A Critical Review on Anticancer Mechanisms of Natural Flavonoid Puerarin

Author(s): Manikanta Murahari, Vikas Singh, Pramila Chaubey, Vasanti Suvarna*

Journal Name: Anti-Cancer Agents in Medicinal Chemistry
(Formerly Current Medicinal Chemistry - Anti-Cancer Agents)

Volume 20 , Issue 6 , 2020

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Graphical Abstract:


Cancer is one of the prominent global causes of death and the foremost worldwide health concern. Despite unprecedented progress in cancer chemoprevention, a vast number of cancers, however, remain an undefeatable challenge for treatment modalities. Immense therapeutic activities of puerarin contribute to its use in various health disorders. In this review, we explored the potential molecular mechanisms and targets of puerarin, proving its potential as a novel anticancer agent, for future cancer therapy and chemoprevention. Several mechanisms account for anticancer activity of puerarin which includes downregulation of NF-kB signalling pathway, mTOR signalling pathway, PI3K and BCl-2 proteins and upregulation of miR-16, caspase proteins, c- Jun N terminal kinase and extracellular signal-regulated kinase 1/2. These alterations result in inhibition of cancer cell proliferation and/or induction of apoptosis. Understanding the molecular mechanisms involved in chemotherapy and chemoprevention could aid in the more pronounced exploration of puerarin in effective cancer treatment.

Keywords: Puerarin, isoflavones, polyphenols, neoplasms, chemoprevention, adjuvant.

Wang, H.; Khor, T.O.; Shu, L.; Su, Z-Y.; Fuentes, F.; Lee, J-H.; Kong, A.N. Plants vs. cancer: a review on natural phytochemicals in preventing and treating cancers and their druggability. Anticancer. Agents Med. Chem., 2012, 12(10), 1281-1305.
[http://dx.doi.org/10.2174/187152012803833026] [PMID: 22583408]
Zhou, Y.; Zheng, J.; Li, Y.; Xu, D.P.; Li, S.; Chen, Y.M.; Li, H.B. Natural polyphenols for prevention and treatment of cancer. Nutrients, 2016, 8(8), E515
[http://dx.doi.org/10.3390/nu8080515] [PMID: 27556486]
Joshi, K.S.; Rathos, M.J.; Joshi, R.D.; Sivakumar, M.; Mascarenhas, M.; Kamble, S.; Lal, B.; Sharma, S. In vitro antitumor properties of a novel cyclin-dependent kinase inhibitor, P276-00. Mol. Cancer Ther., 2007, 6(3), 918-925.
[http://dx.doi.org/10.1158/1535-7163.MCT-06-0613] [PMID: 17363486]
Ullmannova, V.; Popescu, N.C. Inhibition of cell proliferation, induction of apoptosis, reactivation of DLC1, and modulation of other gene expression by dietary flavone in breast cancer cell lines. Cancer Detect. Prev., 2007, 31(2), 110-118.
[http://dx.doi.org/10.1016/j.cdp.2007.02.005] [PMID: 17418982]
Hien, T.T.; Kim, H.G.; Han, E.H.; Kang, K.W.; Jeong, H.G. Molecular mechanism of suppression of MDR1 by puerarin from Pueraria lobata via NF-kappaB pathway and cAMP-responsive element transcriptional activity-dependent up-regulation of AMP-activated protein kinase in breast cancer MCF-7/adr cells. Mol. Nutr. Food Res., 2010, 54(7), 918-928.
[http://dx.doi.org/10.1002/mnfr.200900146] [PMID: 20077420]
Yan, L.P.; Chan, S.W.; Chan, A.S.C.; Chen, S.L.; Ma, X.J.; Xu, H.X. Puerarin decreases serum total cholesterol and enhances thoracic aorta endothelial nitric oxide synthase expression in diet-induced hypercholesterolemic rats. Life Sci., 2006, 79(4), 324-330.
[http://dx.doi.org/10.1016/j.lfs.2006.01.016] [PMID: 16472823]
Meng, X.H.; Ni, C.; Zhu, L.; Shen, Y.L.; Wang, L.L.; Chen, Y.Y. Puerarin protects against high glucose-induced acute vascular dysfunction: role of heme oxygenase-1 in rat thoracic aorta. Vascul. Pharmacol., 2009, 50(3-4), 110-115.
