An Updated Review Summarizing the Pharmaceutical Efficacy of Genistein and its Nanoformulations in Ovarian Carcinoma

Pratibha      Pandey; Seema      Ramniwas; Shivam      Pandey; Meenakshi      Verma; Rahul      Kumar; Sorabh      Lakhanpal; Fahad      Khan; Mohd   Asif   Shah
Abstract

Implementing lifestyle interventions as a primary prevention strategy is a cost-effective approach to reducing the occurrence of cancer, which is a significant contributor to illness and death globally. Recent advanced studies have uncovered the crucial role of nutrients in safeguarding women's health and preventing disorders. Genistein is an abundant isoflavonoid found in soybeans. Genistein functions as a chemotherapeutic drug against various forms of cancer, primarily by modifying apoptosis, the cell cycle, and angiogenesis and suppressing metastasis. Furthermore, Genistein has demonstrated diverse outcomes in women, contingent upon their physiological characteristics, such as being in the early or postmenopausal stages. The primary categories of gynecologic cancers are cervical, ovarian, uterine, vaginal, and vulvar cancers. Understanding the precise mechanism by which Genistein acts on ovarian cancer could contribute to the advancement of anti-breast cancer treatments, particularly in situations where no specific targeted therapies are currently known or accessible. Additional investigation into the molecular action of Genistein has the potential to facilitate the development of a plant-derived cancer medication that has fewer harmful effects. This research could also help overcome drug resistance and prevent the occurrence of ovarian cancers.
Keywords: Genistein, flavonoids, ovarian cancer, natural compound, pharmaceutical efficacy, nanoformulations.
[1]
Dixon R, Ferreira D. Genistein. Phytochemistry  2002; 60(3): 205-11.
 [http://dx.doi.org/10.1016/S0031-9422(02)00116-4] [PMID: 12031439]

[2]
Shafiee G, Saidijam M, Tayebinia H, Khodadadi I. Beneficial effects of genistein in suppression of proliferation, inhibition of metastasis, and induction of apoptosis in PC3 prostate cancer cells. Arch Physiol Biochem  2022; 128(3): 694-702.
 [http://dx.doi.org/10.1080/13813455.2020.1717541] [PMID: 31985311]

[3]
Polkowski K, Mazurek AP. Biological properties of genistein. A review of in vitro and in vivo data. Acta Poloniae Pliarmaceutica. Drug Res  2000; 57(2): l35-55.

[4]
Islam A, Islam MS, Uddin MN, Hasan MMI, Akanda MR. The potential health benefits of the isoflavone glycoside genistin. Arch Pharm Res  2020; 43(4): 395-408.
 [http://dx.doi.org/10.1007/s12272-020-01233-2] [PMID: 32253713]

[5]
Fatima A, Singh R. The chemistry and pharmacology of Genistein. Nat Prod J  2016; 6(1): 3-12.
 [http://dx.doi.org/10.2174/221031550601160208122925]

[6]
Sharifi-Rad J, Quispe C, Imran M, et al. Genistein: An integrative overview of its mode of action, pharmacological properties, and health benefits. Oxid Med Cell Longev  2021; 2021: 1-36.
 [http://dx.doi.org/10.1155/2021/3268136] [PMID: 34336089]

[7]
Russo M, Russo GL, Daglia M, et al. Understanding genistein in cancer: The “good” and the “bad” effects: A review. Food Chem  2016; 196: 589-600.
 [http://dx.doi.org/10.1016/j.foodchem.2015.09.085] [PMID: 26593532]

[8]
Chen T, Wang J, Li M, Wu Q, Cui S. Genistein inhibits proliferation and metastasis in human cervical cancer cells through the focal adhesion kinase signaling pathway: A network pharmacology-based in vitro study in HeLa cells. Molecules  2023; 28(4): 1919.
 [http://dx.doi.org/10.3390/molecules28041919] [PMID: 36838908]

[9]
Saha S, Sadhukhan P, Sil P. Genistein: A phytoestrogen with multifaceted therapeutic properties. Mini Rev Med Chem  2014; 14(11): 920-40.
 [http://dx.doi.org/10.2174/1389557514666141029233442] [PMID: 25355592]

[10]
Aarushi G, Sahoo PK, Tejpal A. Genistein-a potential boon for cancer therapy. Pharma Innov  2016; 5 (6, Part B): 81.

