana, B.D., Pawar, A.P., Shaikh, K.S., Thorat, U.H., Fisetin-loaded nanocochleates: formulation, characterisation, in vitro anticancer testing, bioavailability and biodistribution study. Expert Opin. Drug Deliv. 11 (2014), 17–29.
13. [13] Jeong, D., Choi, J.M., Choi, Y., Jeong, K., Cho, E., Jung, S., Complexation of fisetin with novel cyclosophoroase dimer to improve solubility and bioavailability. Carbohydr. Polym. 97 (2013), 196–202.
14. [14] Seguin, J., Brulle, L., Boyer, R., Lu, Y.M., Ramos Romano, M., Touil, Y.S., et al. Liposomal encapsulation of the natural flavonoid fisetin improves bioavailability and antitumor efficacy. Int. J. Pharm. 444 (2013), 146–154.
15. [15] Ragelle, H., Crauste-Manciet, S., Seguin, J., Brossard, D., Scherman, D., Arnaud, P., et al. Nanoemulsion formulation of fisetin improves bioavailability and antitumour activity in mice. Int. J. Pharm. 427 (2012), 452–459.
16. [16] Aruoma, O.I., Methodological considerations for characterizing potential antioxidant actions of bioactive components in plant foods. Mutat. Res. 52 (2003), 3–524 (9–20).
17. [17] Markovic, Z.S., Mentus, S.V., Dimitric Markovic, J.M., Electrochemical and density functional theory study on the reactivity of fisetin and its radicals: implications on in vitro antioxidant activity. J. Phys. Chem. A 113 (2009), 14170–14179.
18. [18] Ishige, K., Schubert, D., Sagara, Y., Flavonoids protect neuronal cells from oxidative stress by three distinct mechanisms. Free Radic. Biol. Med. 30 (2001), 433–446.
19. [19] Sengupta, B., Banerjee, A., Sengupta, P.K., Investigations on the binding and antioxidant properties of the plant flavonoid fisetin in model biomembranes. FEBS Lett. 570 (2004), 77–81.
20. [20] Firuzi, O., Lacanna, A., Petrucci, R., Marrosu, G., Saso, L., Evaluation of the antioxidant activity of flavonoids by ferric reducing antioxidant power assay and cyclic voltammetry. Biochim. Biophys. Acta 1721 (2005), 174–184.
21. [21] Burdo, J., Schubert, D., Maher, P., Glutathione production is regulated via distinct pathways in stressed and non-stressed cortical neurons. Brain Res. 1189 (2008), 12–22.
22. [22] Cho, N., Choi, J.H., Yang, H., Jeong, E.J., Lee, K.Y., Kim, Y.C., et al. Neuroprotective and anti-inflammatory effects of flavonoids isolated from Rhus verniciflua in neuronal HT22 and microglial BV2 cell lines. Food Chem. Toxicol. 50 (2012), 1940–1945.
23. [23] Lee, S.E., Jeong, S.I., Yang, H., Park, C.S., Jin, Y.H., Park, Y.S., Fisetin induces Nrf2-mediated HO-1 expression through PKC-delta and p38 in human umbilical vein endothelial cells. J. Cell. Biochem. 112 (2011), 2352–2360.
24. [24] Feng, G., Jiang, Z.Y., Sun, B., Fu, J., Li, T.Z., Fisetin alleviates lipopolysaccharide-Induced acute lung injury via TLR4-mediated NF-kappaB signaling pathway in rats. Inflammation 39 (2016), 148–157.
25. [25] Sahu, B.D., Kalvala, A.K., Koneru, M., Mahesh Kumar, J., Kuncha, M., Rachamalla, S.S., et al. Ameliorative effect of fisetin on cisplatin-induced nephrotoxicity in rats via modulation of NF-kappaB activation and antioxidant defence. PLoS One, 9, 2014, e105070.
26. [26] Adhami, V.M., Syed, D.N., Khan, N., Mukhtar, H., Dietary flavonoid fisetin: a novel dual inhibitor of PI3K/Akt and mTOR for prostate cancer management. Biochem. Pharmacol. 84 (2012), 1277–1281.