[http://dx.doi.org/10.1016/j.vph.2008.11.003] [PMID: 19073281]
Liu, X.; Zhao, W.; Wang, W.; Lin, S.; Yang, L. Puerarin suppresses LPS-induced breast cancer cell migration, invasion and adhesion by blockage NF-κB and Erk pathway. Biomed. Pharmacother., 2017, 92, 429-436.
[http://dx.doi.org/10.1016/j.biopha.2017.05.102] [PMID: 28558356]
Chen, T.; Chen, H.; Wang, Y.; Zhang, J. In vitro and in vivo antitumour activities of puerarin 6″-O-xyloside on human lung carcinoma A549 cell line via the induction of the mitochondria-mediated apoptosis pathway. Pharm. Biol., 2016, 54(9), 1793-1799.
[http://dx.doi.org/10.3109/13880209.2015.1127980] [PMID: 26730946]
Guo, X.F.; Yang, Z.R.; Wang, J.; Lei, X.F.; Lv, X.G.; Dong, W.G. Synergistic antitumor effect of puerarin combined with 5-fluorouracil on gastric carcinoma. Mol. Med. Rep., 2015, 11(4), 2562-2568.
[http://dx.doi.org/10.3892/mmr.2014.3016] [PMID: 25434307]
Tan, X-F.; Xia, F. Long-term fatigue state in postoperative patients with breast cancer. Chin. J. Cancer Res., 2014, 26(1), 12-16.
[PMID: 24653622]
Liu, X.; Li, S.; Li, Y.; Cheng, B.; Tan, B.; Wang, G. Puerarin inhibits proliferation and induces apoptosis by up-regulation of miR-16 in bladder cancer cell line T24. Oncol. Res., 2018, 26(8), 1227-1234.
Jiang, K.; Chen, H.; Tang, K.; Guan, W.; Zhou, H.; Guo, X.; Chen, Z.; Ye, Z.; Xu, H. Puerarin inhibits bladder cancer cell proliferation through the mTOR/p70S6K signaling pathway. Oncol. Lett., 2018, 15(1), 167-174.
[http://dx.doi.org/10.3892/ol.2017.7298] [PMID: 29375709]
Kang, H.; Zhang, J.; Wang, B.; Liu, M.; Zhao, J.; Yang, M.; Li, Y. Puerarin inhibits M2 polarization and metastasis of tumor-associated macrophages from NSCLC xenograft model via inactivating MEK/ERK 1/2 pathway. Int. J. Oncol., 2017, 50(2), 545-554.
[http://dx.doi.org/10.3892/ijo.2017.3841] [PMID: 28101568]
Zhang, W-G.; Yin, X-C.; Liu, X-F.; Meng, K-W.; Tang, K.; Huang, F-L.; Xu, G.; Gao, J. Puerarin induces hepatocellular carcinoma cell apoptosis modulated by MAPK signaling pathways in a dose-dependent manner. Anticancer Res., 2017, 37(8), 4425-4431.
[http://dx.doi.org/10.21873/anticanres.12744] [PMID: 28739736]
Zhang, W.G.; Liu, X.F.; Meng, K.W.; Hu, S.Y. Puerarin inhibits growth and induces apoptosis in SMMC-7721 hepatocellular carcinoma cells. Mol. Med. Rep., 2014, 10(5), 2752-2758.
[http://dx.doi.org/10.3892/mmr.2014.2512] [PMID: 25175767]
Zeng, Y.P.; Yang, Z.R.; Guo, X.F.; Jun, W.; Dong, W.G. Synergistic effect of puerarin and 5-fluorouracil on hepatocellular carcinoma. Oncol. Lett., 2014, 8(6), 2436-2442.
[http://dx.doi.org/10.3892/ol.2014.2534] [PMID: 25364405]
Lin, Y-J.; Hou, Y.C.; Lin, C-H.; Hsu, Y-A.; Sheu, J.J.C.; Lai, C-H.; Chen, B-H.; Lee Chao, P.D.; Wan, L.; Tsai, F.J. Puerariae radix isoflavones and their metabolites inhibit growth and induce apoptosis in breast cancer cells. Biochem. Biophys. Res. Commun., 2009, 378(4), 683-688.
[http://dx.doi.org/10.1016/j.bbrc.2008.10.178] [PMID: 19013426]
Yang, J-A.; Li, J-Q.; Shao, L-M.; Yang, Q.; Liu, B-H.; Wu, T-F.; Wu, P.; Yi, W.; Chen, Q-X. Puerarin inhibits proliferation and induces apoptosis in human glioblastoma cell lines. Int. J. Clin. Exp. Med., 2015, 8(6), 10132-10142.