[11]
Mukund V. Genistein: Its role in breast cancer growth and metastasis. Curr Drug Metab  2020; 21(1): 6-10.
 [http://dx.doi.org/10.2174/1389200221666200120121919] [PMID: 31987018]

[12]
Kamboh AA, Zhu WY. Individual and combined effects of genistein and hesperidin supplementation on meat quality in meat-type broiler chickens. J Sci Food Agric  2013; 93(13): 3362-7.
 [http://dx.doi.org/10.1002/jsfa.6185] [PMID: 23605817]

[13]
Katanić Stanković JS, Mihailović N, Mihailović V. Genistein: Advances on resources, biosynthesis pathway, bioavailability, bioactivity, and pharmacology. Handbook of Dietary Flavonoids.  Cham: Springer International Publishing 2023; pp. 1-40.
 [http://dx.doi.org/10.1007/978-3-030-94753-8_45-1]

[14]
Yu L, Rios E, Castro L, Liu J, Yan Y, Dixon D. Genistein: Dual role in women’s health. Nutrients 2021, 13(9): 3048.  

[15]
Barreca D, Trombetta D, Smeriglio A, et al. Food flavonols: Nutraceuticals with complex health benefits and functionalities. Trends Food Sci Technol  2021; 117: 194-204.
 [http://dx.doi.org/10.1016/j.tifs.2021.03.030]

[16]
Ballard CR, Junior MRM. Health benefits of flavonoids. Bioactive compounds.  Woodhead Publishing 2019; pp. 185-201.
 [http://dx.doi.org/10.1016/B978-0-12-814774-0.00010-4]

[17]
Semwal R, Joshi SK, Semwal RB, Semwal DK. Health benefits and limitations of rutin - A natural flavonoid with high nutraceutical value. Phytochem Lett  2021; 46: 119-28.
 [http://dx.doi.org/10.1016/j.phytol.2021.10.006]

[18]
Khan J, Deb PK, Priya S, et al. Dietary flavonoids: Cardioprotective potential with antioxidant effects and their pharmacokinetic, toxicological and therapeutic concerns. Molecules  2021; 26(13): 4021.
 [http://dx.doi.org/10.3390/molecules26134021] [PMID: 34209338]

[19]
Manayi A. Soybeans and phytoestrogen rich foods (Genistein, Daidzein) against cancer. Nutraceuticals and Cancer Signaling: Clinical Aspects and Mode of Action.  Springer, Cham 2021; pp. 419-49.

[20]
Sandoval MJ, Cutini PH, Rauschemberger MB, Massheimer VL. The soyabean isoflavone genistein modulates endothelial cell behaviour. Br J Nutr  2010; 104(2): 171-9.
 [http://dx.doi.org/10.1017/S0007114510000413] [PMID: 20187999]

[21]
Messina M. Soy and health update: Evaluation of the clinical and epidemiologic literature. Nutrients  2016; 8(12): 754.
 [http://dx.doi.org/10.3390/nu8120754] [PMID: 27886135]

[22]
Pillow PC, Duphorne CM, Chang S, et al. Development of a database for assessing dietary phytoestrogen intake. Nutr Cancer  1999; 33(1): 3-19.
 [http://dx.doi.org/10.1080/01635589909514742]

[23]
Kwon Y. Effect of soy isoflavones on the growth of human breast tumors: Findings from preclinical studies. Food Sci Nutr  2014; 2(6): 613-22.
 [http://dx.doi.org/10.1002/fsn3.142] [PMID: 25493176]

[24]
Kim IS. Current perspectives on the beneficial effects of soybean isoflavones and their metabolites for humans. Antioxidants  2021; 10(7): 1064.
 [http://dx.doi.org/10.3390/antiox10071064] [PMID: 34209224]

[25]
Saha T, Makar S, Swetha R, Gutti G, Singh SK. Estrogen signaling: An emanating therapeutic target for breast cancer treatment. Eur J Med Chem  2019; 177: 116-43.
 [http://dx.doi.org/10.1016/j.ejmech.2019.05.023] [PMID: 31129450]

[26]
Mobeen I, Romero MA, Yulaevna IM, Attar R, Jabeen S, Fayyaz S. Regulation of cell signaling pathways by Genistein in different cancers: Progress, prospects and pitfalls. Cell Mol Biol  2022; 67(6): 318-29.
 [http://dx.doi.org/10.14715/cmb/2021.67.6.42] [PMID: 35818180]