27. [27] Khan, N., Asim, M., Afaq, F., Abu Zaid, M., Mukhtar, H., A novel dietary flavonoid fisetin inhibits androgen receptor signaling and tumor growth in athymic nude mice. Cancer Res. 68 (2008), 8555–8563.
28. [28] Suh, Y., Afaq, F., Khan, N., Johnson, J.J., Khusro, F.H., Mukhtar, H., Fisetin induces autophagic cell death through suppression of mTOR signaling pathway in prostate cancer cells. Carcinogenesis 31 (2010), 1424–1433.
29. [29] Syed, D.N., Adhami, V.M., Khan, M.I., Mukhtar, H., Inhibition of Akt/mTOR signaling by the dietary flavonoid fisetin. Anticancer Agents Med. Chem. 13 (2013), 995–1001.
30. [30] Khan, N., Afaq, F., Khusro, F.H., Mustafa Adhami, V., Suh, Y., Mukhtar, H., Dual inhibition of phosphatidylinositol 3-kinase/Akt and mammalian target of rapamycin signaling in human non-small cell lung cancer cells by a dietary flavonoid fisetin. Int. J. Cancer 130 (2012), 1695–1705.
31. [31] Syed, D.N., Afaq, F., Maddodi, N., Johnson, J.J., Sarfaraz, S., Ahmad, A., et al. Inhibition of human melanoma cell growth by the dietary flavonoid fisetin is associated with disruption of Wnt/beta-catenin signaling and decreased Mitf levels. J. Invest. Dermatol. 131 (2011), 1291–1299.
32. [32] Syed, D.N., Chamcheu, J.C., Khan, M.I., Sechi, M., Lall, R.K., Adhami, V.M., et al. Fisetin inhibits human melanoma cell growth through direct binding to p70S6K and mTOR: findings from 3-D melanoma skin equivalents and computational modeling. Biochem. Pharmacol. 89 (2014), 349–360.
33. [33] Pal, H.C., Diamond, A.C., Strickland, L.R., Kappes, J.C., Katiyar, S.K., Elmets, C.A., et al. Fisetin, a dietary flavonoid, augments the anti-invasive and anti-metastatic potential of sorafenib in melanoma. Oncotarget 7 (2016), 1227–1241.
34. [34] Noh, E.M., Park, Y.J., Kim, J.M., Kim, M.S., Kim, H.R., Song, H.K., et al. Fisetin regulates TPA-induced breast cell invasion by suppressing matrix metalloproteinase-9 activation via the PKC/ROS/MAPK pathways. Eur. J. Pharmacol. 764 (2015), 79–86.
35. [35] Yang, P.M., Tseng, H.H., Peng, C.W., Chen, W.S., Chiu, S.J., Dietary flavonoid fisetin targets caspase-3-deficient human breast cancer MCF-7 cells by induction of caspase-7-associated apoptosis and inhibition of autophagy. Int. J. Oncol. 40 (2012), 469–478.
36. [36] Tsiklauri, L., An, G., Ruszaj, D.M., Alaniya, M., Kemertelidze, E., Morris, M.E., Simultaneous determination of the flavonoids robinin and kaempferol in human breast cancer cells by liquid chromatography-tandem mass spectrometry. J. Pharm. Biomed. Anal. 55 (2011), 109–113.
37. [37] Chou, R.H., Hsieh, S.C., Yu, Y.L., Huang, M.H., Huang, Y.C., Hsieh, Y.H., Fisetin inhibits migration and invasion of human cervical cancer cells by down-regulating urokinase plasminogen activator expression through suppressing the p38 MAPK-dependent NF-kappaB signaling pathway. PLoS One, 8, 2013, e71983.
38. [38] Ying, T.H., Yang, S.F., Tsai, S.J., Hsieh, S.C., Huang, Y.C., Bau, D.T., et al. Fisetin induces apoptosis in human cervical cancer HeLa cells through ERK1/2-mediated activation of caspase-8-/caspase-3-dependent pathway. Arch. Toxicol. 86 (2012), 263–273.