[PMID: 26309712]
Peng, X.Y.; Qi, Z.H.; Chen, H.P. [Study on the differentiation and apoptosis of HL-60 cell line induced by Puerarin]. Hunan Yi Ke Da Xue Xue Bao, 2001, 26(2), 126-128.
Wang, Y.; Ma, Y.; Zheng, Y.; Song, J.; Yang, X.; Bi, C.; Zhang, D.; Zhang, Q. In vitro and in vivo anticancer activity of a novel puerarin nanosuspension against colon cancer, with high efficacy and low toxicity. Int. J. Pharm., 2013, 441(1-2), 728-735.
[http://dx.doi.org/10.1016/j.ijpharm.2012.10.021] [PMID: 23089583]
Yu, Z.; Li, W. Induction of apoptosis by puerarin in colon cancer HT-29 cells. Cancer Lett., 2006, 238(1), 53-60.
[http://dx.doi.org/10.1016/j.canlet.2005.06.022] [PMID: 16055262]
Wang, J.; Yang, Z.R.; Guo, X.F.; Song, J.; Zhang, J.X.; Wang, J.; Dong, W.G. Synergistic effects of puerarin combined with 5-fluorouracil on esophageal cancer. Mol. Med. Rep., 2014, 10(5), 2535-2541.
[http://dx.doi.org/10.3892/mmr.2014.2539] [PMID: 25189132]
Huang, L.; Cao, J.; Cao, L.; Gao, L.; Yang, Y.; Xu, L. Puerarin induces cell apoptosis in human chondrosarcoma cell line SW1353 via inhibition of the PI3K/Akt signaling pathway. Oncol. Lett., 2017, 14(5), 5585-5590.
[http://dx.doi.org/10.3892/ol.2017.6901] [PMID: 29113186]
Theodorescu, D. Molecular pathogenesis of urothelial bladder cancer. Histol. Histopathol., 2003, 18(1), 259-274.
[PMID: 12507305]
SEER Data. National Cancer Institute, https://seer.cancer.gov/statfacts/ [Accessed: Jul 7, 2016].
Tong, L.; Spitz, M.R.; Fueger, J.J.; Amos, C.A. Lung carcinoma in former smokers. Cancer, 1996, 78(5), 1004-1010.
[http://dx.doi.org/10.1002/(SICI)1097-0142(19960901)78:5<1004:AID-CNCR10>3.0.CO;2-6] [PMID: 8780538]
Amos, C.I.; Xu, W.; Spitz, M.R. Is there a genetic basis for lung cancer susceptibility? Chemoprevention of Cancer; Springer, 1999, pp. 3-12.
Hecht, S.S. Tobacco smoke carcinogens and lung cancer BT - chemical carcinogenesis. JNCI J. Natl. Cancer Inst., 2011, 91(14), 53-74.
Kumar, S.; Raina, K.; Agarwal, R. Chemopreventive and anticancer efficacy of silibinin against colorectal cancer. Multi-Target. App. Treat. Cancer, 2015, 65(sup1), 339-350.
Hu, Y.; Li, X.; Lin, L.; Liang, S.; Yan, J. Puerarin inhibits non-small cell lung cancer cell growth via the induction of apoptosis. Oncol. Rep., 2018, 39(4), 1731-1738.
[http://dx.doi.org/10.3892/or.2018.6234] [PMID: 29393465]
Zeng, Y.; Shen, Z-J.; Gu, W-Z.; Wu, M-H. Cyclooxygenase-2 mediates puerarin to inhibit the invasion and metastasis of lung cancer A549 cells. Transl. Cancer Res., 2017, 6(3), 493-501.
Jemal, A.; Bray, F.; Center, M.M.; Ferlay, J.; Ward, E.; Forman, D. Global cancer statistics. CA Cancer J. Clin., 2011, 61(2), 69-90.
[http://dx.doi.org/10.3322/caac.20107] [PMID: 21296855]
Zheng, Y.H.; Yin, L.H.; Grahn, T.H.M.; Ye, A.F.; Zhao, Y.R.; Zhang, Q.Y. Anticancer effects of baicalein on hepatocellular carcinoma cells. Phytother. Res., 2014, 28(9), 1342-1348.
[http://dx.doi.org/10.1002/ptr.5135] [PMID: 24596136]
http://globocan.iarc.fr/Default.aspx[Accessed: Feb 2, 2017].
Song, M.; Li, J.L.; Li, X.P.; Kan, S.F. Targeting human poly(ADP-ribose) polymerase-1 with natural medicines and its potential applications in ovarian cancer therapeutics. Arch. Pharm. (Weinheim), 2015, 348(11), 817-823.