[27]
Chen J, Duan Y, Zhang X, Ye Y, Ge B, Chen J. Genistein induces apoptosis by the inactivation of the IGF-1R/p-Akt signaling pathway in MCF-7 human breast cancer cells. Food Funct  2015; 6(3): 995-1000.
 [http://dx.doi.org/10.1039/C4FO01141D] [PMID: 25675448]

[28]
Yousefi H, Karimi P, Alihemmati A, Alipour MR, Habibi P, Ahmadiasl N. Therapeutic potential of genistein in ovariectomy-induced pancreatic injury in diabetic rats: The regulation of MAPK pathway and apoptosis. Iran J Basic Med Sci  2017; 20(9): 1009-15.
 [PMID: 29085595]

[29]
Shin SB, Woo SU, Chin YW, Jang YJ, Yim H. Sensitivity of TP53-mutated cancer cells to the phytoestrogen genistein is associated with direct inhibition of Plk1 activity. J Cell Physiol  2017; 232(10): 2818-28.
 [http://dx.doi.org/10.1002/jcp.25680] [PMID: 27861885]

[30]
Shin SB, Woo SU, Yim H. Cotargeting Plk1 and androgen receptor enhances the therapeutic sensitivity of paclitaxel-resistant prostate cancer. Ther Adv Med Oncol  2019; 11: 1758835919846375.
 [http://dx.doi.org/10.1177/1758835919846375] [PMID: 31156720]

[31]
Amerizadeh A, Asgary S, Vaseghi G, Farajzadegan Z. Effect of genistein intake on some cardiovascular risk factors: An updated systematic review and meta-analysis. Curr Probl Cardiol  2022; 47(9): 100902.
 [http://dx.doi.org/10.1016/j.cpcardiol.2021.100902] [PMID: 34266697]

[32]
Yi XY, Wang ZH, Wang Y. Genistein for glycolipid metabolism in postmenopausal women: A meta-analysis. Climacteric  2021; 24(3): 267-74.
 [http://dx.doi.org/10.1080/13697137.2020.1859473] [PMID: 33410719]

[33]
Abshirini M, Omidian M, Kord-Varkaneh H. Effect of soy protein containing isoflavones on endothelial and vascular function in postmenopausal women: A systematic review and meta-analysis of randomized controlled trials. Menopause  2020; 27(12): 1425-33.
 [http://dx.doi.org/10.1097/GME.0000000000001622] [PMID: 32881829]

[34]
Nazari-Khanamiri F, Ghasemnejad-Berenji M. Cellular and molecular mechanisms of genistein in prevention and treatment of diseases: An overview. J Food Biochem  2021; 45(11): e13972.
 [http://dx.doi.org/10.1111/jfbc.13972] [PMID: 34664285]

[35]
de Oliveira HP, Dias Soares JM, Pereira Leal AEB, Silva JC, Almeida JRGS. Influence of flavonoids on mechanism of modulation of insulin secretion. Pharmacogn Mag  2017; 13(52): 639-46.
 [http://dx.doi.org/10.4103/pm.pm_87_17] [PMID: 29200726]

[36]
Goswami K, Badruddeen , Arif M, Akhtar J, Khan MI, Ahmad M. Flavonoids, isoflavonoids and others bioactives for insulin sensitizations. Curr Diabetes Rev  2024; 20(2): e270423216247.
 [http://dx.doi.org/10.2174/1573399819666230427095200] [PMID: 37102490]

[37]
Kaufman PB, Duke JA, Brielmann H, Boik J, Hoyt JE. A comparative survey of leguminous plants as sources of the isoflavones, genistein and daidzein: Implications for human nutrition and health. J Altern Complement Med  1997; 3(1): 7-12.
 [http://dx.doi.org/10.1089/acm.1997.3.7] [PMID: 9395689]

[38]
Kim BG. Biological synthesis of genistein in Escherichia coli. J Microbiol Biotechnol  2020; 30(5): 770-6.
 [http://dx.doi.org/10.4014/jmb.1911.11009] [PMID: 32482944]

[39]
Xiong P, Wang R, Zhang X, et al. Design, synthesis, and evaluation of genistein analogues as anticancer agents. Anticancer Agents Med Chem  2015; 15(9): 1197-203.