39. [39] Chen, Y., Wu, Q., Song, L., He, T., Li, Y., Li, L., et al. Polymeric micelles encapsulating fisetin improve the therapeutic effect in colon cancer. ACS Appl. Mater. Interfaces 7 (2015), 534–542.
40. [40] Wu, M.S., Lien, G.S., Shen, S.C., Yang, L.Y., Chen, Y.C., N-acetyl-L-cysteine enhances fisetin-induced cytotoxicity via induction of ROS-independent apoptosis in human colonic cancer cells. Mol. Carcinog. 53:Suppl. 1 (2014), 119–129.
41. [41] Wu, M.S., Lien, G.S., Shen, S.C., Yang, L.Y., Chen, Y.C., HSP90 inhibitors, geldanamycin and radicicol, enhance fisetin-induced cytotoxicity via induction of apoptosis in human colonic cancer cells. Evid. Based Complement. Altern. Med., 2013, 2013, 987612.
42. [42] Lim do, Y., Park, J.H., Induction of p53 contributes to apoptosis of HCT-116 human colon cancer cells induced by the dietary compound fisetin. Am. J. Physiol. Gastrointest. Liver Physiol. 296 (2009), G1060–8.
43. [43] Suh, Y., Afaq, F., Johnson, J.J., Mukhtar, H., A plant flavonoid fisetin induces apoptosis in colon cancer cells by inhibition of COX2 and Wnt/EGFR/NF-kappaB-signaling pathways. Carcinogenesis 30 (2009), 300–307.
44. [44] Dickson, M.A., Schwartz, G.K., Development of cell-cycle inhibitors for cancer therapy. Curr. Oncol. 16 (2009), 36–43.
45. [45] Lee, Y., Bae, E.J., Inhibition of mitotic clonal expansion mediates fisetin-exerted prevention of adipocyte differentiation in 3T3-L1 cells. Arch. Pharmacal Res. 36 (2013), 1377–1384.
46. [46] Haddad, A.Q., Venkateswaran, V., Viswanathan, L., Teahan, S.J., Fleshner, N.E., Klotz, L.H., Novel antiproliferative flavonoids induce cell cycle arrest in human prostate cancer cell lines. Prostate Cancer Prostatic Dis. 9 (2006), 68–76.
47. [47] Lu, X., Jung, J., Cho, H.J., Lim, D.Y., Lee, H.S., Chun, H.S., et al. Fisetin inhibits the activities of cyclin-dependent kinases leading to cell cycle arrest in HT-29 human colon cancer cells. J. Nutr. 135 (2005), 2884–2890.
48. [48] Lu, H., Chang, D.J., Baratte, B., Meijer, L., Schulze-Gahmen, U., Crystal structure of a human cyclin-dependent kinase 6 complex with a flavonol inhibitor, fisetin. J. Med. Chem. 48 (2005), 737–743.
49. [49] Khuntawee, W., Rungrotmongkol, T., Hannongbua, S., Molecular dynamic behavior and binding affinity of flavonoid analogues to the cyclin dependent kinase 6/cyclin D complex. J. Chem. Inf. Model. 52 (2012), 76–83.
50. [50] Mitchison, T.J., Microtubule dynamics and kinetochore function in mitosis. Annu. Rev. Cell Biol. 4 (1988), 527–549.
51. [51] Giannakakou, P., Sackett, D., Fojo, T., Tubulin/microtubules: still a promising target for new chemotherapeutic agents. J. Natl. Cancer Inst. 92 (2000), 182–183.
52. [52] Salmela, A.L., Pouwels, J., Varis, A., Kukkonen, A.M., Toivonen, P., Halonen, P.K., et al. Dietary flavonoid fisetin induces a forced exit from mitosis by targeting the mitotic spindle checkpoint. Carcinogenesis 30 (2009), 1032–1040.
