A B C D E F G H I J K L M N O P Q R S T U V W X Y Z All
Antony Joseph Velanganni, A.
- Inhibition of Breast Cancer Proteins by the Flavonoid Naringenin and its Derivative: A Molecular Docking Study
Authors
1 Department of Biotechnology, Periyar Maniammai Institute of Science & Technology, Thanjavur – 613403, Tamil Nadu, IN
2 Department of Biochemistry, Bharathidasan University, Tiruchirappalli – 620024, Tamil Nadu, IN
Source
Journal of Natural Remedies, Vol 22, No 1 (2022), Pagination: 51 - 64Abstract
Cancer is a multifaceted disease and is a major health burden in the world. Breast cancer is leading cause of mortality among women worldwide. Plant derived compounds have also been used in the treatment of cancer. Amongst them, flavonoids have been well documented for their therapeutic potential against cancer cells. Naringenin is a flavanone abundantly available in grapefruit and tomato among other sources. Several natural and synthetic derivatives of naringenin have been reported for anticancer activity. In this study, naringenin (Nar) and its derivative, naringenin 2-hydroxy benzoyl hydrazone (Nar-Bhz) were studied for their inhibitory potential against proteins involved in breast cancer. Molecular docking simulation by AutoDock was utilized to investigate the interaction of Nar and Nar-Bhz with Survivin, Estrogen receptor α (ERα), progesterone receptor (PR), Akt1, and Epidermal growth factor receptor (EGFR). Doxorubicin was used as positive control because of its clinical importance in breast cancer treatment. Discovery Studio Visualizer was used to visualize the interactions and the docking results showed that the protein ligand complexes were stabilized by hydrogen bonding and hydrophobic interactions. The binding energies ranged between -7.66 to -7.91 kcal/mol with Nar-Bhz and between -5.49 and -11.05 kcal/mol for Nar. Significant inhibition constant was observed for Nar-Bhz interaction with Akt1 and EGFR. Also, several residues of Akt1 interacted with both the ligands. It can be concluded that naringenin and its derivative have promising inhibitory potential against the breast cancer proteins. The findings of this study may pave the way for detailed exploration of naringenin as breast cancer drug and as a nutraceutical or dietary supplement in daily intake.
Keywords
Breast Cancer, Docking, Flavonoids, Molecular, Naringenin, Naringenin DerivativeReferences
- Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 can- cers in 185 countries. CA: Cancer J. Clin. 2021; 71(3):209–49. https://doi.org/10.3322/caac.21660. PMid:33538338
- McPherson K, Steel CM, Dixon JM. ABC of breast diseases: Breast cancer-epidemiology, risk factors, and genetics. BMJ: Br. Med. J. 2000; 321(7261):624. https://doi.org/10.1136/ bmj.321.7261.624. PMid:10977847. PMCid:PMC1118507
- Stuckey A. Breast cancer: Epidemiology and risk factors. Clin. Obstet. Gynecol. 2011; 54(1):96–102. https://doi. org/10.1097/GRF.0b013e3182080056. PMid:21278508
- Yuan E, Liu B, Ning Z, Chen C. Preparative separation of flavonoids in Adinandra nitida leaves by high-speed counter-current chromatography and their effects on human epidermal carcinoma cancer cells. Food Chem. 2009; 115(3):1158–63. https://doi.org/10.1016/j.food- chem.2009.01.009
- Ravishankar D, Rajora AK, Greco F, Osborn HMI. Flavonoids as prospective compounds for anti-cancer ther- apy. Int. J. Biochem. Cell Biol. 2013; 45(12):2821–31. https:// doi.org/10.1016/j.biocel.2013.10.004. PMid:24128857
- Kumar S, Pandey AK. Chemistry and biological activities of flavonoids: An overview. Sci. World J. 2013; 2013:162750. https://doi.org/10.1155/2013/162750. PMid:24470791. PMCid:PMC3891543