[40]
Guan Y, Zhang Y, Zou J, et al. Synthesis and biological evaluation of genistein-IR783 conjugate: Cancer cell targeted delivery in MCF-7 for superior anticancer therapy. Molecules  2019; 24(22): 4120.
 [http://dx.doi.org/10.3390/molecules24224120] [PMID: 31739548]

[41]
Wang R, Zhao S, Wang Z, Koffas MAG. Recent advances in modular co-culture engineering for synthesis of natural products. Curr Opin Biotechnol  2020; 62: 65-71.
 [http://dx.doi.org/10.1016/j.copbio.2019.09.004] [PMID: 31605875]

[42]
Liu Y, Hu M. Absorption and metabolism of flavonoids in the Caco-2 cell culture model and a perused rat intestinal model. Drug Metab Dispos  2002; 30(4): 370-7.
 [http://dx.doi.org/10.1124/dmd.30.4.370] [PMID: 11901089]

[43]
Walsh KR, Haak SJ, Bohn T, Tian Q, Schwartz SJ, Failla ML. Isoflavonoid glucosides are deconjugated and absorbed in the small intestine of human subjects with ileostomies. Am J Clin Nutr  2007; 85(4): 1050-6.
 [http://dx.doi.org/10.1093/ajcn/85.4.1050] [PMID: 17413104]

[44]
Bokkenheuser VD, Shackleton CH, Winter J. Hydrolysis of dietary flavonoid glycosides by strains of intestinal Bacteroides from humans. Biochem J  1987; 248(3): 953-6.
 [http://dx.doi.org/10.1042/bj2480953] [PMID: 3435494]

[45]
Mattison DR, Karyakina N, Goodman M, LaKind JS. Pharmaco- and toxicokinetics of selected exogenous and endogenous estrogens: A review of the data and identification of knowledge gaps. Crit Rev Toxicol  2014; 44(8): 696-724.
 [http://dx.doi.org/10.3109/10408444.2014.930813] [PMID: 25099693]

[46]
Rozman KK, Bhatia J, Calafat AM, et al. NTP-CERHR expert panel report on the reproductive and developmental toxicity of genistein. Birth Defects Res B Dev Reprod Toxicol  2006; 77(6): 485-638.
 [http://dx.doi.org/10.1002/bdrb.20087] [PMID: 17186522]

[47]
Yang Z, Zhu W, Gao S, et al. Simultaneous determination of genistein and its four phase II metabolites in blood by a sensitive and robust UPLC–MS/MS method: Application to an oral bioavailability study of genistein in mice. J Pharm Biomed Anal  2010; 53(1): 81-9.
 [http://dx.doi.org/10.1016/j.jpba.2010.03.011] [PMID: 20378296]

[48]
Setchell KDR, Brown NM, Desai P, et al. Bioavailability of pure isoflavones in healthy humans and analysis of commercial soy isoflavone supplements. J Nutr  2001; 131(4) (Suppl.): 1362S-75S.
 [http://dx.doi.org/10.1093/jn/131.4.1362S] [PMID: 11285356]

[49]
Riches Z, Stanley EL, Bloomer JC, Coughtrie MWH. Quantitative evaluation of the expression and activity of five major sulfotransferases (SULTs) in human tissues: the SULT “pie”. Drug Metab Dispos  2009; 37(11): 2255-61.
 [http://dx.doi.org/10.1124/dmd.109.028399] [PMID: 19679676]

[50]
Boronat A, Rodriguez-Morató J, Serreli G, et al. Contribution of biotransformations carried out by the microbiota, drug-metabolizing enzymes, and transport proteins to the biological activities of phytochemicals found in the diet. Adv Nutr  2021; 12(6): 2172-89.
 [http://dx.doi.org/10.1093/advances/nmab085] [PMID: 34388248]

[51]
Stewart C, Ralyea C, Lockwood S. Ovarian cancer: An integrated review. Semin Oncol Nurs  2019; 35(2): 151-6.
 [http://dx.doi.org/10.1016/j.soncn.2019.02.001] [PMID: 30867104]

[52]
Nash Z, Menon U. Ovarian cancer screening: Current status and future directions. Best Pract Res Clin Obstet Gynaecol  2020; 65: 32-45.
 [http://dx.doi.org/10.1016/j.bpobgyn.2020.02.010] [PMID: 32273169]

[53]
Zamwar UM, Anjankar AP. Aetiology, epidemiology, histopathology, classification, detailed evaluation, and treatment of ovarian cancer. Cureus  2022; 14(10): e30561.
 [http://dx.doi.org/10.7759/cureus.30561] [PMID: 36415372]

[54]
Hollis RL, Croy I, Churchman M, et al. Ovarian carcinosarcoma is a distinct form of ovarian cancer with poorer survival compared to tubo-ovarian high-grade serous carcinoma. Br J Cancer  2022; 127(6): 1034-42.
 [http://dx.doi.org/10.1038/s41416-022-01874-8] [PMID: 35715633]

