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Flavonoids as Emerging Anticancer Agents: Current Trends and Recent Advances in Phytotherapy

  • Dharambir Kashyap
  • Hardeep Singh Tuli
  • Mukerrem Betul Yerer
  • Anil K. Sharma
  • Harpal Singh Buttar
  • M. Youns
  • Javad Sharifi-Rad
  • Bahare Salehi
  • William N. Setzer
Chapter

Abstract

In recent years, the burden of several chronic diseases, including cancer, has increased rapidly worldwide. Although there are several diagnostic and treatment options available to health-care providers, the cancer-induced mortality rate is escalating globally. Interestingly enough, the development and utilization of plant-derived natural compounds therapy for the prevention and treatment of cancer are being rigorously pursued by overwhelming number of investigators. In the category of natural compounds, flavonoids occupy an important place and are being extensively studied in animal models and cancer patients to evaluate their anticancer potential. The chemopreventive role of flavonoids and their underlying mechanisms of action against cancer have been well documented in the literature. The present chapter summarizes the purported cellular, molecular, and genetic mechanisms of anticancer action of flavonoids, such as apoptosis induction, cell cycle arrest, anti-angiogenesis, anti-metastasis, and anti-inflammatory and antioxidant aspects. In addition, the anticancer roles of related flavonols (quercetin), flavones (luteolin), isoflavone (genistein), anthocyanidin (cyanidin), flavanone (naringenin), and flavan-3-ols (epigallocatechin-3-gallate) are also described.

Keywords

Flavonoids Apoptosis Cell cycle arrest Anti-angiogenesis Anti-metastasis Synergistic effect Topoisomerase II miRNA 

Notes

Acknowledgments

The authors would like to acknowledge the assistance of Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, and Maharishi Markandeshwar (deemed to be university), Mullana, Ambala, Haryana, for providing the required facilities to complete this study.

Conflict of Interest

There exists no conflict of interest amongst authors regarding the publication of this book chapter.

References

  1. Aalinkeel R, Bindukumar B, Reynolds JL, Sykes DE, Mahajan SD, Chadha KC, Schwartz SA (2008) The dietary bioflavonoid, quercetin, selectively induces apoptosis of prostate cancer cells by down-regulating the expression of heat shock protein 90. Prostate 68:1773–1789.  https://doi.org/10.1002/pros.20845 PubMedPubMedCentralCrossRefGoogle Scholar
  2. Ahamad MS, Siddiqui S, Jafri A, Ahmad S, Afzal M, Arshad M (2014) Induction of apoptosis and antiproliferative activity of naringenin in human epidermoid carcinoma cell through ROS generation and cell cycle arrest. PLoS One 9:e110003.  https://doi.org/10.1371/journal.pone.0110003 PubMedPubMedCentralCrossRefGoogle Scholar
  3. Alberts B, Johnson A, Lewis J et al (2014) Components of the cell-cycle control system. In: Molecular biology of the cell. Garland Science, New York, p 2002Google Scholar
  4. Aneknan P, Kukongviriyapan V, Prawan A, Kongpetch S, Sripa B, Senggunprai L (2014) Luteolin arrests cell cycling, induces apoptosis and inhibits the JAK/STAT3 pathway in human cholangiocarcinoma cells. Asian Pac J Cancer Prev 15:5071–5076.  https://doi.org/10.7314/APJCP.2014.15.12.5071 CrossRefGoogle Scholar
  5. Appari M, Babu KR, Kaczorowski A, Gross W, Herr I (2014) Sulforaphane, quercetin and catechins complement each other in elimination of advanced pancreatic cancer by miR-let-7 induction and K-ras inhibition. Int J Oncol 45:1391–1400.  https://doi.org/10.3892/ijo.2014.2539 PubMedPubMedCentralCrossRefGoogle Scholar
  6. Argyriou AA, Giannopoulou E, Kalofonos HP (2009) Angiogenesis and anti-angiogenic molecularly targeted therapies in malignant gliomas. Oncology 77:1.  https://doi.org/10.1159/000218165 CrossRefGoogle Scholar
  7. Arias N, Macarulla MT, Aguirre L, Milton I, Portillo MP (2016) The combination of resveratrol and quercetin enhances the individual effects of these molecules on triacylglycerol metabolism in white adipose tissue. Eur J Nutr 55:341–348.  https://doi.org/10.1007/s00394-015-0854-9 CrossRefGoogle Scholar
  8. Article O, Samavati SF, Mostafaie A (2014) A highly pure sub-fraction of shallot extract with potent in vitro anti-angiogenic activity. Int J Mol Cell Med 3:237–245Google Scholar
  9. Arul D, Subramanian P (2013) Naringenin (Citrus Flavonone) induces growth inhibition, cell cycle arrest and apoptosis in human hepatocellular carcinoma cells. Pathol Oncol Res 19:763–770.  https://doi.org/10.1007/s12253-013-9641-1 CrossRefGoogle Scholar
  10. Ashokkumar P, Sudhandiran G (2008) Protective role of luteolin on the status of lipid peroxidation and antioxidant defense against azoxymethane-induced experimental colon carcinogenesis. Biomed Pharmacother 62:590–597.  https://doi.org/10.1016/j.biopha.2008.06.031 CrossRefGoogle Scholar
  11. Ashokkumar P, Sudhandiran G (2011) Luteolin inhibits cell proliferation during Azoxymethane-induced experimental colon carcinogenesis via Wnt/β-catenin pathway. Investig New Drugs 29:273–284.  https://doi.org/10.1007/s10637-009-9359-9 CrossRefGoogle Scholar
  12. Atashpour S, Fouladdel S, Movahhed TK, Barzegar E, Ghahremani MH, Ostad SN, Azizi E (2015) Quercetin induces cell cycle arrest and apoptosis in CD133 + cancer stem cells of human colorectal HT29 cancer cell line and enhances anticancer effects of doxorubicin. Iran J Basic Med Sci 18:635–643PubMedPubMedCentralGoogle Scholar
  13. Bądziul D, Jakubowicz-Gil J, Langner E, Rzeski W, Głowniak K, Gawron A (2014) The effect of quercetin and imperatorin on programmed cell death induction in T98G cells in vitro. Pharmacol Rep 66:292–300.  https://doi.org/10.1016/j.pharep.2013.10.003 CrossRefGoogle Scholar
  14. Balamurugan K, Karthikeyan J (2012a) Evaluation of the antioxidant and anti-inflammatory nature of luteolin in experimentally induced hepatocellular carcinoma. Biomed Prev Nutr 2:86–90.  https://doi.org/10.1016/j.bionut.2012.01.002 CrossRefGoogle Scholar
  15. Balamurugan K, Karthikeyan J (2012b) Evaluation of luteolin in the prevention of N-nitrosodiethylamine-induced hepatocellular carcinoma using animal model system. Indian J Clin Biochem 27:157–163.  https://doi.org/10.1007/s12291-011-0166-7 CrossRefGoogle Scholar
  16. Banerjee T, Van der Vliet A, Ziboh VA (2002) Downregulation of COX-2 and iNOS by amentoflavone and quercetin in A549 human lung adenocarcinoma cell line. Prostaglandins Leukot Essent Fat Acids 66:485–492.  https://doi.org/10.1054/plef.2002.0387 CrossRefGoogle Scholar
  17. Bao L, Liu F, Guo H b, Li Y, Tan B b, Zhang W x, Peng Y h (2016) Naringenin inhibits proliferation, migration, and invasion as well as induces apoptosis of gastric cancer SGC7901 cell line by downregulation of AKT pathway. Tumor Biol 37:11365–11374.  https://doi.org/10.1007/s13277-016-5013-2 CrossRefGoogle Scholar
  18. Battegay EJ (1995) Angiogenesis: mechanistic insights, neovascular diseases, and therapeutic prospects. J Mol Med 73:333.  https://doi.org/10.1007/BF00192885 CrossRefGoogle Scholar
  19. Bauer D, Redmon N, Mazzio E, Soliman KF (2017) Apigenin inhibits TNFα/IL-1α-induced CCL2 release through IKBK-epsilon signaling in MDA-MB-231 human breast cancer cells. PLoS One 12(4):e0175558.  https://doi.org/10.1371/journal.pone.0175558 CrossRefPubMedPubMedCentralGoogle Scholar
  20. Bodduluru LN, Kasala ER, Madhana RM, Barua CC, Hussain MI, Haloi P, Borah P (2016) Naringenin ameliorates inflammation and cell proliferation in benzo(a)pyrene induced pulmonary carcinogenesis by modulating CYP1A1, NFκB and PCNA expression. Int Immunopharmacol 30:102–110.  https://doi.org/10.1016/j.intimp.2015.11.036 CrossRefGoogle Scholar
  21. Brito AF, Ribeiro M, Abrantes AM, Pires AS, Teixo RJ, Tralhão JG, Botelho MF (2015) Quercetin in cancer treatment, alone or in combination with conventional therapeutics? Curr Med Chem 22:3025–3039.  https://doi.org/10.2174/0929867322666150812145435 CrossRefGoogle Scholar