- Rodriguez-Mateos A, Vauzour D, Krueger CG, Shanmuganayagam D, Reed J, Calani L, et al. Bioavailability, bioactivity and impact on health of dietary flavonoids and related compounds: An update. Arch. Toxicol. 2014; 88(10):1803–53. https://doi.org/10.1007/s00204-014-1330- 7. PMid:25182418
- Zhao J, Zhang J, Yu M, Xie Y, Huang Y, Wolff DW, et al. Mitochondrial dynamics regulates migration and invasion of breast cancer cells. Oncogene. 2013; 32(40):4814–24. https://doi.org/10.1038/onc.2012.494. PMid:23128392. PMCid:PMC3911914
- Plochmann K, Korte G, Koutsilieri E, Richling E, Riederer P, Rethwilm A, et al. Structure-activity relationships of flavonoid-induced cytotoxicity on human leukemia cells. Arch. Biochem. Biophys. 2007; 460(1):1–9. https://doi. org/10.1016/j.abb.2007.02.003. PMid:17353006
- Sghaier MB, Skandrani I, Nasr N, Franca MGD, Chekir- Ghedira L, Ghedira K. Flavonoids and sesquiterpenes from Tecurium ramosissimum promote antiproliferation of human cancer cells and enhance antioxidant activity: A structure-activity relationship study. Environ. Toxicol. Pharm. 2011; 32(3):336–48. https://doi.org/10.1016/j. etap.2011.07.003. PMid:22004952
- Salehi B, Fokou PVT, Sharifi-Rad M, Zucca P, Pezzani R, Martins N, et al. The therapeutic potential of naringenin: A review of clinical trials. Pharmaceuticals. 2019; 12(1):1– 18. https://doi.org/10.3390/ph12010011. PMid:30634637. PMCid:PMC6469163
- Chandrika BB, Steephan M, Kumar TRS, Sabu A, Haridas M. Hesperetin and Naringenin sensitize HER2 positive cancer cells to death by serving as HER2 Tyrosine Kinase inhibi- tors. Life Sci. 2016; 160:47–56. https://doi.org/10.1016/j. lfs.2016.07.007. PMid:27449398
- Zhang F, Dong W, Zeng W, Zhang L, Zhang C, Qiu Y, et al. Naringenin prevents TGF-β1 secretion from breast cancer and suppresses pulmonary metastasis by inhibiting PKC activation. Breast Cancer Res. : BCR. 2016; 18(1):38. https:// doi.org/10.1186/s13058-016-0698-0. PMid:27036297. PMCid:PMC4818388
- Mir IA, Tiku AB. Chemopreventive and therapeutic poten- tial of “Naringenin,” a flavanone present in citrus fruits. Nutr. Cancer. 2015; 67(1):27–42. https://doi.org/10.1080/0 1635581.2015.976320. PMid:25514618
- Wang BD, Yang ZY, Wang Q, Cai TK, Crewdson P. Synthesis, characterization, cytotoxic activities, and DNA-binding properties of the La(III) complex with Naringenin Schiff- base. Bioorg. Med. Chem. 2006;14(6):1880–8. https://doi. org/10.1016/j.bmc.2005.10.031. PMid:16310358
- Li T-R, Yang Z-Y, Wang B-D. Synthesis, characteriza- tion and antioxidant activity of naringenin Schiff base and its Cu(II), Ni(II), Zn(II) complexes. Chem. Pharm. Bull. (Tokyo). 2007; 55(1):26–8. https://doi.org/10.1248/ cpb.55.26. PMid:17202696
- Sun TM, Wang YC, Wang F, Du JZ, Mao CQ, Sun CY, et al. Cancer stem cell therapy using doxorubicin conjugated to gold nanoparticles via hydrazone bonds. Biomaterials. 2014; 35(2):836–45. https://doi.org/10.1016/j.biomateri- als.2013.10.011. PMid:24144908
- Jiang T, Li YM, Lv Y, Cheng YJ, He F, Zhuo RX. Amphiphilic polycarbonate conjugates of doxorubicin with pH-sen- sitive hydrazone linker for controlled release. Colloids Surf. B. 2013; 111:542–8. https://doi.org/10.1016/j.col- surfb.2013.06.054. PMid:23893028
- Nikolova-Mladenova B, Momekov G, Ivanov D, Bakalova A. Design and drug-like properties of new 5-methoxysali- cylaldehyde based hydrazones with anti-breast cancer activity. J. Appl. Biomed. 2017; 15(3):233–40. https://doi. org/10.1016/j.jab.2017.04.004
- Gradishar WJ, Anderson BO, Balassanian R, Blair SL, Burstein HJ, Cyr A, et al. Invasive breast cancer ver- sion 1.2016. JNCCN J. Natl. Compr. Cancer Netw. 2016; 14(3):324–54. https://doi.org/10.6004/jnccn.2016.0037. PMid:26957618
- Garg H, Suri P, Gupta JC, Talwar GP, Dubey S. Survivin: A unique target for tumor therapy. Cancer Cell Int. 2016; 16(1):1–14. https://doi.org/10.1186/s12935-016-0326-1. PMid:27340370. PMCid:PMC4917988