[55]
Mazidimoradi A, Momenimovahed Z, Allahqoli L, et al. The global, regional and national epidemiology, incidence, mortality, and burden of ovarian cancer. Health Sci Rep  2022; 5(6): e936.
 [http://dx.doi.org/10.1002/hsr2.936] [PMID: 36439044]

[56]
Malik P, Singh R, Kumar M, Malik A, Mukherjee TK. Understanding the phytoestrogen genistein actions on breast cancer: Insights on estrogen receptor equivalence, pleiotropic essence and emerging paradigms in bioavailability modulation. Curr Top Med Chem  2023; 23(15): 1395-413.
 [http://dx.doi.org/10.2174/1568026623666230103163023] [PMID: 36597609]

[57]
Jiang H, Fan J, Cheng L, Hu P, Liu R. The anticancer activity of genistein is increased in estrogen receptor beta 1-positive breast cancer cells. OncoTargets Ther  2018; 11: 8153-63.
 [http://dx.doi.org/10.2147/OTT.S182239] [PMID: 30532556]

[58]
Lee AH, Su D, Pasalich M, Tang L, Binns CW, Qiu L. Soy and isoflavone intake associated with reduced risk of ovarian cancer in southern Chinese women. Nutr Res  2014; 34(4): 302-7.
 [http://dx.doi.org/10.1016/j.nutres.2014.02.005] [PMID: 24774066]

[59]
Wang Y, Li W, Wang Z, et al. Genistein upregulates cyclin D1 and CDK4 expression and promotes the proliferation of ovarian cancer OVCAR-5 cells. Clin Chim Acta  2021; 512: 100-5.
 [http://dx.doi.org/10.1016/j.cca.2019.08.023] [PMID: 31465770]

[60]
Sohel M, Biswas P, Al Amin M, et al. Genistein, a potential phytochemical against breast cancer treatment-insight into the molecular mechanisms. Processes  2022; 10(2): 415.
 [http://dx.doi.org/10.3390/pr10020415]

[61]
Mukund V, Mukund D, Sharma V, Mannarapu M, Alam A. Genistein: Its role in metabolic diseases and cancer. Crit Rev Oncol Hematol  2017; 119: 13-22.
 [http://dx.doi.org/10.1016/j.critrevonc.2017.09.004] [PMID: 29065980]

[62]
Carbonel AAF, de Oliveira Bruno L, de Paula C, Teixeira RSS, Girão JHC, de Jesus M. Effects of genistein and daidzein in female reproductive tract. Genistein and daidzein: Food sources, biological activity and health benefits.  New York: Nova Science 2015; pp. 11788-3619.

[63]
Malla A, Ramalingam S. Health perspectives of an isoflavonoid genistein and its quantification in economically important plants. Role of Materials Science in Food Bioengineering.  Academic Press 2018; pp. 353-79.
 [http://dx.doi.org/10.1016/B978-0-12-811448-3.00011-5]

[64]
Gali-Muhtasib H, Hmadi R, Kareh M, Tohme R, Darwiche N. Cell death mechanisms of plant-derived anticancer drugs: Beyond apoptosis. Apoptosis  2015; 20(12): 1531-62.
 [http://dx.doi.org/10.1007/s10495-015-1169-2] [PMID: 26362468]

[65]
Moga M, Dimienescu O, Arvatescu C, Mironescu A, Dracea L, Ples L. The role of natural polyphenols in the prevention and treatment of cervical cancer-An overview. Molecules  2016; 21(8): 1055.
 [http://dx.doi.org/10.3390/molecules21081055] [PMID: 27548122]

[66]
Wang TTY, Sathyamoorthy N, Phang JM. Molecular effects of genistein on estrogen receptor mediated pathways. Carcinogenesis  1996; 17(2): 271-5.
 [http://dx.doi.org/10.1093/carcin/17.2.271] [PMID: 8625449]

[67]
Dhananjaya K, Sibi G, Mallesha H, Ravikumar KR, Awasthi S. Insilico studies of Daidzein and Genistein with human estrogen receptor α. Asian Pac J Trop Biomed  2012; 2(3): S1747-53.
 [http://dx.doi.org/10.1016/S2221-1691(12)60489-4]

[68]
Santoro N, Worsley R, Miller KK, Parish SJ, Davis SR. Role of estrogens and estrogen-like compounds in female sexual function and dysfunction. J Sex Med  2016; 13(3): 305-16.
 [http://dx.doi.org/10.1016/j.jsxm.2015.11.015] [PMID: 26944462]