  22. Brooks SA, Lomax-Browne HJ, Carter TM, Kinch CE, Hall DMS (2010) Molecular interactions in cancer cell metastasis. Acta Histochem.  https://doi.org/10.1016/j.acthis.2008.11.022 CrossRefGoogle Scholar
  23. Brown A, Jolly P, Wei H (1998) Genistein modulates neuroblastoma cell proliferation and differentiation through induction of apoptosis and regulation of tyrosine kinase activity and N-myc expression. Carcinogenesis 19:991–997.  https://doi.org/10.1093/carcin/19.6.991 CrossRefGoogle Scholar
  24. Cai X, Ye T, Liu C, Lu W, Lu M, Zhang J, Wang M, Cao P (2011) Luteolin induced G2 phase cell cycle arrest and apoptosis on non-small cell lung cancer cells. Toxicol Vitr 25:1385–1391.  https://doi.org/10.1016/j.tiv.2011.05.009 CrossRefGoogle Scholar
  25. Cai X, Lu W, Ye T, Lu M, Wang J, Huo J, Qian S, Wang X, Cao P (2012) The molecular mechanism of luteolin-induced apoptosis is potentially related to inhibition of angiogenesis in human pancreatic carcinoma cells. Oncol Rep 28:1353–1361.  https://doi.org/10.3892/or.2012.1914 CrossRefGoogle Scholar
  26. Cao HH, Tse AKW, Kwan HY, Yu H, Cheng CY, Su T, Fong WF, Yu ZL (2014) Quercetin exerts anti-melanoma activities and inhibits STAT3 signaling. Biochem Pharmacol 87:424–434.  https://doi.org/10.1016/j.bcp.2013.11.008 CrossRefGoogle Scholar
  27. Cao H-H, Cheng C-Y, Su T, Fu X-Q, Guo H, Li T, Tse AK-W, Kwan H-Y, Yu H, Yu Z-L (2015) Quercetin inhibits HGF/c-Met signaling and HGF-stimulated melanoma cell migration and invasion. Mol Cancer 14:103.  https://doi.org/10.1186/s12943-015-0367-4 PubMedPubMedCentralCrossRefGoogle Scholar
  28. Chakrabarti M, Ray SK (2016) Anti-tumor activities of luteolin and silibinin in glioblastoma cells: overexpression of miR-7-1-3p augmented luteolin and silibinin to inhibit autophagy and induce apoptosis in glioblastoma in vivo. Apoptosis 21:312–328.  https://doi.org/10.1007/s10495-015-1198-x CrossRefGoogle Scholar
  29. Chan S-T, Yang N-C, Huang C-S, Liao J-W, Yeh S-L (2013) Quercetin enhances the antitumor activity of Trichostatin a through upregulation of p53 protein expression in vitro and in vivo. PLoS One 8(1):e54255.  https://doi.org/10.1371/journal.pone.0054255 CrossRefPubMedPubMedCentralGoogle Scholar
  30. Chandrika BB, Steephan M, Kumar TRRS, Sabu A, Haridas M (2016) Hesperetin and Naringenin sensitize HER2 positive cancer cells to death by serving as HER2 Tyrosine Kinase inhibitors. Life Sci 160:47–56.  https://doi.org/10.1016/j.lfs.2016.07.007 CrossRefGoogle Scholar
  31. Chang KL, Kung ML, Chow NH, Su SJ (2004) Genistein arrests hepatoma cells at G2/M phase: Involvement of ATM activation and upregulation of p21waf1/cip1and Wee1. Biochem Pharmacol 67:717–726.  https://doi.org/10.1016/j.bcp.2003.10.003 CrossRefGoogle Scholar
  32. Chang JS, Hsu YL, Kuo PL, Kuo YC, Chiang LC, Lin CC (2005) Increase of Bax/Bcl-XLratio and arrest of cell cycle by luteolin in immortalized human hepatoma cell line. Life Sci 76:1883–1893.  https://doi.org/10.1016/j.lfs.2004.11.003 CrossRefGoogle Scholar
  33. Chen D, Daniel KG, Chen MS, Kuhn DJ, Landis-Piwowar KR, Dou QP (2005a) Dietary flavonoids as proteasome inhibitors and apoptosis inducers in human leukemia cells. Biochem Pharmacol 69:1421–1432.  https://doi.org/10.1016/j.bcp.2005.02.022 CrossRefGoogle Scholar
  34. Chen J, Duan Y, Zhang X, Ye Y, Ge B, Chen J (2015a) Genistein induces apoptosis by the inactivation of the IGF-1R/p-Akt signaling pathway in MCF-7 human breast cancer cells. Food Funct 6:995–1000.  https://doi.org/10.1039/C4FO01141D CrossRefGoogle Scholar
  35. Chen Y, Li F, Meng X, Li X (2015b) Suppression of retinal angiogenesis by quercetin in a rodent model of retinopathy of prematurity. Zhonghua Yi Xue Za Zhi 95:1113–1115.Google Scholar
  36. Chen Z, Zhang B, Gao F, Shi R (2018) Modulation of G2/M cell cycle arrest and apoptosis by luteolin in human colon cancer cells and xenografts. Oncol Lett 15:1559–1565Google Scholar
  37. Cheng WY, Chiao MT, Liang YJ, Yang YC, Shen CC, Yang CY (2013) Luteolin inhibits migration of human glioblastoma U-87 MG and T98G cells through downregulation of Cdc42 expression and PI3K/AKT activity. Mol Biol Rep 40:5315–5326.  https://doi.org/10.1007/s11033-013-2632-1 PubMedPubMedCentralCrossRefGoogle Scholar
  38. Cheong E, Ivory K, Doleman J, Parker ML, Rhodes M, Johnson IT (2004) Synthetic and naturally occurring COX-2 inhibitors suppress proliferation in a human oesophageal adenocarcinoma cell line (OE33) by inducing apoptosis and cell cycle arrest. Carcinogenesis 25:1945–1952.  https://doi.org/10.1093/carcin/bgh184 CrossRefGoogle Scholar
  39. Chien SY, Wu YC, Chung JG, Yang JS, Lu HF, Tsou MF, Wood W, Kuo SJ, Chen DR (2009) Quercetin-induced apoptosis acts through mitochondrial- and caspase-3-dependent pathways in human breast cancer MDA-MB-231 cells. Hum Exp Toxicol 28:493–503.  https://doi.org/10.1177/0960327109107002 CrossRefGoogle Scholar
  40. Chiyomaru T, Yamamura S, Fukuhara S, Yoshino H, Kinoshita T, Majid S, Saini S, Chang I, Tanaka Y, Enokida H, Seki N, Nakagawa M, Dahiya R (2013a) Genistein inhibits prostate cancer cell growth by targeting miR-34a and oncogenic HOTAIR. PLoS One 8:e70372.  https://doi.org/10.1371/journal.pone.0070372 PubMedPubMedCentralCrossRefGoogle Scholar
  41. Chiyomaru T, Yamamura S, Fukuhara S, Hidaka H, Majid S, Saini S, Arora S, Deng G, Shahryari V, Chang I, Tanaka Y, Tabatabai ZL, Enokida H, Seki N, Nakagawa M, Dahiya R (2013b) Genistein up-regulates tumor suppressor MicroRNA-574-3p in prostate cancer. PLoS One 8:e58929.  https://doi.org/10.1371/journal.pone.0058929 PubMedPubMedCentralCrossRefGoogle Scholar
  42. Cho HJ, Ahn KC, Choi JY, Hwang SG, Kim WJ, Um HD, Park JK (2015) Luteolin acts as a radiosensitizer in non-small cell lung cancer cells by enhancing apoptotic cell death through activation of a p38/ROS/caspase cascade. Int J Oncol 46:1149–1158.  https://doi.org/10.3892/ijo.2015.2831 CrossRefGoogle Scholar
  43. Choi YH, Zhang L, Lee WH, Park KY (1998) Genistein-induced G2/M arrest is associated with the inhibition of cyclin B1 and the induction of p21 in human breast carcinoma cells. Int J Oncol 13:391–396Google Scholar
  44. Choi YH, Won Ho L, Park KY, Zhang L (2000) p53-independent induction of p21 (WAF1/CIP1), reduction of cyclin B1 and G2/M arrest by the isoflavone genistein in human prostate carcinoma cells. Japanese J. Cancer Res. 91:164–173.  https://doi.org/10.1111/j.1349-7006.2000.tb00928.x CrossRefGoogle Scholar
  45. Choi JA, Kim JY, Lee JY, Kang CM, Kwon HJ, Yoo YD, Kim TW, Lee YS, Lee SJ (2001) Induction of cell cycle arrest and apoptosis in human breast cancer cells by quercetin. Int J Oncol 19:837–844Google Scholar
  46. Choi AY, Choi JH, Yoon H, Hwang KY, Noh MH, Choe W, Yoon KS, Ha J, Yeo EJ, Kang I (2011) Luteolin induces apoptosis through endoplasmic reticulum stress and mitochondrial dysfunction in Neuro-2a mouse neuroblastoma cells. Eur J Pharmacol 668:115–126.  https://doi.org/10.1016/j.ejphar.2011.06.047 CrossRefGoogle Scholar
  47. Chou C-C, Yang J-S, Lu H-F, Ip S-W, Lo C, Wu C-C, Lin J-P, Tang N-Y, Chung J-G, Chou M-J, Teng Y-H, Chen D-R (2010) Quercetin-mediated cell cycle arrest and apoptosis involving activation of a caspase cascade through the mitochondrial pathway in human breast cancer MCF-7 cells. Arch Pharm Res 33:1181–1191.  https://doi.org/10.1007/s12272-010-0808-y CrossRefGoogle Scholar
  48. Chow J-M, Shen S-C, Huan SK, Lin H-Y, Chen Y-C (2005) Quercetin, but not rutin and quercitrin, prevention of H2O2-induced apoptosis via anti-oxidant activity and heme oxygenase 1 gene expression in macrophages. Biochem Pharmacol 69:1839–1851.  https://doi.org/10.1016/j.bcp.2005.03.017 CrossRefGoogle Scholar
  49. Cohen O, Inbal B, Kissil JL, Raveh T, Berissi H, Spivak KT, Feinstein E, Kimchi A (1999) DAP-kinase participates in TNF-alpha- and Fas-induced apoptosis and its function requires the death domain. J Cell Biol 46(1):141–148CrossRefGoogle Scholar