[http://dx.doi.org/10.1002/ardp.201500183] [PMID: 26344206]
Han, J.; Yu, C-Q.; Shen, W. Inhibitory effects of puerarin on invasion and metastasis of oophoroma cells HO-8910. Zhongguo Zhong Xi Yi Jie He Za Zhi Zhongguo Zhongxiyi Jiehe Zazhi = Ch. J. Integr. Tradit. West. Med., 2009, 29(7), 632-635.
Ferlay, J.; Soerjomataram, I.; Dikshit, R.; Eser, S.; Mathers, C.; Rebelo, M.; Parkin, D.M.; Forman, D.; Bray, F. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int. J. Cancer, 2015, 136(5), E359-E386.
[http://dx.doi.org/10.1002/ijc.29210] [PMID: 25220842]
Cherdshewasart, W.; Sriwatcharakul, S. Metabolic activation promotes estrogenic activity of the phytoestrogen-rich plant. Maturitas, 2008, 59(2), 128-136.
[http://dx.doi.org/10.1016/j.maturitas.2008.01.002] [PMID: 18313242]
Louis, D.N.; Ohgaki, H.; Wiestler, O.D.; Cavenee, W.K.; Burger, P.C.; Jouvet, A.; Scheithauer, B.W.; Kleihues, P. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol., 2007, 114(2), 97-109.
[http://dx.doi.org/10.1007/s00401-007-0243-4] [PMID: 17618441]
Stupp, R.; Mason, W.P.; van den Bent, M.J.; Weller, M.; Fisher, B.; Taphoorn, M.J.; Belanger, K.; Brandes, A.A.; Marosi, C.; Bogdahn, U.; Curschmann, J.; Janzer, R.C.; Ludwin, S.K.; Gorlia, T.; Allgeier, A.; Lacombe, D.; Cairncross, J.G.; Eisenhauer, E.; Mirimanoff, R.O. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N. Engl. J. Med., 2005, 352(10), 987-996.
[http://dx.doi.org/10.1056/NEJMoa043330] [PMID: 15758009]
Ostrom, Q.T.; Gittleman, H.; Fulop, J.; Liu, M.; Blanda, R.; Kromer, C.; Wolinsky, Y.; Kruchko, C.; Barnholtz-Sloan, J.S. CBTRUS statistical report: Primary brain and central nervous system tumors diagnosed in the United States in 2008-2012. Neuro-oncol., 2015, 17(Suppl. 4), iv1-iv62.
[http://dx.doi.org/10.1093/neuonc/nov189] [PMID: 26511214]
Cheng, Y.; Leng, W.; Zhang, J. Protective effect of puerarin against oxidative stress injury of neural cells and related mechanisms. Med. Sci. Monit., 2016, 22, 1244-1249.
[http://dx.doi.org/10.12659/MSM.896058] [PMID: 27074962]
Shao, H.M.; Tang, Y.H.; Jiang, P.J.; Zhu, H.Q.; Zhang, Y.C.; Ji, J.M.; Ji, O.; Shen, Q. [Inhibitory effect of flavonoids of puerarin on proliferation of different human acute myeloid leukemia cell lines in vitro.]. Zhongguo Shi Yan Xue Ye Xue Za Zhi, 2010, 18(2), 296-299.
[PMID: 20416155]
Tang, Y.H.; Zhu, H.Q.; Zhang, Y.C.; Shao, H.M.; Ji, J.M.; Zhu, G.R.; Jiang, P.J.; Ji, O.; Shen, Q. [Apoptosis of NB4 cells induced by flavonoids of puerarin in vitro.]. Zhongguo Shi Yan Xue Ye Xue Za Zhi, 2010, 18(2), 326-329.
[PMID: 20416161]
Gan, M.; Yin, X. Puerarin induced in mantle cell lymphoma apoptosis and its possible mechanisms involving multi-signaling pathway. Cell Biochem. Biophys., 2015, 71(1), 367-373.
[http://dx.doi.org/10.1007/s12013-014-0207-y] [PMID: 25173778]
World Health Organization, Cancer, . http://www.who.int/mediacentre/factsheets/fs297/en/ [Accessed: Mar 23, 2017]..
SEER Stat Facts: Stomach Cancer,. https://seer.cancer.gov/statfacts/[Accessed: Mar 23, 2017]..