53. [53] Gollapudi, P., Hasegawa, L.S., Eastmond, D.A., A comparative study of the aneugenic and polyploidy-inducing effects of fisetin and two model Aurora kinase inhibitors. Mutat. Res. Genet. Toxicol. Environ. Mutagen. 767 (2014), 37–43.
54. [54] Touil, Y.S., Fellous, A., Scherman, D., Chabot, G.G., Flavonoid-induced morphological modifications of endothelial cells through microtubule stabilization. Nutr. Cancer 61 (2009), 310–321.
55. [55] Mukhtar, E., Adhami, V.M., Sechi, M., Mukhtar, H., Dietary flavonoid fisetin binds to beta-tubulin and disrupts microtubule dynamics in prostate cancer cells. Cancer Lett. 367 (2015), 173–183.
56. [56] Toso, A., Revandkar, A., Di Mitri, D., Guccini, I., Proietti, M., Sarti, M., et al. Enhancing chemotherapy efficacy in Pten-deficient prostate tumors by activating the senescence-associated antitumor immunity. Cell Rep. 9 (2014), 75–89.
57. [57] Antonarakis, E.S., Keizman, D., Zhang, Z., Gurel, B., Lotan, T.L., Hicks, J.L., et al. An immunohistochemical signature comprising PTEN, MYC, and Ki67 predicts progression in prostate cancer patients receiving adjuvant docetaxel after prostatectomy. Cancer 118 (2012), 6063–6071.
58. [58] Mukhtar, E., Adhami, V.M., Mukhtar, H., Fisetin enhances the efficacy of cabazitaxel chemotherapy in prostate metastatic and multidrug-resistant cancer cells. Cancer Res., 74(Suppl. 19), 2014 (Abstract # 835).
59. [59] Mukhtar, E., Adhami, V.M., Sechi, M., Mukhtar, H., Fisetin enhances the efficacy of cabazitaxel: an in vitro and in vivo study in prostate cancer. Cancer Res., 75(Suppl. 15), 2015 (Abstract # 2531).
60. [60] Chien, C.S., Shen, K.H., Huang, J.S., Ko, S.C., Shih, Y.W., Antimetastatic potential of fisetin involves inactivation of the PI3 K/Akt and JNK signaling pathways with downregulation of MMP-2/9 expressions in prostate cancer PC-3 cells. Mol. Cell. Biochem. 333 (2010), 169–180.
61. [61] Liao, Y.C., Shih, Y.W., Chao, C.H., Lee, X.Y., Chiang, T.A., Involvement of the ERK signaling pathway in fisetin reduces invasion and migration in the human lung cancer cell line A549. J. Agric. Food Chem. 57 (2009), 8933–8941.
62. [62] Chen, C.M., Hsieh, Y.H., Hwang, J.M., Jan, H.J., Hsieh, S.C., Lin, S.H., et al. Fisetin suppresses ADAM9 expression and inhibits invasion of glioma cancer cells through increased phosphorylation of ERK1/2. Tumour Biol. 36 (2015), 3407–3415.
63. [63] Chaffer, C.L., Weinberg, R.A., A perspective on cancer cell metastasis. Science. 331 (2011), 1559–1564.
64. [64] Li, R., Zhao, Y., Chen, J., Shao, S., Zhang, X., Fisetin inhibits migration, invasion and epithelial-mesenchymal transition of LMP1-positive nasopharyngeal carcinoma cells. Mol. Med. Rep. 9 (2014), 413–418.
65. [65] Khan, M.I., Adhami, V.M., Lall, R.K., Sechi, M., Joshi, D.C., Haidar, O.M., et al. YB-1 expression promotes epithelial-to-mesenchymal transition in prostate cancer that is inhibited by a small molecule fisetin. Oncotarget 5 (2014), 2462–2474.
66. [66] Lee, W.R., Shen, S.C., Lin, H.Y., Hou, W.C., Yang, L.L., Chen, Y.C., Wogonin and fisetin induce apoptosis in human promyeloleukemic cells, accompanied by a decrease of reactive oxygen species, and activation of caspase 3 and Ca(2+)-dependent endonuclease. Biochem. Pharmacol. 63 (2002), 225–236.