  50. Conklin CMJ, Bechberger JF, MacFabe D, Guthrie N, Kurowska EM, Naus CC (2007) Genistein and quercetin increase connexin43 and suppress growth of breast cancer cells. Carcinogenesis 28:93–100.  https://doi.org/10.1093/carcin/bgl106 CrossRefGoogle Scholar
  51. Cook MT, Liang Y, Besch-Williford C, Hyder SM (2016) Luteolin inhibits lung metastasis, cell migration, and viability of triple-negative breast cancer cells. Breast Cancer Targets Ther 9:9–19.  https://doi.org/10.2147/BCTT.S124860 CrossRefGoogle Scholar
  52. Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420(6917):860–867.  https://doi.org/10.1038/nature01322 CrossRefPubMedPubMedCentralGoogle Scholar
  53. Cui S, Wang J, Wu Q, Qian J, Yang C, Bo P (2017) Genistein inhibits the growth and regulates the migration and invasion abilities of melanoma cells via the FAK/paxillin and MAPK pathways. Oncotarget 8:21674–21691.  https://doi.org/10.18632/oncotarget.15535 PubMedPubMedCentralGoogle Scholar
  54. Darband SG, Kaviani M, Yousefi B, Sadighparvar S, Pakdel FG, Attari JA et al (2018) Quercetin: a functional dietary flavonoid with potential chemo-preventive properties in colorectal cancer. J Cell Physiol.  https://doi.org/10.1002/jcp.26595 CrossRefGoogle Scholar
  55. Davis JN, Singh B, Bhuiyan M, Sarkar FH (1998) Genistein-induced upregulation of p21 WAF1, downregulation of cyclin B, and induction of apoptosis in prostate cancer cells. Nutr Cancer 32:123–131.  https://doi.org/10.1080/01635589809514730 CrossRefGoogle Scholar
  56. De La Parra C, Castillo-Pichardo L, Cruz-Collazo A, Cubano L, Redis R, Calin GA, Dharmawardhane S (2016) Soy isoflavone genistein-mediated downregulation of miR-155 contributes to the anticancer effects of genistein. Nutr Cancer 68:154–164.  https://doi.org/10.1080/01635581.2016.1115104 PubMedPubMedCentralCrossRefGoogle Scholar
  57. Di Lorenzo G, Pagliuca M, Perillo T, Zarrella A, Verde A, De Placido S, Buonerba C (2016) Complete response and fatigue improvement with the combined use of cyclophosphamide and quercetin in a patient with metastatic bladder cancer a case report. Med (United States) 95:e2598.  https://doi.org/10.1097/MD.0000000000002598 Google Scholar
  58. Duo J, Ying G-G, Wang G-W, Zhang L (2012) Quercetin inhibits human breast cancer cell proliferation and induces apoptosis via Bcl-2 and Bax regulation. Mol Med Rep 5:1453–1456.  https://doi.org/10.3892/mmr.2012.845 Google Scholar
  59. El Touny LH, Banerjee PP (2007) Genistein induces the metastasis suppressor kangai-1 which mediates its anti-invasive effects in TRAMP cancer cells. Biochem Biophys Res Commun 361:169–175.  https://doi.org/10.1016/j.bbrc.2007.07.010 PubMedPubMedCentralCrossRefGoogle Scholar
  60. Fan Y, Dutta J, Gupta N, Fan G, Gélinas C (2008) Regulation of programmed cell death by NF-kappaB and its role in tumorigenesis and therapy. Adv Exp Med Biol 615:223–250CrossRefGoogle Scholar
  61. Fimognari C, Nüsse M, Berti F, Iori R, Cantelli FG, Hrelia P (2004) A mixture of isothiocyanates induces cyclin B1- and p53-mediated cell-cycle arrest and apoptosis of human T lymphoblastoid cells. Mutat Res 554(1–2):205–214CrossRefGoogle Scholar
  62. Franke TF, Hornik CP, Segev L, Shostak GA, Sugimoto C (2003, December 8) PI3K/Akt and apoptosis: size matters. Oncogene.  https://doi.org/10.1038/sj.onc.1207115 CrossRefGoogle Scholar
  63. Frey RS, Li J, Singletary KW (2001) Effects of genistein on cell proliferation and cell cycle arrest in nonneoplastic human mammary epithelial cells: Involvement of Cdc2, p21waf/cip1, p27kip1, and Cdc25C expression. Biochem Pharmacol 61:979–989.  https://doi.org/10.1016/S0006-2952(01)00572-X CrossRefGoogle Scholar
  64. Fu J, Chen D, Zhao B, Zhao Z, Zhou J, Xu Y, Xin Y, Liu C, Luo L, Yin Z (2012) Luteolin induces carcinoma cell apoptosis through binding Hsp90 to suppress constitutive activation of STAT3. PLoS One 7:e49194.  https://doi.org/10.1371/journal.pone.0049194 PubMedPubMedCentralCrossRefGoogle Scholar
  65. Gérard C, Tyson JJ, Coudreuse D, Novák B (2015) Cell cycle control by a minimal Cdk network. PLoS Comput Biol 11(2):e1004056PubMedPubMedCentralCrossRefGoogle Scholar
  66. Granado-Serrano AB, Martín MA, Bravo L, Goya L, Ramos S (2006) Quercetin induces apoptosis via caspase activation, regulation of Bcl-2, and inhibition of PI-3-kinase/Akt and ERK pathways in a human hepatoma cell line (HepG2). J Nutr 136:2715–2721.  https://doi.org/10.1093/jn/136.11.2715 CrossRefGoogle Scholar
  67. Gowda Saralamma VV, Nagappan A, Hong GE, Lee HJ, Yumnam S, Raha S et al (2015) Poncirin induces apoptosis in AGS human gastric cancer cells through extrinsic apoptotic pathway by up-regulation of fas ligand. Int J Mol Sci 16(9):22676–22691.  https://doi.org/10.3390/ijms160922676 CrossRefGoogle Scholar
  68. Gu Y, Zhu C-F, Dai Y-L, Zhong Q, Sun B (2009) Inhibitory effects of genistein on metastasis of human hepatocellular carcinoma. World J Gastroenterol 15:4952–4957.  https://doi.org/10.3748/wjg.15.4952 PubMedPubMedCentralCrossRefGoogle Scholar
  69. Gulati N, Laudet B, Zohrabian VM, Murali R, Jhanwar-Uniyal M (2006) The antiproliferative effect of Quercetin in cancer cells is mediated via inhibition of the PI3K-Akt/PKB pathway. Anticancer Res 26:1177–1181Google Scholar
  70. Guo S, Colbert LS, Fuller M, Zhang Y, Gonzalez-Perez RR (2010) Vascular endothelial growth factor receptor-2 in breast cancer. Biochimica et Biophysica Acta (BBA) - Reviews on Cancer 1806(1):108–121.  https://doi.org/10.1016/j.bbcan.2010.04.004 CrossRefGoogle Scholar
  71. Haghiac M, Walle T (2005) Quercetin induces necrosis and apoptosis in SCC-9 oral cancer cells. Nutr Cancer 53:220–231.  https://doi.org/10.1207/s15327914nc5302_11 CrossRefGoogle Scholar
  72. Han H, Zhong C, Zhang X, Liu R, Pan M, Tan L, Li Y, Wu J, Zhu Y, Huang W (2010) Genistein induces growth inhibition and G2/M arrest in nasopharyngeal carcinoma cells. Nutr Cancer 62:641–647.  https://doi.org/10.1080/01635581003605490 CrossRefGoogle Scholar
  73. Han J, Kurita Y, Isoda H (2013) Genistein-induced G2/M cell cycle arrest of human intestinal colon cancer Caco-2 cells is associated with Cyclin B1 and Chk2 down-regulation. Cytotechnology 65:973–978.  https://doi.org/10.1007/s10616-013-9592-0 PubMedPubMedCentralCrossRefGoogle Scholar
  74. Han K, Meng W, Zhang J-J, Zhou Y, Wang Y, Su Y, Lin S, Gan Z, Sun Y, Min D-L (2016) Luteolin inhibited proliferation and induced apoptosis of prostate cancer cells through miR-301. Onco Targets Ther 9:3085–3094.  https://doi.org/10.2147/OTT.S102862 PubMedPubMedCentralCrossRefGoogle Scholar
  75. Hatkevich T, Ramos J, Santos-Sanchez I, Patel YM (2014) A naringenin-tamoxifen combination impairs cell proliferation and survival of MCF-7 breast cancer cells. Exp Cell Res 327:331–339.  https://doi.org/10.1016/j.yexcr.2014.05.017 CrossRefGoogle Scholar
  76. Hayashi A, Gillen AC, Lott JR (2000) Effects of daily oral administration of quercetin chalcone and modified citrus pectin on implanted colon-25 tumor growth in balb-c mice. Altern Med Rev 5:546–552Google Scholar
  77. Hirata H, Ueno K, Nakajima K, Tabatabai ZL, Hinoda Y, Ishii N, Dahiya R (2013) Genistein downregulates onco-miR-1260b and inhibits Wnt-signalling in renal cancer cells. Br J Cancer 108:2070–2078.  https://doi.org/10.1038/bjc.2013.173 PubMedPubMedCentralCrossRefGoogle Scholar
  78. Hold GL, El-Omar EM (2008) Genetic aspects of inflammation and cancer. Biochem J 410(2):225–235.  https://doi.org/10.1042/BJ20071341 CrossRefGoogle Scholar
  79. Hong J, Fristiohady A, Nguyen CH, Milovanovic D, Huttary N, Krieger S et al (2018) Apigenin and luteolin attenuate the breaching of MDA-MB231 breast cancer spheroids through the lymph endothelial barrier in vitro. Front Pharmacol 9(MAR):220.  https://doi.org/10.3389/fphar.2018.00220 CrossRefPubMedPubMedCentralGoogle Scholar
  80. Horinaka M, Yoshida T, Shiraishi T, Nakata S, Wakada M, Nakanishi R, Nishino H, Matsui H, Sakai T (2005) Luteolin induces apoptosis via death receptor 5 upregulation in human malignant tumor cells. Oncogene 24:7180–7189.  https://doi.org/10.1038/sj.onc.1208874 CrossRefGoogle Scholar