[69]
Septadina IS. An overview of the female reproductive system: A narrative literature review. Sriwijaya J Obstet Gynecol  2023; 1(1): 16-23.
 [http://dx.doi.org/10.59345/sjog.v1i1.25]

[70]
Amenyogbe E, Chen G, Wang Z, Lu X, Lin M, Lin AY. A review on sex steroid hormone estrogen receptors in mammals and fish. Int J Endocrinol  2020; 2020: 1-9.
 [http://dx.doi.org/10.1155/2020/5386193] [PMID: 32089683]

[71]
Hwang WJ, Lee TY, Kim NS, Kwon JS. The role of estrogen receptors and their signaling across psychiatric disorders. Int J Mol Sci  2020; 22(1): 373.
 [http://dx.doi.org/10.3390/ijms22010373] [PMID: 33396472]

[72]
Patel S, Homaei A, Raju AB, Meher BR. Estrogen: The necessary evil for human health, and ways to tame it. Biomed Pharmacother  2018; 102: 403-11.
 [http://dx.doi.org/10.1016/j.biopha.2018.03.078] [PMID: 29573619]

[73]
Wu Z, Liu L. The protective activity of genistein against bone and cartilage diseases. Front Pharmacol  2022; 13: 1016981.
 [http://dx.doi.org/10.3389/fphar.2022.1016981] [PMID: 36160403]

[74]
Mas-Bargues C, Borrás C, Viña J. The multimodal action of genistein in Alzheimer’s and other age-related diseases. Free Radic Biol Med  2022; 183: 127-37.
 [http://dx.doi.org/10.1016/j.freeradbiomed.2022.03.021] [PMID: 35346775]

[75]
Myung S-K, Ju W, Choi HJ, Kim SC. Soy intake and risk of endocrine-related gynaecological cancer: A meta-analysis. BJOG  2009; 116(13): 1697-705.
 [http://dx.doi.org/10.1111/j.1471-0528.2009.02322.x] [PMID: 19775307]

[76]
Bi C, Chng WJ. MicroRNA: important player in the pathobiology of multiple myeloma. BioMed Res Int  2014; 2014: 1-12.
 [http://dx.doi.org/10.1155/2014/521586] [PMID: 24991558]

[77]
Liz J, Esteller M. lncRNAs and microRNAs with a role in cancer development. Biochimica et Biophysica Acta (BBA)-. Gene Regul Mech  2016; 1859(1): 169-76.

[78]
Loh HY, Norman BP, Lai KS, Rahman NMANA, Alitheen NBM, Osman MA. The regulatory role of microRNAs in breast cancer. Int J Mol Sci  2019; 20(19): 4940.
 [http://dx.doi.org/10.3390/ijms20194940] [PMID: 31590453]

[79]
Petersen PHD, Lopacinska-Jørgensen J, Høgdall CK, Høgdall EV. Identification of stably expressed microRNAs in plasma from high-grade serous ovarian carcinoma and benign tumor patients. Mol Biol Rep  2023; 50(12): 10235-47.
 [http://dx.doi.org/10.1007/s11033-023-08795-6] [PMID: 37934368]

[80]
Xu L, Xiang J, Shen J, et al. Oncogenic MicroRNA-27a is a target for Genistein in ovarian cancer cells. Anticancer Agents Med Chem  2013; 13(7): 1126-32.

[81]
Iida M, Tsuboi K, Niwa T, Ishida T, Hayashi S. Compensatory role of insulin-like growth factor 1 receptor in estrogen receptor signaling pathway and possible therapeutic target for hormone therapy-resistant breast cancer. Breast Cancer  2019; 26(3): 272-81.
 [http://dx.doi.org/10.1007/s12282-018-0922-0] [PMID: 30328006]

[82]
Hwang KA, Park MA, Kang NH, et al. Anticancer effect of genistein on BG-1 ovarian cancer growth induced by 17 β-estradiol or bisphenol A via the suppression of the crosstalk between estrogen receptor alpha and insulin-like growth factor-1 receptor signaling pathways. Toxicol Appl Pharmacol  2013; 272(3): 637-46.
 [http://dx.doi.org/10.1016/j.taap.2013.07.027] [PMID: 23933164]

[83]
Chimento A, De Luca A, Avena P, et al. Estrogen receptors-mediated apoptosis in hormone-dependent cancers. Int J Mol Sci  2022; 23(3): 1242.
 [http://dx.doi.org/10.3390/ijms23031242] [PMID: 35163166]