67. [67] Chen, Y.C., Shen, S.C., Lee, W.R., Lin, H.Y., Ko, C.H., Shih, C.M., et al. Wogonin and fisetin induction of apoptosis through activation of caspase 3 cascade and alternative expression of p21 protein in hepatocellular carcinoma cells SK-HEP-1. Arch. Toxicol. 76 (2002), 351–359.
68. [68] Ravichandran, N., Suresh, G., Ramesh, B., Manikandan, R., Choi, Y.W., Vijaiyan Siva, G., Fisetin modulates mitochondrial enzymes and apoptotic signals in benzo(a)pyrene-induced lung cancer. Mol. Cell. Biochem. 390 (2014), 225–234.
69. [69] Yu, S.H., Yang, P.M., Peng, C.W., Yu, Y.C., Chiu, S.J., Securin depletion sensitizes human colon cancer cells to fisetin-induced apoptosis. Cancer Lett. 300 (2011), 96–104.
70. [70] Monasterio, A., Urdaci, M.C., Pinchuk, I.V., Lopez-Moratalla, N., Martinez-Irujo, J.J., Flavonoids induce apoptosis in human leukemia U937 cells through caspase- and caspase-calpain-dependent pathways. Nutr. Cancer 50 (2004), 90–100.
71. [71] Yuan, C.H., Filippova, M., Tungteakkhun, S.S., Duerksen-Hughes, P.J., Krstenansky, J.L., Small molecule inhibitors of the HPV16-E6 interaction with caspase 8. Bioorg. Med. Chem. Lett. 22 (2012), 2125–2129.
72. [72] Murtaza, I., Adhami, V.M., Hafeez, B.B., Saleem, M., Mukhtar, H., Fisetin a natural flavonoid, targets chemoresistant human pancreatic cancer AsPC-1 cells through DR3-mediated inhibition of NF-kappaB. Int. J. Cancer 125 (2009), 2465–2473.
73. [73] Sung, B., Pandey, M.K., Aggarwal, B.B., Fisetin an inhibitor of cyclin-dependent kinase 6, down-regulates nuclear factor-kappaB-regulated cell proliferation, antiapoptotic and metastatic gene products through the suppression of TAK-1 and receptor-interacting protein-regulated IkappaBalpha kinase activation. Mol. Pharmacol. 71 (2007), 1703–1714.
74. [74] Li, R., Liang, H.Y., Li, M.Y., Lin, C.Y., Shi, M.J., Zhang, X.J., Interference of fisetin with targets of the nuclear factor-kappaB signal transduction pathway activated by Epstein-Barr virus encoded latent membrane protein 1. Asian Pac. J. Cancer Prev. (APJCP) 15 (2014), 9835–9839.
75. [75] Li, J., Cheng, Y., Qu, W., Sun, Y., Wang, Z., Wang, H., et al. Fisetin, a dietary flavonoid, induces cell cycle arrest and apoptosis through activation of p53 and inhibition of NF-kappa B pathways in bladder cancer cells. Basic Clin. Pharmacol. Toxicol. 108 (2011), 84–93.
76. [76] Li, J., Qu, W., Cheng, Y., Sun, Y., Jiang, Y., Zou, T., et al. The inhibitory effect of intravesical fisetin against bladder cancer by induction of p53 and down-regulation of NF-kappa B pathways in a rat bladder carcinogenesis model. Basic Clin. Pharmacol. Toxicol. 115 (2014), 321–329.
77. [77] Kang, K.A., Piao, M.J., Hyun, J.W., Fisetin induces apoptosis in human non-small lung cancer cells via a mitochondria-mediated pathway. In Vitro Cell. Dev. Biol. Anim. 51 (2015), 300–309.
78. [78] Kim, J.Y., Jeon, Y.K., Jeon, W., Nam, M.J., Fisetin induces apoptosis in Huh-7 cells via downregulation of BIRC8 and Bcl2L2. Food Chem. Toxicol. 48 (2010), 2259–2264.