Schatzkin, A.; Freedman, L.S.; Dawsey, S.M.; Lanza, E. Interpreting precursor studies: what polyp trials tell us about large-bowel cancer. J. Natl. Cancer Inst., 1994, 86(14), 1053-1057.
[http://dx.doi.org/10.1093/jnci/86.14.1053] [PMID: 7802771]
Evans, H.L.; Ayala, A.G.; Romsdahl, M.M. Prognostic factors in chondrosarcoma of bone: a clinicopathologic analysis with emphasis on histologic grading. Cancer, 1977, 40(2), 818-831.
[http://dx.doi.org/10.1002/1097-0142(197708)40:2<818:AID-CNCR2820400234>3.0.CO;2-B] [PMID: 890662]
Outani, H.; Hamada, K.; Imura, Y.; Oshima, K.; Sotobori, T.; Demizu, Y.; Kakunaga, S.; Joyama, S.; Imai, R.; Okimoto, T.; Naka, N.; Kudawara, I.; Ueda, T.; Araki, N.; Kamada, T.; Yoshikawa, H. Comparison of clinical and functional outcome between surgical treatment and carbon ion radiotherapy for pelvic chondrosarcoma. Int. J. Clin. Oncol., 2016, 21(1), 186-193.
[http://dx.doi.org/10.1007/s10147-015-0870-z] [PMID: 26150259]
Isakoff, M.S.; Bielack, S.S.; Meltzer, P.; Gorlick, R. Osteosarcoma: Current treatment and a collaborative pathway to success. J. Clin. Oncol., 2015, 33(27), 3029-3035.
[http://dx.doi.org/10.1200/JCO.2014.59.4895] [PMID: 26304877]
Prasain, J.K.; Peng, N.; Acosta, E.; Moore, R.; Arabshahi, A.; Meezan, E.; Barnes, S.; Wyss, J.M. Pharmacokinetic study of puerarin in rat serum by liquid chromatography tandem mass spectrometry. Biomed. Chromatogr., 2007, 21(4), 410-414.
[http://dx.doi.org/10.1002/bmc.772] [PMID: 17221935]
Guo, Y.J.; Liang, D.L.; Xu, Z.S.; Ye, Q. In vivo inhibitory effects of puerarin on selected rat cytochrome P450 isoenzymes. Pharmazie, 2014, 69(5), 367-370.
[http://dx.doi.org/10.1691/ph.2014.3823] [PMID: 24855829]
Shao, J.; Chen, J.; Li, T.; Zhao, X. Spectroscopic and molecular docking studies of the in vitro interaction between puerarin and cytochrome P450. Molecules, 2014, 19(4), 4760-4769.
[http://dx.doi.org/10.3390/molecules19044760] [PMID: 24743933]
Kopečná-Zapletalová, M.; Krasulová, K.; Anzenbacher, P.; Hodek, P.; Anzenbacherová, E. Interaction of isoflavonoids with human liver microsomal cytochromes P450: inhibition of CYP enzyme activities. Xenobiotica, 2017, 47(4), 324-331.
[http://dx.doi.org/10.1080/00498254.2016.1195028] [PMID: 27312150]
Huihua, Q.; Feng, W.; Wenchao, S.; Xueqian, W.; Jinjun, C.; Hui, K.; Yan, Z.; Qingguo, W. Pharmacokinetic analysis of orally administered puerarin in human saliva using an indirect competition ELISA. Anal. Methods, 2015, 7(19), 8335-8343.
Lu, W. In vitro antitumor efficacy of puerarin nanosuspension against human HepG2 cells. Adv. Mat. Res., 2014, 1083, 27-31.
Anukunwithaya, T.; Poo, P.; Hunsakunachai, N.; Rodsiri, R.; Malaivijitnond, S.; Khemawoot, P. Absolute oral bioavailability and disposition kinetics of puerarin in female rats. BMC Pharmacol. Toxicol., 2018, 19(1), 25.
Cheng, W.; Chen, L.; Yang, S.; Han, J.; Zhai, D.; Ni, J.; Yu, C.; Cai, Z. Puerarin suppresses proliferation of endometriotic stromal cells partly via the MAPK signaling pathway induced by 17ß-estradiol-BSA. PLoS One, 2012, 7(9), e45529
[http://dx.doi.org/10.1371/journal.pone.0045529] [PMID: 23029074]
Bunton, C.A.; Fendler, J.H. The hydrolysis of acetyl fluoride. J. Org. Chem., 1966, 31(7), 2307-2312.

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Year: 2020
Published on: 14 June, 2020
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DOI: 10.2174/1871520620666200227091811
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