[84]
Chan KKL, Siu MKY, Jiang Y, Wang J, Leung THY, Ngan HYS. Estrogen receptor modulators genistein, daidzein and ERB-041 inhibit cell migration, invasion, proliferation and sphere formation via modulation of FAK and PI3K/AKT signaling in ovarian cancer. Cancer Cell Int  2018; 18(1): 65.
 [http://dx.doi.org/10.1186/s12935-018-0559-2] [PMID: 29743815]

[85]
Ning YX, Luo X, Xu M, Feng X, Wang J. Let-7d increases ovarian cancer cell sensitivity to a genistein analog by targeting c-Myc. Oncotarget  2017; 8(43): 74836-45.
 [http://dx.doi.org/10.18632/oncotarget.20413] [PMID: 29088827]

[86]
Patra A, Satpathy S, Naik PK, Kazi M, Hussain MD. Folate receptor-targeted PLGA-PEG nanoparticles for enhancing the activity of Genistein in ovarian cancer. Artif Cells Nanomed Biotechnol  2022; 50(1): 228-39.
 [http://dx.doi.org/10.1080/21691401.2022.2118758] [PMID: 36330543]

[87]
Pistollato F, Calderón Iglesias R, Ruiz R, et al. The use of natural compounds for the targeting and chemoprevention of ovarian cancer. Cancer Lett  2017; 411: 191-200.
 [http://dx.doi.org/10.1016/j.canlet.2017.09.050] [PMID: 29017913]

[88]
Gercel-Taylor C, Feitelson AK, Taylor DD. Inhibitory effect of genistein and daidzein on ovarian cancer cell growth. Anticancer Res  2004; 24(2B): 795-800.
 [PMID: 15161029]

[89]
Rucinska A, Kirko S, Gabryelak T. Effect of the phytoestrogen, genistein-8-C-glucoside, on Chinese hamster ovary cells in vitro. Cell Biol Int  2007; 31(11): 1371-8.
 [http://dx.doi.org/10.1016/j.cellbi.2007.05.012] [PMID: 17601753]

[90]
Choi EJ, Kim T, Lee MS. Pro-apoptotic effect and cytotoxicity of genistein and genistin in human ovarian cancer SK-OV-3 cells. Life Sci  2007; 80(15): 1403-8.
 [http://dx.doi.org/10.1016/j.lfs.2006.12.031] [PMID: 17291540]

[91]
Lee JY, Kim HS, Song YS. Genistein as a potential anticancer agent against ovarian cancer. J Tradit Complement Med  2012; 2(2): 96-104.
 [http://dx.doi.org/10.1016/S2225-4110(16)30082-7] [PMID: 24716121]

[92]
Ahmed AA, Goldsmith J, Fokt I, et al. A genistein derivative, ITB-301, induces microtubule depolymerization and mitotic arrest in multidrug-resistant ovarian cancer. Cancer Chemother Pharmacol  2011; 68(4): 1033-44.
 [http://dx.doi.org/10.1007/s00280-011-1575-2] [PMID: 21340606]

[93]
Yang Z, Kulkarni K, Zhu W, Hu M. Bioavailability and pharmacokinetics of Genistein: Mechanistic studies on its ADME Anticancer Agents Med Chem  2012; 12(10): 1264-80.

[94]
Huang SL, Chang TC, Chao CCK, Sun NK. Role of the TLR4-androgen receptor axis and genistein in taxol-resistant ovarian cancer cells. Biochem Pharmacol  2020; 177: 113965.
 [http://dx.doi.org/10.1016/j.bcp.2020.113965] [PMID: 32278794]

[95]
Mittal P, Vrdhan H, Ajmal G, Bonde G, Kapoor R, Mishra B. Formulation and characterization of genistein-loaded nanostructured lipid carriers: Pharmacokinetic, biodistribution and in vitro cytotoxicity studies. Curr Drug Deliv  2019; 16(3): 215-25.
 [http://dx.doi.org/10.2174/1567201816666181120170137] [PMID: 30465502]

[96]
Mamagkaki A, Bouris I, Parsonidis P, Vlachou I, Gougousi M, Papasotiriou I. Genistein as a dietary supplement; Formulation, analysis and pharmacokinetics study. PLoS One  2021; 16(4): e0250599.
 [http://dx.doi.org/10.1371/journal.pone.0250599] [PMID: 33905453]