79. [79] Jang, K.Y., Jeong, S.J., Kim, S.H., Jung, J.H., Kim, J.H., Koh, W., et al. Activation of reactive oxygen species/AMP activated protein kinase signaling mediates fisetin-induced apoptosis in multiple myeloma U266 cells. Cancer Lett. 319 (2012), 197–202.
80. [80] Ash, D., Subramanian, M., Surolia, A., Shaha, C., Nitric oxide is the key mediator of death induced by fisetin in human acute monocytic leukemia cells. Am. J. Cancer Res. 5 (2015), 481–497.
81. [81] Piao, M.J., Kim, K.C., Chae, S., Keum, Y.S., Kim, H.S., Hyun, J.W., Protective effect of fisetin (3,7,3’,4’-tetrahydroxyflavone) against gamma-irradiation-induced oxidative stress and cell damage. Biomolecules Ther. 21 (2013), 210–215.
82. [82] Mukhopadhyay, S., Panda, P.K., Sinha, N., Das, D.N., Bhutia, S.K., Autophagy and apoptosis: where do they meet?. Apoptosis 19 (2014), 555–566.
83. [83] Yi, C., Zhang, Y., Yu, Z., Xiao, Y., Wang, J., Qiu, H., et al. Melatonin enhances the anti-tumor effect of fisetin by inhibiting COX-2/iNOS and NF-kappaB/p300 signaling pathways. PLoS One, 9, 2014, e99943.
84. [84] Pal, H.C., Baxter, R.D., Hunt, K.M., Agarwal, J., Elmets, C.A., Athar, M., et al. Fisetin, a phytochemical, potentiates sorafenib-induced apoptosis and abrogates tumor growth in athymic nude mice implanted with BRAF-mutated melanoma cells. Oncotarget 6 (2015), 28296–28311.
85. [85] Lin, M.T., Lin, C.L., Lin, T.Y., Cheng, C.W., Yang, S.F., Lin, C.L., et al. Synergistic effect of fisetin combined with sorafenib in human cervical cancer HeLa cells through activation of death receptor-5 mediated caspase-8/caspase-3and the mitochondria-dependent apoptotic pathway. Tumour Biol., 2015 (Epub ahead of print).
86. [86] Adan, A., Baran, Y., Fisetin and hesperetin induced apoptosis and cell cycle arrest in chronic myeloid leukemia cells accompanied by modulation of cellular signaling. Tumour Biol., 2015 (Epub ahead of print).
87. [87] Chen, W.S., Lee, Y.J., Yu, Y.C., Hsaio, C.H., Yen, J.H., Yu, S.H., et al. Enhancement of p53-mutant human colorectal cancer cells radiosensitivity by flavonoid fisetin. Int. J. Radiat. Oncol. Biol. Phys. 77 (2010), 1527–1535.
88. [88] Tripathi, R., Samadder, T., Gupta, S., Surolia, A., Shaha, C., Anticancer activity of a combination of cisplatin and fisetin in embryonal carcinoma cells and xenograft tumors. Mol. Cancer Ther. 10 (2011), 255–268.
89. [89] Zhuo, W., Zhang, L., Zhu, Y., Zhu, B., Chen, Z., Fisetin, a dietary bioflavonoid, reverses acquired Cisplatin-resistance of lung adenocarcinoma cells through MAPK/Survivin/Caspase pathway. Am. J. Transl. Res. 7 (2015), 2045–2052.
90. [90] Watjen, W., Michels, G., Steffan, B., Niering, P., Chovolou, Y., Kampkotter, A., et al. Low concentrations of flavonoids are protective in rat H4IIE cells whereas high concentrations cause DNA damage and apoptosis. J. Nutr. 135 (2005), 525–531.
91. [91] Inkielewicz-Stepniak, I., Radomski, M.W., Wozniak, M., Fisetin prevents fluoride- and dexamethasone-induced oxidative damage in osteoblast and hippocampal cells. Food Chem. Toxicol. 50 (2012), 583–589.