  81. Hsieh TC, Wu JM (2009) Targeting CWR22Rv1 prostate cancer cell proliferation and gene expression by combinations of the phytochemicals EGCG, genistein and quercetin. Anticancer Res 29:4025–4032. https://doi.org/29/10/4025 [pii]PubMedPubMedCentralGoogle Scholar
  82. Hu J, Yu Q, Zhao F, Ji J, Jiang Z, Chen X, Gao P, Ren Y, Shao S, Zhang L, Yan M (2015) Protection of Quercetin against Triptolide-induced apoptosis by suppressing oxidative stress in rat Leydig cells. Chem Biol Interact 240:38–46.  https://doi.org/10.1016/j.cbi.2015.08.004 CrossRefGoogle Scholar
  83. Huang CY, Chan CY, Chou IT, Lien CH, Hung HC, Lee MF (2013) Quercetin induces growth arrest through activation of FOXO1 transcription factor in EGFR-overexpressing oral cancer cells. Journal of Nutritional Biochemistry 24(9):1596–1603.  https://doi.org/10.1016/j.jnutbio.2013.01.010 CrossRefGoogle Scholar
  84. Hussain A, Harish G, Prabhu SA, Mohsin J, Khan MA, Rizvi TA, Sharma C (2012) Inhibitory effect of genistein on the invasive potential of human cervical cancer cells via modulation of matrix metalloproteinase-9 and tissue inhibitors of matrix metalloproteinase-1 expression. Cancer Epidemiol 36:e387–e393.  https://doi.org/10.1016/j.canep.2012.07.005 CrossRefGoogle Scholar
  85. Hwang JT, Ha J, Ock JP (2005) Combination of 5-fluorouracil and genistein induces apoptosis synergistically in chemo-resistant cancer cells through the modulation of AMPK and COX-2 signaling pathways. Biochem Biophys Res Commun 332:433–440.  https://doi.org/10.1016/j.bbrc.2005.04.143 CrossRefGoogle Scholar
  86. Igura K, Ohta T, Kuroda Y, Kaji K (2001) Resveratrol and quercetin inhibit angiogenesis in vitro. Cancer Lett 171:11–16.  https://doi.org/10.1016/S0304-3835(01)00443-8 CrossRefGoogle Scholar
  87. Jagadeesh S, Kyo S, Banerjee PP (2006) Genistein represses telomerase activity via both transcriptional and posttranslational mechanisms in human prostate cancer cells. Cancer Res 66:2107–2115.  https://doi.org/10.1158/0008-5472.CAN-05-2494 CrossRefGoogle Scholar
  88. Jeong J-H, An JY, Kwon YT, Rhee JG, Lee YJ (2009) Effects of low dose quercetin: cancer cell-specific inhibition of cell cycle progression. J Cell Biochem 106:73–82.  https://doi.org/10.1002/jcb.21977 PubMedPubMedCentralCrossRefGoogle Scholar
  89. Jiang Z-Q, Li M-H, Qin Y-M, Jiang H-Y, Zhang X, Wu M-H (2018) Luteolin inhibits tumorigenesis and induces apoptosis of non-small cell lung cancer cells via regulation of MicroRNA-34a-5p. Int J Mol Sci 19:447.  https://doi.org/10.3390/ijms19020447 CrossRefGoogle Scholar
  90. Jin CY, Park C, Cheong JH, Choi BT, Lee TH, Lee JD, Lee WH, Kim GY, Ryu CH, Choi YH (2007) Genistein sensitizes TRAIL-resistant human gastric adenocarcinoma AGS cells through activation of caspase-3. Cancer Lett 257:56–64.  https://doi.org/10.1016/j.canlet.2007.06.019 CrossRefGoogle Scholar
  91. Jin CY, Park C, Kim GY, Lee SJ, Kim WJ, Choi YH (2009) Genistein enhances TRAIL-induced apoptosis through inhibition of p38 MAPK signaling in human hepatocellular carcinoma Hep3B cells. Chem Biol Interact 180:143–150.  https://doi.org/10.1016/j.cbi.2009.03.020 CrossRefGoogle Scholar
  92. Ju W, Wang X, Shi H, Chen W, Belinsky SA, Lin Y (2007) A critical role of luteolin-induced reactive oxygen species in blockage of tumor necrosis factor-activated nuclear factor- B pathway and sensitization of apoptosis in lung cancer cells. Mol Pharmacol 71:1381–1388.  https://doi.org/10.1124/mol.106.032185 CrossRefGoogle Scholar
  93. Kaltschmidt B, Christian K, Thomas GH, Steffen PH, Wulf D, Lienhard MS (2000) The pro- or anti-apoptotic function of NF-kB is determined by the nature the apoptotic stimulus. Eur J Biochem 267(12):3828–3835CrossRefGoogle Scholar
  94. Kang KA, Piao MJ, Ryu YS, Hyun YJ, Park JE, Shilnikova K, Zhen AX, Kang HK, Koh YS, Jeong YJ, Hyun JW (2017) Luteolin induces apoptotic cell death via antioxidant activity in human colon cancer cells. Int J Oncol 51:1169–1178.  https://doi.org/10.3892/ijo.2017.4091 CrossRefGoogle Scholar
  95. Kanno S-i, Tomizawa A, Ohtake T, Koiwai K, Ujibe M, Ishikawa M (2006) Naringenin-induced apoptosis via activation of NF-κB and necrosis involving the loss of ATP in human promyeloleukemia HL-60 cells. Toxicol Lett 166:131–139.  https://doi.org/10.1016/j.toxlet.2006.06.005 CrossRefGoogle Scholar
  96. Kashyap D, Kumar G, Sharma A, Sak K, Tuli HS, Mukherjee TK (2016a) Mechanistic insight into carnosol-mediated pharmacological effects: Recent trends and advancements. Life Sci 169:27–36.  https://doi.org/10.1016/j.lfs.2016.11.013 CrossRefGoogle Scholar
  97. Kashyap D, Mondal R, Tuli HS, Kumar G, Sharma AK (2016b) Molecular targets of gambogic acid in cancer: recent trends and advancements. Tumor Biol 3:208–215.  https://doi.org/10.1007/s13277-016-5194-8 Google Scholar
  98. Kashyap D, Sharma A, Garg V, Tuli HS, Kumar G, Kumar M (2016c) Reactive oxygen species (ROS ): an activator of apoptosis and autophagy in cancer. J Biol Chem Sci 3:256–264Google Scholar
  99. Kashyap D, Sharma AAK, Tuli HS, Punia S, Sharma AAK (2016d) Ursolic acid and oleanolic acid: pentacyclic terpenoids with promising anti-inflammatory activities. Recent Patents Inflamm Allergy Drug Discov 10:1–13.  https://doi.org/10.2174/1872213x10666160711143904 CrossRefGoogle Scholar
  100. Kashyap D, Tuli HS, Sharma AK (2016e) Ursolic acid (UA): a metabolite with promising therapeutic potential. Life Sci 146:201–213.  https://doi.org/10.1016/j.lfs.2016.01.017 CrossRefGoogle Scholar
  101. Kashyap D, Sharma A, Tuli HS, Sak K, Punia S, Mukherjee TK (2017) Kaempferol – a dietary anticancer molecule with multiple mechanisms of action: recent trends and advancements. J Funct Foods 30:203–219.  https://doi.org/10.1016/j.jff.2017.01.022 CrossRefGoogle Scholar
  102. Kashyap D, Sharma A, Sak K, Tuli HS, Buttar HS, Bishayee A (2018) Fisetin: a bioactive phytochemical with potential for cancer prevention and pharmacotherapy. Life Sci 194:75–87.  https://doi.org/10.1016/j.lfs.2017.12.005 CrossRefGoogle Scholar
  103. Kim S-H, Kim S-H, Lee S-C, Song Y-S (2009) Involvement of both extrinsic and intrinsic apoptotic pathways in apoptosis induced by genistein in human cervical cancer cells. Ann N Y Acad Sci 1171:196–201.  https://doi.org/10.1111/j.1749-6632.2009.04902.x CrossRefGoogle Scholar
  104. Kim MJ, Woo JS, Kwon CH, Kim JH, Kim YK, Kim KH (2012) Luteolin induces apoptotic cell death through AIF nuclear translocation mediated by activation of ERK and p38 in human breast cancer cell lines. Cell Biol Int 36:339–344.  https://doi.org/10.1042/CBI20110394 CrossRefGoogle Scholar
  105. Kim HY, Jung SK, Byun S, Son JE, Oh MH, Lee J, Kang MJ, Heo YS, Lee KW, Lee HJ (2013) Raf and PI3K are the molecular targets for the anti-metastatic effect of luteolin. Phyther Res 27:1481–1488.  https://doi.org/10.1002/ptr.4888 Google Scholar
  106. Kim MC, Lee HJ, Lim B, Ha KT, Kim SY, So I, Kim BJ (2014) Quercetin induces apoptosis by inhibiting MAPKs and TRPM7 channels in AGS cells. Int J Mol Med 33:1657–1663.  https://doi.org/10.3892/ijmm.2014.1704 CrossRefGoogle Scholar
  107. Klagsbrun M, Moses MA (1999) Molecular angiogenesis. Chem Biol 6:R217.  https://doi.org/10.1016/S1074-5521(99)80081-7 CrossRefGoogle Scholar
  108. Klaunig JE, Kamendulis LM, Hocevar BA (2010) Oxidative stress and oxidative damage in carcinogenesis. Toxicol Pathol 38(1):96–109.  https://doi.org/10.1177/0192623309356453 CrossRefGoogle Scholar
  109. Kong L, Wu K, Lin H (2005) Inhibitory effects of quercetin on angiogenesis of experimental mammary carcinoma. Chin J Clin Oncol 2(3):631–636.  https://doi.org/10.1007/BF02739722 CrossRefGoogle Scholar
  110. Kumi-Diaka J, Sanderson NA, Hall A (2000) The mediating role of caspase-3 protease in the intracellular mechanism of genistein-induced apoptosis in human prostatic carcinoma cell lines, DU145 and LNCaP. Biol Cell 92:595–604.  https://doi.org/10.1016/S0248-4900(00)01109-6 CrossRefGoogle Scholar
  111. Lai W-W, Hsu S-C, Chueh F-S, Chen Y-Y, Yang J-S, Lin J-P, Lien J-C, Tsai C-H, Chung J-G (2013) Quercetin inhibits migration and invasion of SAS human oral cancer cells through inhibition of NF-κB and matrix metalloproteinase-2/-9 signaling pathways. Anticancer Res 33:1941–1950Google Scholar