- Jia M, Dahlman-Wright K, Gustafsson JÅ. Estrogen recep- tor alpha and beta in health and disease. Best Pract. Res. Clin. Endocrinol. Metab. 2015; 29(4):557–68. https://doi. org/10.1016/j.beem.2015.04.008. PMid:26303083
- Arnal JF, Lenfant F, Metivier R, Flouriot G, Henrion D, Adlanmerini M, et al. Membrane and nuclear estrogen receptor alpha actions: From tissue specificity to medical implications. Physiol. Rev.. 2017; 97(3):1045–87. https:// doi.org/10.1152/physrev.00024.2016. PMid:28539435
- Siersbæk R, Kumar S, Carroll JS. Signaling pathways and steroid receptors modulating estrogen receptor α function in breast cancer. Genes Dev. 2018; 32(17–18):1141–54. https://doi.org/10.1101/gad.316646.118. PMid:30181360. PMCid:PMC6120708
- Li X, O’Malley BW. Unfolding the action of progesterone receptors. J. Biol. Chem. 2003; 278(41):39261–4. https://doi. org/10.1074/jbc.R300024200. PMid:12893816
- Osborne CK. Steroid hormone receptors in breast cancer management. Breast Cancer Res. Treat. 1998; 51(3):227–38. https://doi.org/10.1023/A:1006132427948. PMid:10068081
- Shyamala G, Chou YC, Louie SG, Guzman RC, Smith GH, Nandi S. Cellular expression of estrogen and progesterone receptors in mammary glands: Regulation by hormones, development and aging. J. Steroid Biochem. Mol. Biol. 2002; 80(2):137–48. https://doi.org/10.1016/S0960- 0760(01)00182-0
- Datta SR, Brunet A, Greenberg ME. Cellular survival: A play in three akts. Genes Dev. 1999; 13(22):2905–27. https://doi. org/10.1101/gad.13.22.2905. PMid:10579998
- Ciardiello F, Tortora G. EGFR antagonists in cancer treat- ment. N. Engl. J. Med. 2008; 358:1160–74. https://doi. org/10.1056/NEJMra0707704. PMid:18337605
- Ioannou N, Seddon AM, Dalgleish A, Mackintosh D, Modjtahedi H. Expression pattern and targeting of HER family members and IGF-IR in pancreatic cancer. Front. Biosci. 2012; 17(4):2698–724. https://doi.org/10.2741/4081. PMid:22652808
- Khelwatty SA, Essapen S, Seddon AM, Modjtahedi H. Prognostic significance and targeting of HER family in colorectal cancer. Front. Biosci. 2013; 18:394–421.https:// doi.org/10.2741/4110. PMid:23276932
- Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, et al. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J. Comput. Chem. 2009; 30(16):2785– 91. https://doi.org/10.1002/jcc.21256. PMid:19399780. PMCid:PMC2760638
- Raeisi S, Chavoshi H, Mohammadi M, Ghorbani M, Sabzichi M, Ramezani F. Naringenin-loaded nano-struc- tured lipid carrier fortifies oxaliplatin-dependent apoptosis in HT-29 cell line. Process. Chem. 2019; 83:168–75. https:// doi.org/10.1016/j.procbio.2019.05.013
- Ryan BM, O’Donovan N, Duffy MJ. Survivin: A new tar- get for anti-cancer therapy. Cancer Treat. Rev. 2009; 35(7):553–62. https://doi.org/10.1016/j.ctrv.2009.05.003. PMid:19559538
- Taglieri L, De Iuliis F, Giuffrida A, Giantulli S, Silvestri I, Scarpa S. Resistance to the mTOR inhibitor everoli- mus is reversed by the downregulation of survivin in breast cancer cells. Oncol. Lett. 2017; 14(3):3832–38. https://doi.org/10.3892/ol.2017.6597. PMid:28927154. PMCid:PMC5587981
- McGuire WL. Estrogen receptors in human breast cancer. J. Clin. Investig. 1973; 52(1):73–77. https://doi.org/10.1172/ JCI107175. PMid:4345203. PMCid:PMC302228
- Ali S, Mondal N, Choudhry H, Rasool M, Pushparaj PN, Khan MA, et al. Current management strategies in breast cancer by targeting key altered molecular play- ers. Front. Oncol. 2016; 6(Mar). https://doi.org/10.3389/ fonc.2016.00045
- Colditz GA. Relationship between estrogen levels, use of hormone replacement therapy, and breast cancer. J Natl Cancer Inst. 1998; 90(11):814–23. https://doi.org/10.1093/ jnci/90.11.814. PMid:9625169
- Hankinson SE, Colditz GA, Willett WC. The lifelong interplay of genes, lifestyle, and hormones. Breast Cancer Res. 2004; 6(5):213–18. https://doi.org/10.1186/bcr921. PMid:15318928. PMCid:PMC549181