[97]
Phan V, Walters J, Brownlow B, Elbayoumi T. Enhanced cytotoxicity of optimized liposomal genistein via specific induction of apoptosis in breast, ovarian and prostate carcinomas. J Drug Target  2013; 21(10): 1001-11.
 [http://dx.doi.org/10.3109/1061186X.2013.847099] [PMID: 24151835]

[98]
Bindhya KP, Uma Maheswari P, Meera Sheriffa Begum KM. Milk protein inspired multifunctional magnetic carrier targeting progesterone receptors: Improved anticancer potential of soybean-derived genistein against breast and ovarian cancers. Mater Chem Phys  2021; 272: 125055.
 [http://dx.doi.org/10.1016/j.matchemphys.2021.125055]

[99]
Wei Y, Xin X, Huang Y, Shao J, Duan H. Effect of Genistein on increasing apoptosis of drug-resistant ovarian cancer cell SKOV-3 induced by cisplatin. Xiandai Shengwu Yixue Jinzhan  2010; 10(23): 4446-50.

[100]
Liu H, Lee G, Lee JI, Ahn TG, Kim SA. Effects of genistein on anti-tumor activity of cisplatin in human cervical cancer cell lines. Obstet Gynecol Sci  2019; 62(5): 322-8.
 [http://dx.doi.org/10.5468/ogs.2019.62.5.322] [PMID: 31538075]

[101]
Maheri H, Hashemzadeh F, Shakibapour N, et al. Glucokinase activity enhancement by cellulose nanocrystals isolated from jujube seed: A novel perspective for type II diabetes mellitus treatment (In vitro). J Mol Struct  2022; 1269: 133803.
 [http://dx.doi.org/10.1016/j.molstruc.2022.133803]

[102]
Kalhori F, Yazdyani H, Khademorezaeian F, et al. Enzyme activity inhibition properties of new cellulose nanocrystals from Citrus medica L. pericarp: A perspective of cholesterol lowering. Luminescence  2022; 37(11): 1836-45.
 [http://dx.doi.org/10.1002/bio.4360] [PMID: 35946171]

[103]
Arman S, Hadavi M, Rezvani-Noghani A, et al. Cellulose nanocrystals from celery stalk as quercetin scaffolds: A novel perspective of human holo-transferrin adsorption and digestion behaviours. Luminescence  2024; 39(1): e4634.
 [http://dx.doi.org/10.1002/bio.4634] [PMID: 38286605]

[104]
Jouyaeian P, Kamkar-Vatanparast M, Tehranian-Torghabeh F, Hoseinpoor S, Saberi MR, Chamani J. New perspective into the interaction behavior explore of nano-berberine with alpha-lactalbumin in the presence of beta-lactoglobulin: Multi-spectroscopic and molecular dynamic investigations. J Mol Struct  2024; 1316: 139020.
 [http://dx.doi.org/10.1016/j.molstruc.2024.139020]

[105]
Chen HH, Chen SP, Zheng QL, et al. Genistein promotes proliferation of human cervical cancer cells through estrogen receptor-mediated PI3K/Akt-NF-κB pathway. J Cancer  2018; 9(2): 288-95.
 [http://dx.doi.org/10.7150/jca.20499] [PMID: 29344275]

[106]
Puri A, Mohite P, Ansari Y, et al. Plant-derived selenium nanoparticles: Investigating unique morphologies, enhancing therapeutic uses, and leading the way in tailored medical treatments. Mat Adv  2024; 5(9): 3602-28.
 [http://dx.doi.org/10.1039/D3MA01126G]

[107]
Puri A, Mohite P, Maitra S, et al. From nature to nanotechnology: The interplay of traditional medicine, green chemistry, and biogenic metallic phytonanoparticles in modern healthcare innovation and sustainability. Biomed Pharmacother  2024; 170: 116083.
 [http://dx.doi.org/10.1016/j.biopha.2023.116083] [PMID: 38163395]

[108]
Puri A, Mohite P, Patil S, et al. Facile green synthesis and characterization of Terminalia arjuna bark phenolic–selenium nanogel: A biocompatible and green nano-biomaterial for multifaceted biological applications. Front Chem  2023; 11: 1273360.
 [http://dx.doi.org/10.3389/fchem.2023.1273360] [PMID: 37810585]
Cite As
Current Pharmaceutical Design

An Updated Review Summarizing the Pharmaceutical Efficacy of Genistein and its Nanoformulations in Ovarian Carcinoma

Abstract