  112. Lautraite S, Musonda AC, Doehmer J, Edwards GO, Chipman JK (2002) Flavonoids inhibit genetic toxicity produced by carcinogens in cells expressing CYP1A2 and CYP1A1. Mutagenesis 17:45–53.  https://doi.org/10.1093/mutage/17.1.45 CrossRefGoogle Scholar
  113. Leber MF, Efferth T (2009) Molecular principles of cancer invasion and metastasis. Int J Oncol 34(4):881–895.  https://doi.org/10.3892/ijo CrossRefGoogle Scholar
  114. Lee K-H, Yoo C-G (2013) Simultaneous inactivation of GSK-3 suppresses quercetin-induced apoptosis by inhibiting the JNK pathway. AJP Lung Cell Mol Physiol 304:L782–L789.  https://doi.org/10.1152/ajplung.00348.2012 CrossRefGoogle Scholar
  115. Lee KW, Kang NJ, Heo YS, Rogozin EA, Pugliese A, Hwang MK, Bowden GT, Bode AM, Lee HJ, Dong Z (2008) Raf and MEK protein kinases are direct molecular targets for the chemopreventive effect of quercetin, a major flavonol in red wine. Cancer Res 8:946–955CrossRefGoogle Scholar
  116. Lee YJ, Song JH, Oh MH, Lee YJ, Kim YB, Im JH, Lee SH (2011) ERK1/2 activation in quercetin-treated BEAS-2B cell plays a role in Nrf2-driven HO-1 expression. Mol Cell Toxicol 7:347–355.  https://doi.org/10.1007/s13273-011-0044-7 CrossRefGoogle Scholar
  117. Lee Y-J, Lee DM, Lee S-H (2015) Nrf2 expression and apoptosis in quercetin-treated malignant mesothelioma cells. Mol Cell 38:416–425.  https://doi.org/10.14348/molcells.2015.2268 CrossRefGoogle Scholar
  118. Lee C-F, Yang J-S, Tsai F-J, Chiang N-N, Lu C-C, Huang Y-S et al (2016) Kaempferol induces ATM/p53-mediated death receptor and mitochondrial apoptosis in human umbilical vein endothelial cells. Int J Oncol 48(5):2007–2014.  https://doi.org/10.3892/ijo.2016.3420 CrossRefGoogle Scholar
  119. Li Y, Upadhyay S, Bhuiyan M, Sarkar FH (1999) Induction of apoptosis in breast cancer cells MDA-MB-231 by genistein. Oncogene 18:3166–3172.  https://doi.org/10.1038/sj.onc.1202650 CrossRefGoogle Scholar
  120. Li Z, Li J, Mo B, Hu C, Liu H, Qi H, Wang X, Xu J (2008a) Genistein induces cell apoptosis in MDA-MB-231 breast cancer cells via the mitogen-activated protein kinase pathway. Toxicol. Vitr. 22:1749–1753.  https://doi.org/10.1016/j.tiv.2008.08.001 CrossRefGoogle Scholar
  121. Li Z, Li J, Mo B, Hu C, Liu H, Qi H, Wang X, Xu J (2008b) Genistein induces G2/M cell cycle arrest via stable activation of ERK1/2 pathway in MDA-MB-231 breast cancer cells. Cell Biol Toxicol 24:401–409.  https://doi.org/10.1007/s10565-008-9054-1 CrossRefGoogle Scholar
  122. Li H, Zhu F, Chen H, Cheng KW, Zykova T, Oi N, Lubet RA, Bode AM, Wang M, Dong Z (2014) 6-C-(E-phenylethenyl)-naringenin suppresses colorectal cancer growth by inhibiting cyclooxygenase-1. Cancer Res 74:243–252.  https://doi.org/10.1158/0008-5472.CAN-13-2245 CrossRefGoogle Scholar
  123. Li F, Bai Y, Zhao M, Huang L, Li S, Li X, Chen Y (2015a) Quercetin inhibits vascular endothelial growth factor-induced choroidal and retinal angiogenesis in vitro. Ophthalmic Res 53:109–116.  https://doi.org/10.1159/000369824 CrossRefGoogle Scholar
  124. Li RF, Feng YQ, Chen JH, Ge LT, Xiao SY, Zuo XL (2015b) Naringenin suppresses K562 human leukemia cell proliferation and ameliorates Adriamycin-induced oxidative damage in polymorphonuclear leukocytes. Exp Ther Med 9:697–706.  https://doi.org/10.3892/etm.2015.2185 PubMedPubMedCentralCrossRefGoogle Scholar
  125. Li C-Y, Liang G-Y, Yao W-Z, Sui J, Shen X, Zhang Y-Q, Peng H, Hong W-W, Ye Y-C, Zhang Z-Y, Zhang W-H, Yin L-H, Pu Y-P (2016) Luteolin induced growth inhibition and apoptosis in hepatoma cells involving TGF-β and Fas/Fas-ligand signaling pathways. Int J Oncol 48:1965–1976CrossRefGoogle Scholar
  126. Lian F, Li Y, Bhuiyan M, Sarkar FH (1999) p53-Independent apoptosis induced by genistein in lung cancer cells. Nutr Cancer 33:125–131.  https://doi.org/10.1207/S15327914NC330202 CrossRefGoogle Scholar
  127. Liao ACH, Kuo CC, Huang YC, Yeh CW, Hseu YC, Liu JY, Hsu LS (2014) Naringenin inhibits migration of bladder cancer cells through downregulation of AKT and MMP-2. Mol Med Rep 10:1531–1536.  https://doi.org/10.3892/mmr.2014.2375 CrossRefGoogle Scholar
  128. Lim W, Park S, Bazer FW, Song G (2017) Naringenin-induced apoptotic cell death in prostate cancer cells is mediated via the PI3K/AKT and MAPK signaling pathways. J Cell Biochem 118:1118–1131.  https://doi.org/10.1002/jcb.25729 CrossRefGoogle Scholar
  129. Lin CW, Hou WC, Shen SC, Juan SH, Ko CH, Wang LM, Chen YC (2008) Quercetin inhibition of tumor invasion via suppressing PKCδ/ERK/ AP-1-dependent matrix metalloproteinase-9 activation in breast carcinoma cells. Carcinogenesis 29:1807–1815.  https://doi.org/10.1093/carcin/bgn162 CrossRefGoogle Scholar
  130. Liu X, Sun C, Jin X, Li P, Ye F, Zhao T, Gong L, Li Q (2013a) Genistein enhances the radiosensitivity of breast cancer cells via G2/M cell cycle arrest and apoptosis. Molecules 18:13200–13217.  https://doi.org/10.3390/molecules181113200 PubMedPubMedCentralCrossRefGoogle Scholar
  131. Liu Y-L, Zhang G-Q, Yang Y, Zhang C-Y, Fu R-X, Yang Y-M (2013b) Genistein induces G2/M arrest in gastric cancer cells by increasing the tumor suppressor PTEN expression. Nutr Cancer 65:1034–1041.  https://doi.org/10.1080/01635581.2013.810290 CrossRefGoogle Scholar
  132. Lou C, Zhang F, Yang M, Zhao J, Zeng W, Fang X, Zhang Y, Zhang C, Liang W (2012) Naringenin decreases invasiveness and metastasis by inhibiting TGF-β-induced epithelial to mesenchymal transition in pancreatic cancer cells. PLoS One 7:e50956.  https://doi.org/10.1371/journal.pone.0050956 PubMedPubMedCentralCrossRefGoogle Scholar
  133. Lou G, Liu Y, Wu S, Xue J, Yang F, Fu H, Zheng M, Chen Z (2015) The p53/miR-34a/SIRT1 positive feedback loop in quercetin-induced apoptosis. Cell Physiol Biochem 35:2192–2202.  https://doi.org/10.1159/000374024 CrossRefGoogle Scholar
  134. Lu X, Li Y, Li X, Aisa HA (2017) Luteolin induces apoptosis in vitro through suppressing the MAPK and PI3K signaling pathways in gastric cancer. Oncol Lett 14:1993–2000.  https://doi.org/10.3892/ol.2017.6380 PubMedPubMedCentralCrossRefGoogle Scholar
  135. Ma Q (2013) Role of nrf2 in oxidative stress and toxicity. Annu Rev Pharmacol Toxicol 53:401–426.  https://doi.org/10.1146/annurev-pharmtox-011112-140320 CrossRefPubMedPubMedCentralGoogle Scholar
  136. Ma J, Cheng L, Liu H, Zhang J, Shi Y, Zeng F, Miele L, Sarkar FH, Xia J, Wang Z (2013) Genistein down-regulates miR-223 expression in pancreatic cancer cells. Curr Drug Targets 14:1150–1156.  https://doi.org/10.2174/13894501113149990187 CrossRefGoogle Scholar
  137. Ma L, Peng H, Li K, Zhao R, Li L, Yu Y, Wang X, Han Z (2015) Luteolin exerts an anticancer effect on NCI-H460 human non-small cell lung cancer cells through the induction of Sirt1-mediated apoptosis. Mol Med Rep 12:4196–4202.  https://doi.org/10.3892/mmr.2015.3956 PubMedPubMedCentralCrossRefGoogle Scholar
  138. Majid S, Dar AA, Saini S, Chen Y, Shahryari V, Liu J, Zaman MS, Hirata H, Yamamura S, Ueno K, Tanaka Y, Dahiya R (2010) Regulation of minichromosome maintenance gene family by MicroRNA-1296 and genistein in prostate cancer. Cancer Res 70:2809–2818.  https://doi.org/10.1158/0008-5472.CAN-09-4176 CrossRefGoogle Scholar
  139. Mantovani A, Mantovani A, Allavena P, Allavena P, Sica A, Sica A et al (2008) Cancer-related inflammation. Nature 454(7203):436–444.  https://doi.org/10.1038/nature07205 CrossRefGoogle Scholar
  140. Martindale JL, Holbrook NJ (2002, July) Cellular response to oxidative stress: Signaling for suicide and survival. J Cell Physiol.  https://doi.org/10.1002/jcp.10119 CrossRefGoogle Scholar
  141. Meng G, Chai K, Li X, Zhu Y, Huang W (2016) Luteolin exerts pro-apoptotic effect and anti-migration effects on A549 lung adenocarcinoma cells through the activation of MEK/ERK signaling pathway. Chem Biol Interact 257:26–34.  https://doi.org/10.1016/j.cbi.2016.07.028 CrossRefGoogle Scholar