- Patel HK, Bihani T. Selective Estrogen Receptor Modulators (SERMs) and Selective Estrogen Receptor Degraders (SERDs) in cancer treatment. Pharmacol. Ther. 2018; 186:1– 24. https://doi.org/10.1016/j.pharmthera.2017.12.012. PMid:29289555
- Kumar N, Gulati HK, Sharma A, Heer S, Jassal AK, Arora L, et al. Most recent strategies targeting estrogen receptor alpha for the treatment of breast cancer. Mol. Divers. 2021; 25(1):603–24. https://doi.org/10.1007/s11030-020-10133-y. PMid:32886304
- Al-Bader M, Ford C, Al-Ayadhy B, Francis I. Analysis of estro- gen receptor isoforms and variants in breast cancer cell lines. Exp. Ther. Med. 2011; 2(3):537–44. https://doi.org/10.3892/ etm.2011.226. PMid:22977537. PMCid:PMC3440683
- El-Kersh DM, Ezzat SM, Salama MM, Mahrous EA, Attia YM, Ahmed MS, et al. Anti-estrogenic and anti-aromatase activities of citrus peels major compounds in breast cancer. Sci. Rep. 2021; 11(1):1–14. https://doi.org/10.1038/s41598- 021-86599-z. PMid:33782546. PMCid:PMC8007834
- So FV, Guthrie N, Chambers AF, Carroll KK. Inhibition of proliferation of estrogen receptor-positive MCF-7 human breast cancer cells by flavonoids in the presence and absence of excess estrogen. Cancer Lett. 1997; 112(2):127– 33. https://doi.org/10.1016/S0304-3835(96)04557-0
- Mohammed H, Russell IA, Stark R, Rueda OM, Hickey TE, Tarulli GA, et al. Progesterone receptor modulates ERα action in breast cancer. Nature. 2015; 523(7560):313–17. https://doi.org/10.1038/nature14583. PMid:26153859. PMCid:PMC4650274
- Wagenfeld A, Saunders PTK, Whitaker L, Critchley HOD. Selective progesterone receptor modulators (SPRMs): Progesterone receptor action, mode of action on the endo- metrium and treatment options in gynecological therapies. Expert Opin. Ther. Targets. 2016; 20(9):1045–54. https:// doi.org/10.1080/14728222.2016.1180368. PMid:27138351. PMCid:PMC4989858
- Miller TW, Rexer BN, Garrett JT, Arteaga CL. Mutations in the phosphatidylinositol 3-kinase pathway: Role in tumor progression and therapeutic implications in breast cancer. Breast Cancer Res. 2011; 13(6). https://doi.org/10.1186/ bcr3039. PMid:22114931. PMCid:PMC3315683
- Rao VV, Mane SR, Kishore A, Das Sarma J, Shunmugam R. Norbornene derived doxorubicin copolymers as drug carriers with pH responsive hydrazone linker. Biomacromolecules. 2012; 13(1):221–30. https://doi. org/10.1021/bm201478k. PMid:22107051
- Shin SY, Yong Y, Kim CG, Lee YH, Lim Y. Deoxypodo- phyllotoxin induces G2/M cell cycle arrest and apoptosis in HeLa cells. Cancer Lett. 2010; 287(2):231–9. https://doi. org/10.1016/j.canlet.2009.06.019. PMid:19616373
- Ju X, Katiyar S, Wang C, Liu M, Jiao X, Li S, et al. Akt1 governs breast cancer progression in vivo. Proc Natl Acad Sci USA. 2007; 104(18):7438–43. https://doi.org/10.1073/ pnas.0605874104. PMid:17460049. PMCid:PMC1863437
- Bak Y, Kim H, Kang J-W, Lee DH, Kim MS, Park YS, et al. A synthetic naringenin derivative, 5-Hydroxy-7, 4‘-diacetyloxyflavanone-N-phenyl Hydrazone (N101- 43), induces apoptosis through Up-regulation of Fas/FasL expression and inhibition of PI3K/Akt signaling pathways in non-small-cell lung cancer cells. J. Agric. Food Chem. 2011; 59(18):10286–97. https://doi.org/10.1021/jf2017594. PMid:21877710
- Kim J-H, Kang JW, Kim MS, Bak Y, Park YS, Jung K-Y, et al. The apoptotic effects of the flavonoid N101-2 in human cer- vical cancer cells. Toxicology In Vitro. 2012; 26(1):67–73. https://doi.org/10.1016/j.tiv.2011.10.012. PMid:22056764
- Zhang H, Berezov A, Wang Q, Zhang G, Drebin J, Murali R, et al. Review series ErbB receptors : from oncogenes to targeted cancer therapies. Molecules. 2007; 117(8):2051–8. https://doi.org/10.1172/JCI32278. PMid:17671639. PMCid:PMC1934579