  142. Mojzis J, Varinska L, Mojzisova G, Kostova I, Mirossay L (2008) Antiangiogenic effects of flavonoids and chalcones. Pharmacol Res 57:259.  https://doi.org/10.1016/j.phrs.2008.02.005 CrossRefGoogle Scholar
  143. Moon S-K, Cho G-O, Jung S-Y, Gal S-W, Kwon TK, Lee Y-C, Madamanchi NR, Kim C-H (2003) Quercetin exerts multiple inhibitory effects on vascular smooth muscle cells: role of ERK1/2, cell-cycle regulation, and matrix metallopteinase-9. Biochem Biophys Res Commun 301:1069–1078.  https://doi.org/10.1016/S0006-291X(03)00091-3 CrossRefGoogle Scholar
  144. Mozhgan FS (2011) The Cuscuta kotschyana effects on breast cancer cells line MCF7. J Med Plant Res 5:6344–6351.  https://doi.org/10.5897/JMPR11.1048 Google Scholar
  145. Mu C, Jia P, Yan Z, Liu X, Li X, Liu H (2007) Quercetin induces cell cycle G1 arrest through elevating Cdk inhibitors p21 and p27 in human hepatoma cell line (HepG2). Methods Find Exp Clin Pharmacol 29:179–183.  https://doi.org/10.1358/mf.2007.29.3.1092095 CrossRefGoogle Scholar
  146. Mukherjee A, Khuda-Bukhsh AR (2015) Quercetin Down-regulates IL-6/STAT-3 Signals to Induce Mitochondrial-mediated Apoptosis in a Nonsmall- cell Lung-cancer Cell Line, A549. J Pharmacop 18:19–26.  https://doi.org/10.3831/KPI.2015.18.002 CrossRefGoogle Scholar
  147. Mukherjee P, Winter SL, Alexandrow MG (2010) Cell cycle arrest by transforming growth factor beta1 near G1/S is mediated by acute abrogation of prereplication complex activation involving an Rb-MCM interaction. Mol Cell Biol 30(3):845–856.  https://doi.org/10.1128/MCB.01152-09 CrossRefGoogle Scholar
  148. Mutoh M, Takahashi M, Fukuda K, Komatsu H, Enya T, Matsushima-Hibiya Y, Mutoh H, Sugimura T, Wakabayashi K (2000) Suppression by flavonoids of cyclooxygenase-2 promoter-dependent transcriptional activity in colon cancer cells: structure-activity relationship. Jpn J Cancer Res 91:686–691.  https://doi.org/10.1111/j.1349-7006.2000.tb01000.x PubMedPubMedCentralCrossRefGoogle Scholar
  149. Nagase M, Oto J, Sugiyama S, Yube K, Takaishi Y (2009) Sakato, NobuoApoptosis induction in HL-60 cells and inhibition of topoisomerase II by triterpene celastrol. Biosci Biotechnol Biochem 9(67):1883–1887Google Scholar
  150. Nakamura A, Aizawa J, Sakayama K, Kidani T, Takata T, Norimatsu Y, Miura H, Masuno H (2012) Genistein inhibits cell invasion and motility by inducing cell differentiation in murine osteosarcoma cell line LM8. BMC Cell Biol 13:24.  https://doi.org/10.1186/1471-2121-13-24 PubMedPubMedCentralCrossRefGoogle Scholar
  151. Nam Deuk Kim, Su-Bog Yee, Mi-Na Kim, Sang Eun Park, Mohammad Akbar Hossain, Min Young Kim GYK, Y (2007) Luteolin induced growth inhibition and apoptosis in hepatoma cells involving TGF-β and Fas/Fas-ligand signaling pathways, Cancer Research. Waverly Press.Google Scholar
  152. Nessa MU, Beale P, Chan C, Yu JQ, Huq F (2011) Synergism from combinations of cisplatin and oxaliplatin with quercetin and thymoquinone in human ovarian tumour models. Anticancer Res 31:3789–3797Google Scholar
  153. Nishida N, Yano H, Nishida T, Kamura T, Kojiro M (2006) Angiogenesis in cancer. Vasc Health Risk Manag. Dove Press.  https://doi.org/10.2147/vhrm.2006.2.3.213 PubMedPubMedCentralCrossRefGoogle Scholar
  154. Niu G, Yin S, Xie S, Li Y, Nie D, Ma L, Wang X, Wu Y (2011) Quercetin induces apoptosis by activating caspase-3 and regulating Bcl-2 and cyclooxygenase-2 pathways in human HL-60 cells. Acta Biochim Biophys Sin Shanghai 43:30–37.  https://doi.org/10.1093/abbs/gmq107 CrossRefGoogle Scholar
  155. Olsson AK, Dimberg A, Kreuger J, Claesson WL (2006) VEGF receptor signalling - in control of vascular function. Nat Rev Mol Cell Biol 7(5):359–371CrossRefGoogle Scholar
  156. Ozben T (2007) Oxidative stress and apoptosis: impact on cancer therapy. J Pharm Sci 96(9):2181–2196.  https://doi.org/10.1002/jps.20874 CrossRefGoogle Scholar
  157. Pandurangan AK, Dharmalingam P, Sadagopan SKA, Ganapasam S (2014) Luteolin inhibits matrix metalloproteinase 9 and 2 in azoxymethane-induced colon carcinogenesis. Hum Exp Toxicol 33:1176–1185.  https://doi.org/10.1177/0960327114522502 CrossRefGoogle Scholar
  158. Park S-S, Kim Y-N, Jeon YK, Kim YA, Kim JE, Kim H, Kim CW (2005) Genistein-induced apoptosis via Akt signaling pathway in anaplastic large-cell lymphoma. Cancer Chemother Pharmacol 56:271–278.  https://doi.org/10.1007/s00280-004-0974-z CrossRefGoogle Scholar
  159. Park JH, Jin CY, Lee BK, Kim GY, Choi YH, Jeong YK (2008) Naringenin induces apoptosis through downregulation of Akt and caspase-3 activation in human leukemia THP-1 cells. Food Chem Toxicol 46:3684–3690.  https://doi.org/10.1016/j.fct.2008.09.056 CrossRefGoogle Scholar
  160. Park SH, Ham S, Kwon TH, Kim MS, Lee DH, Kang JW, Oh SR, Yoon DY (2014) Luteolin induces cell cycle arrest and apoptosis through extrinsic and intrinsic signaling pathways in mcf-7 breast cancer cells. J Environ Pathol Toxicol Oncol 33:219–231CrossRefGoogle Scholar
  161. Pietenpol JA, Stewart ZA (2002) Cell cycle checkpoint signaling: cell cycle arrest versus apoptosis. Toxicology:181, 475–182, 481.  https://doi.org/10.1016/S0300-483X(02)00460-2 CrossRefGoogle Scholar
  162. Pratheeshkumar P, Son Y-O, Budhraja A, Wang X, Ding S, Wang L, Hitron A, Lee J-C, Kim D, Divya SP, Chen G, Zhang Z, Luo J, Shi X (2012) Luteolin inhibits human prostate tumor growth by suppressing vascular endothelial growth factor receptor 2-mediated angiogenesis. PLoS One 7:e52279.  https://doi.org/10.1371/journal.pone.0052279 PubMedPubMedCentralCrossRefGoogle Scholar
  163. Prietsch RF, Monte LG, Da Silva FA, Beira FT, Del Pino FAB, Campos VF, Collares T, Pinto LS, Spanevello RM, Gamaro GD, Braganhol E (2014) Genistein induces apoptosis and autophagy in human breast MCF-7 cells by modulating the expression of proapoptotic factors and oxidative stress enzymes. Mol Cell Biochem 390:235–242.  https://doi.org/10.1007/s11010-014-1974-x CrossRefGoogle Scholar
  164. Qin L, Jin L, Lu L, Lu X, Zhang C, Zhang F, Liang W (2011) Naringenin reduces lung metastasis in a breast cancer resection model. Protein Cell 2:507–516.  https://doi.org/10.1007/s13238-011-1056-8 PubMedPubMedCentralCrossRefGoogle Scholar
  165. Qin J, Teng J, Zhu Z, Chen J, Huang WJ (2016) Genistein induces activation of the mitochondrial apoptosis pathway by inhibiting phosphorylation of Akt in colorectal cancer cells. Pharm Biol 54:74–79.  https://doi.org/10.3109/13880209.2015.1014921 CrossRefGoogle Scholar
  166. Raffoul JJ, Wang Y, Kucuk O, Forman JD, Sarkar FH, Hillman GG (2006) Genistein inhibits radiation-induced activation of NF-κB in prostate cancer cells promoting apoptosis and G2/M cell cycle arrest. BMC Cancer 6:107.  https://doi.org/10.1186/1471-2407-6-107 PubMedPubMedCentralCrossRefGoogle Scholar
  167. Ramyaa P, Krishnaswamy R, Padma VV (2014) Quercetin modulates OTA-induced oxidative stress and redox signalling in HepG2 cells – Up regulation of Nrf2 expression and down regulation of NF-κB and COX-2. Biochim Biophys Acta, Gen Subj 1840:681–692.  https://doi.org/10.1016/j.bbagen.2013.10.024 CrossRefGoogle Scholar
  168. Rastogi RP, Richa, Sinha RP (2009, March) Apoptosis: molecular mechanisms and pathogenicity. EXCLI Journal Hindawi Limited.  https://doi.org/10.17877/DE290R-8930
  169. Reed JC (2000) Mechanisms of apoptosis. Am J Pathol 157(5):1415–1430.  https://doi.org/10.1016/S0002-9440(10)64779-7 CrossRefPubMedPubMedCentralGoogle Scholar
  170. Refolo MG, D’Alessandro R, Malerba N, Laezza C, Bifulco M, Messa C, Caruso MG, Notarnicola M, Tutino V (2015) Anti proliferative and pro apoptotic effects of flavonoid quercetin are mediated by CB1 receptor in human colon cancer cell lines. J Cell Physiol 230:2973–2980.  https://doi.org/10.1002/jcp.25026 CrossRefGoogle Scholar
  171. Rendic S, Peter Guengerich F (2012) Summary of information on the effects of ionizing and non-ionizing radiation on cytochrome P450 and other drug metabolizing enzymes and transporters. Curr Drug Metab 13(6):787–814.  https://doi.org/10.2174/138920012800840356 CrossRefPubMedPubMedCentralGoogle Scholar
  172. Russo M, Palumbo R, Tedesco I, Mazzarella G, Russo P, Iacomino G, Russo GL (1999) Quercetin and anti-CD95(Fas/Apo1) enhance apoptosis in HPB-ALL cell line. FEBS Lett 462:322–328.  https://doi.org/10.1016/S0014-5793(99)01544-6 CrossRefGoogle Scholar
  173. Russo M, Spagnuolo C, Bilotto S, Tedesco I, Maiani G, Russo GL (2014) Inhibition of protein kinase CK2 by quercetin enhances CD95-mediated apoptosis in a human thymus-derived T cell line. Food Res Int 63:244–251.  https://doi.org/10.1016/j.foodres.2014.05.022 CrossRefGoogle Scholar
  174. Sabarinathan D, Mahalakshmi P, Vanisree AJ (2010) Naringenin promote apoptosis in cerebrally implanted C6 glioma cells. Mol Cell Biochem 345:215–222.  https://doi.org/10.1007/s11010-010-0575-6 CrossRefGoogle Scholar
  175. Salti GI, Grewal S, Mehta RR, Das Gupta TK, Boddie AW, Constantinou AI (2000) Genistein induces apoptosis and topoisomerase II-mediated DNA breakage in colon cancer cells. Eur J Cancer 36:796–802.  https://doi.org/10.1016/S0959-8049(00)00017-4 CrossRefGoogle Scholar
  176. Schieber M, Chandel NS (2014, May 19) ROS function in redox signaling and oxidative stress. Current biology. Elsevier.  https://doi.org/10.1016/j.cub.2014.03.034 CrossRefGoogle Scholar
  177. Schmidt F, Knobbe CB, Frank B, Wolburg H, Weller M (2008) The topoisomerase II inhibitor, genistein, induces G2/M arrest and apoptosis in human malignant glioma cell lines. Oncol Rep 19:1061–1066Google Scholar
  178. Semenza GL (2003, October 1) Targeting HIF-1 for cancer therapy. Nat Rev Cancer. Nature Publishing Group.  https://doi.org/10.1038/nrc1187 CrossRefGoogle Scholar
  179. Senggunprai L, Kukongviriyapan V, Prawan A, Kukongviriyapan U (2014) Quercetin and EGCG exhibit chemopreventive effects in cholangiocarcinoma cells via suppression of JAK/STAT signaling pathway. Phyther Res 28:841–848.  https://doi.org/10.1002/ptr.5061 CrossRefGoogle Scholar
  180. Seo H-S, Jo JK, Ku JM, Choi H-S, Choi YK, Woo J-K et al (2015) Induction of caspasedependent 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 35(6):e00276–e00276.  https://doi.org/10.1042/BSR20150165 CrossRefPubMedPubMedCentralGoogle Scholar
  181. Seo HS, Ku JM, Choi HS, Choi YK, Woo JK, Kim M et al (2016) Quercetin induces caspasedependent extrinsic apoptosis through inhibition of signal transducer and activator of transcription 3 signaling in HER2-overexpressing BT-474 breast cancer cells. Oncol Rep 36(1):31–42.  https://doi.org/10.3892/or.2016.4786 CrossRefPubMedPubMedCentralGoogle Scholar
  182. Shafiee G, Saidijam M, Tavilani H, Ghasemkhani N, Khodadadi I (2016) Genistein induces apoptosis and inhibits proliferation of HT29 colon cancer cells. Int J Mol Cell Med 5:178–191PubMedPubMedCentralGoogle Scholar
  183. Shankar S, Marsh L, Srivastava RK (2013) EGCG inhibits growth of human pancreatic tumors orthotopically implanted in Balb C nude mice through modulation of FKHRL1/FOXO3a and neuropilin. Mol Cell Biochem 372(1–2):83–94.  https://doi.org/10.1007/s11010-012-1448-y CrossRefGoogle Scholar
  184. Shen SC, Lee WR, Yang LY, Tsai HH, Yang LL, Chen YC (2012) Quercetin enhancement of arsenic-induced apoptosis via stimulating ROS-dependent p53 protein ubiquitination in human HaCaT keratinocytes. Exp Dermatol 21:370–375.  https://doi.org/10.1111/j.1600-0625.2012.01479.x CrossRefGoogle Scholar
  185. Shi R-X, Ong C-N, Shen H-M (2004) Luteolin sensitizes tumor necrosis factor-alpha-induced apoptosis in human tumor cells. Oncogene 23:7712–7721.  https://doi.org/10.1038/sj.onc.1208046 CrossRefGoogle Scholar
  186. Shukla S, Bhaskaran N, Babcook MA, Fu P, MacLennan GT, Gupta S (2014) Apigenin inhibits prostate cancer progression in TRAMP mice via targeting PI3K/Akt/FoxO pathway. Carcinogenesis 35(2):452–460.  https://doi.org/10.1093/carcin/bgt316 CrossRefGoogle Scholar
  187. Steeg PS (2016) Targeting metastasis. Nat Rev Cancer 16(4):201–218.  https://doi.org/10.1038/nrc.2016.25 CrossRefGoogle Scholar
  188. Storniolo A, Raciti M, Cucina A, Bizzarri M, Di Renzo L (2015) Quercetin affects Hsp70/IRE1 α mediated protection from death induced by endoplasmic reticulum stress. Oxidative Med Cell Longev 2015:645157.  https://doi.org/10.1155/2015/645157 CrossRefGoogle Scholar
  189. Su SJ, Yeh TM, Chuang WJ, Ho CL, Chang KL, Cheng HL, Liu HS, Cheng HL, Hsu PY, Chow NH (2005) The novel targets for anti-angiogenesis of genistein on human cancer cells. Biochem Pharmacol 69:307–318.  https://doi.org/10.1016/j.bcp.2004.09.025 CrossRefGoogle Scholar
  190. Sun Q, Cong R, Yan H, Gu H, Zeng Y, Liu N, Chen J, Wang B (2009) Genistein inhibits growth of human uveal melanoma cells and affects microRNA-27a and target gene expression. Oncol Rep 22:563–567.  https://doi.org/10.3892/or_00000472 CrossRefGoogle Scholar
  191. Tanigawa S, Fujii M, Hou DX (2007) Action of Nrf2 and Keap1 in ARE-mediated NQO1 expression by quercetin. Free Radic Biol Med 42:1690–1703.  https://doi.org/10.1016/j.freeradbiomed.2007.02.017 CrossRefGoogle Scholar
  192. Totta P, Acconcia F, Leone S, Cardillo I, Marino M (2004) Mechanisms of naringenin-induced apoptotic cascade in cancer cells: involvement of estrogen receptor α and β signalling. IUBMB Life 56:491–499.  https://doi.org/10.1080/15216540400010792 CrossRefGoogle Scholar
  193. Tsai YD, Chen HJ, Hsu HF, Lu K, Liang CL, Liliang PC, Wang KW, Wang HK, Wang CP, Houng JY (2013) Luteolin inhibits proliferation of human glioblastoma cells via induction of cell cycle arrest and apoptosis. J Taiwan Inst Chem Eng 44:837–845.  https://doi.org/10.1016/j.jtice.2013.03.005 CrossRefGoogle Scholar
  194. Tu SH, Ho CT, Liu MF, Huang CS, Chang HW, Chang CH, Wu CH, Ho YS (2013) Luteolin sensitises drug-resistant human breast cancer cells to tamoxifen via the inhibition of cyclin E2 expression. Food Chem 141:1553–1561.  https://doi.org/10.1016/j.foodchem.2013.04.077 CrossRefGoogle Scholar
  195. Tuli HS, Kashyap D, Bedi SK, Kumar P, Kumar G, Sandhu SS (2015a) Molecular aspects of metal oxide nanoparticle (MO-NPs) mediated pharmacological effects. Life Sci 143:71–79.  https://doi.org/10.1016/j.lfs.2015.10.021 CrossRefGoogle Scholar
  196. Tuli HS, Kashyap D, Sharma AK, Sandhu SS (2015b) Molecular aspects of melatonin (MLT)-mediated therapeutic effects. Life Sci 135:147–157.  https://doi.org/10.1016/j.lfs.2015.06.004 CrossRefGoogle Scholar
  197. Tuli HS, Kashyap D, Sharma AK (2015c) Cordycepin: a cordyceps metabolite with promising therapeutic potential. In: Fungal metabolites. Springer International Publishing, Cham, pp 1–22.  https://doi.org/10.1007/978-3-319-19456-1_2-1 Google Scholar
  198. Ujiki MB, Ding X-Z, Salabat MR, Bentrem DJ, Golkar L, Milam B, Talamonti MS, Bell RH, Iwamura T, Adrian TE (2006) Apigenin inhibits pancreatic cancer cell proliferation through G2/M cell cycle arrest. Mol Cancer 5:76.  https://doi.org/10.1186/1476-4598-5-76 PubMedPubMedCentralCrossRefGoogle Scholar
  199. Vidya Priyadarsini R, Senthil Murugan R, Maitreyi S, Ramalingam K, Karunagaran D, Nagini S (2010) The flavonoid quercetin induces cell cycle arrest and mitochondria-mediated apoptosis in human cervical cancer (HeLa) cells through p53 induction and NF-κB inhibition. Eur J Pharmacol 649(1–3):84–91.  https://doi.org/10.1016/j.ejphar.2010.09.020 CrossRefGoogle Scholar
  200. Wang IK, Lin-Shiau SY, Lin JK (1999) Induction of apoptosis by apigenin and related flavonoids through cytochrome c release and activation of caspase-9 and caspase-3 in leukaemia HL-60 cells. Eur J Cancer 35:1517–1525.  https://doi.org/10.1016/S0959-8049(99)00168-9 CrossRefGoogle Scholar
  201. Wang S, El-deiry WS, El Deiry WS (2007) P53 , cell cycle arrest and apoptosis. In: 25 years of p53 research. Springer Netherlands, Dordrecht, pp 141–163.  https://doi.org/10.1007/978-1-4020-2922-6_6 CrossRefGoogle Scholar
  202. Wang G, Song L, Wang H, Xing N (2013a) Quercetin synergizes with 2-methoxyestradiol inhibiting cell growth and inducing apoptosis in human prostate cancer cells. Oncol Rep 30:357–363.  https://doi.org/10.3892/or.2013.2469 CrossRefGoogle Scholar
  203. Wang Y, Wang H, Zhang W, Shao C, Xu P, Shi CH, Shi JG, Li YM, Fu Q, Xue W, Lei YH, Gao JY, Wang JY, Gao XP, Li JQ, Yuan JL, Zhang YT (2013b) Genistein sensitizes bladder cancer cells to HCPT Treatment in vitro and in vivo via ATM/NF-κB/IKK pathway-induced apoptosis. PLoS One 8:e50175.  https://doi.org/10.1371/journal.pone.0050175 PubMedPubMedCentralCrossRefGoogle Scholar
  204. Wang S-D, Chen B-C, Kao S-T, Liu C-J, Yeh C-C (2014) Genistein inhibits tumor invasion by suppressing multiple signal transduction pathways in human hepatocellular carcinoma cells. BMC Complement Altern Med 14:26.  https://doi.org/10.1186/1472-6882-14-26 PubMedPubMedCentralCrossRefGoogle Scholar
  205. Wang W, Zhao F-L, Zhang J, Gao D-D (2017) Luteolin induces apoptosis in mouse liver cancer cells through ROS mediated pathway: a mechanistic investigation. Biomed ResGoogle Scholar
  206. Wu B, Zhang Q, Shen W, Zhu J (2008) Anti-proliferative and chemosensitizing effects of luteolin on human gastric cancer AGS cell line. Mol Cell Biochem 313:125–132.  https://doi.org/10.1007/s11010-008-9749-x CrossRefGoogle Scholar
  207. Wu H, Huang M, Liu Y, Shu Y, Liu P (2015) Luteolin induces apoptosis by up-regulating miR-34a in human gastric cancer cells. Technol Cancer Res Treat 14:747–755.  https://doi.org/10.7785/tcrt.2012.500434 CrossRefGoogle Scholar
  208. Xia J, Duan Q, Ahmad A, Bao B, Banerjee S, Shi Y, Ma J, Geng J, Chen Z, Wahidur Rahman K, Miele L, H Sarkar F, Wang Z (2012) Genistein inhibits cell growth and induces apoptosis through up-regulation of miR-34a in pancreatic cancer cells. Curr Drug Targets 13:1750–1756.  https://doi.org/10.2174/138945012804545597 CrossRefGoogle Scholar
  209. Xu L (2006) Genistein inhibits matrix metalloproteinase type 2 activation and prostate cancer cell invasion by blocking the transforming growth factor beta-mediated activation of mitogen-activated protein kinase-activated protein kinase 2-27-kDa heat shock protein Pa. Mol Pharmacol 70:869–877.  https://doi.org/10.1124/mol.106.023861 CrossRefGoogle Scholar
  210. Xu L, Xiang J, Shen J, Zou X, Zhai S, Yin Y, Li P, Wang X, Sun Q (2013) Oncogenic MicroRNA-27a is a target for genistein in ovarian cancer cells. Anti Cancer Agents Med Chem 13:1126–1132. https://doi.org/CMCACA-EPUB-20130207-7 [pii]CrossRefGoogle Scholar
  211. Xu H, Yang T, Liu X, Tian Y, Chen X, Yuan R, Su S, Lin X, Du G (2016) Luteolin synergizes the antitumor effects of 5-fluorouracil against human hepatocellular carcinoma cells through apoptosis induction and metabolism. Life Sci 144:138–147.  https://doi.org/10.1016/j.lfs.2015.12.002 CrossRefGoogle Scholar
  212. Yan J, Wang Q, Zheng X, Sun H, Zhou Y, Li D, Lin Y, Wang X (2012) Luteolin enhances TNF-related apoptosis-inducing ligand’s anticancer activity in a lung cancer xenograft mouse model. Biochem Biophys Res Commun 417:842–846.  https://doi.org/10.1016/j.bbrc.2011.12.055 CrossRefGoogle Scholar
  213. Yang S-F, Yang W-E, Chang H-R, Chu S-C, Hsieh Y-S (2008) Luteolin induces apoptosis in oral squamous cancer cells. J Dent Res 87:401–406.  https://doi.org/10.1177/154405910808700413 CrossRefGoogle Scholar
  214. Yang MY, Wang CJ, Chen NF, Ho WH, Lu FJ, Tseng TH (2014) Luteolin enhances paclitaxel-induced apoptosis in human breast cancer MDA-MB-231 cells by blocking STAT3. Chem Biol Interact 213:60–68.  https://doi.org/10.1016/j.cbi.2014.02.002 CrossRefGoogle Scholar
  215. Yang F, Jiang X, Song L, Wang H, Mei Z, Xu Z, Xing N (2016) Quercetin inhibits angiogenesis through thrombospondin-1 upregulation to antagonize human prostate cancer PC-3 cell growth in vitro and in vivo. Oncol Rep 35:1602–1610.  https://doi.org/10.3892/or.2015.4481 CrossRefGoogle Scholar
  216. Yanishlieva N, Gordon M, Pokorný J (2001) Antioxidants in food: practical applications. CRC PressGoogle Scholar
  217. Yao P, Nussler A, Liu L, Hao L, Song F, Schirmeier A, Nussler N (2007) Quercetin protects human hepatocytes from ethanol-derived oxidative stress by inducing heme oxygenase-1 via the MAPK/Nrf2 pathways. J Hepatol 47:253–261.  https://doi.org/10.1016/j.jhep.2007.02.008 CrossRefGoogle Scholar
  218. Yeh TC, Chiang PC, Li TK, Hsu JL, Lin CJ, Wang SW, Peng CY, Guh JH (2007) Genistein induces apoptosis in human hepatocellular carcinomas via interaction of endoplasmic reticulum stress and mitochondrial insult. Biochem Pharmacol 73:782–792.  https://doi.org/10.1016/j.bcp.2006.11.027 CrossRefGoogle Scholar
  219. Yen HR, Liu CJ, Yeh CC (2015) Naringenin suppresses TPA-induced tumor invasion by suppressing multiple signal transduction pathways in human hepatocellular carcinoma cells. Chem Biol Interact 235:1–9.  https://doi.org/10.1016/j.cbi.2015.04.003 CrossRefGoogle Scholar
  220. Yu Z, Li W, Liu F (2004) Inhibition of proliferation and induction of apoptosis by genistein in colon cancer HT-29 cells. Cancer Lett 215:159–166.  https://doi.org/10.1016/j.canlet.2004.06.010 CrossRefGoogle Scholar
  221. Yu X, Zhu J, Mi M, Chen W, Pan Q, Wei M (2012) Anti-angiogenic genistein inhibits VEGF-induced endothelial cell activation by decreasing PTK activity and MAPK activation. Med Oncol 29:349–357.  https://doi.org/10.1007/s12032-010-9770-2 PubMedPubMedCentralCrossRefGoogle Scholar
  222. Yuan C-S (2013) Genistein induces G2/M cell cycle arrest and apoptosis via ATM/p53-dependent pathway in human colon cancer cells. Int J Oncol 43:289–296.  https://doi.org/10.3892/ijo.2013.1946 PubMedPubMedCentralCrossRefGoogle Scholar
  223. Zhang Q, Zhao XH, Wang ZJ (2009) Cytotoxicity of flavones and flavonols to a human esophageal squamous cell carcinoma cell line (KYSE-510) by induction of G2/M arrest and apoptosis. Toxicol. Vitr. 23:797–807.  https://doi.org/10.1016/j.tiv.2009.04.007 CrossRefGoogle Scholar
  224. Zhang JY, Yi T, Liu J, Zhao ZZ, Chen HB (2013) Quercetin induces apoptosis via the mitochondrial pathway in KB and KBv200 cells. J Agric Food Chem 61:2188–2195.  https://doi.org/10.1021/jf305263r CrossRefGoogle Scholar
  225. Zhang X, Guo Q, Chen J, Chen Z (2015) Quercetin enhances cisplatin sensitivity of human osteosarcoma cells by modulating microRNA-217-KRAS axis. Mol Cell 38:638–642.  https://doi.org/10.14348/molcells.2015.0037 CrossRefGoogle Scholar
  226. Zhao LR, Du YJ, Chen L, Liu ZG, Pan YH, Liu JF, Liu B (2014a) Quercetin protects against high glucose-induced damage in bone marrow-derived endothelial progenitor cells. Int J Mol Med 34:1025–1031.  https://doi.org/10.3892/ijmm.2014.1852 CrossRefGoogle Scholar
  227. Zhao P, Mao J-M, Zhang S-Y, Zhou Z-Q, Tan Y, Zhang Y (2014b) Quercetin induces HepG2 cell apoptosis by inhibiting fatty acid biosynthesis. Oncol Lett 8:765–769.  https://doi.org/10.3892/ol.2014.2159 PubMedPubMedCentralCrossRefGoogle Scholar
  228. Zhou N, Yan Y, Li W, Wang Y, Zheng L, Han S, Yan Y, Li Y (2009) Genistein inhibition of topoisomerase II?? expression participated by Sp1 and Sp3 in HeLa cell. Int J Mol Sci 10:3255–3268.  https://doi.org/10.3390/ijms10073255 PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  • Dharambir Kashyap
    • 1
  • Hardeep Singh Tuli
    • 2
  • Mukerrem Betul Yerer
    • 3
  • Anil K. Sharma
    • 2
  • Harpal Singh Buttar
    • 4
  • M. Youns
    • 5
  • Javad Sharifi-Rad
    • 6
  • Bahare Salehi
    • 7
  • William N. Setzer
    • 8
  1. 1.Department of HistopathologyPostgraduate Institute of Medical Education and Research (PGIMER)ChandigarhIndia
  2. 2.Department of BiotechnologyMaharishi Markandeshwar (Deemed to be University)Mullana-AmbalaIndia
  3. 3.Department of Pharmacology, Faculty of PharmacyUniversity of ErciyesKayseriTurkey
  4. 4.Department of Pathology and Laboratory Medicine, Faculty of MedicineUniversity of OttawaOttawaCanada
  5. 5.Department of Biochemistry and Molecular biologyHelwan UniversityHelwanEgypt
  6. 6.Food Safety Research Center (salt)Semnan University of Medical SciencesSemnanIran
  7. 7.Student Research Committee, School of MedicineBam University of Medical SciencesBamIran
  8. 8.Department of ChemistryUniversity of Alabama in HuntsvilleHuntsvilleUSA

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