THERAPEUTIC PROFILING OF NANO ENCAPSULATED DIOSGENIN VIA ATTENUATING HORMONAL STATUS, CELL PROLIFERATION, INFLAMMATORY RESPONSES, AND APOPTOSIS IN AN ANIMAL MODEL OF MAMMARY ONCOGENESIS

MANOBHARATHI VENGAIMARAN; KALAIYARASI DHAMODHARAN; MIRUNALINI SANKARAN

doi:10.22159/ijap.2021v13i6.42777

Authors

MANOBHARATHI VENGAIMARAN Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar 608002, Tamil Nadu, India
KALAIYARASI DHAMODHARAN Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar 608002, Tamil Nadu, India
MIRUNALINI SANKARAN Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar 608002, Tamil Nadu, India

DOI:

https://doi.org/10.22159/ijap.2021v13i6.42777

Keywords:

Diosgenin, Mammary carcinogenesis, Hormonal status, Cell proliferation, Apoptosis, Molecular docking

Abstract

Objective: The central motive of this study is to explore the therapeutic impact of Diosgenin encapsulated Chitosan nanoparticles (DG@CS-NP) on mammary carcinogenesis in female Sprague Dawley rats via modulating hormonal status, cell proliferation, inflammatory responses, and Apoptosis.

Methods: 7,12-dimethylbenz(a)anthracene (DMBA) was administered subcutaneously near the mammary gland (25 mg/kg b. wt) to provoke mammary tumor in female Sprague Dawley rats. Following the progress of a tumor, DMBA-induced tumor-bearing rats were medicated orally with 5 mg/kg b. wt of DG@CS-NP. Consequently, the expression of ER, PR, PCNA, Cyclin D1, NF-κB, TNF-α, Bcl-2, Caspases-3, and p53 in experimental rats were revealed via architectural immunohistochemistry. Further, Diosgenin interactions with these proteins were evidently confirmed by molecular docking analysis.

Results: As a result, we noticed diminished levels of ER, PR, PCNA, Cyclin D1, NF-κB, TNF-α, and Bcl-2 expressions in DG@CS-NP medicated rats as well as with elevated levels of Caspases-3 and p53 expressions. In DMBA rats, the expressions were vice versa. Additionally, molecular docking analyses support these outcomes by highlighting the strong interaction between Diosgenin and breast cancer targets.

Conclusion: These reports prove that DG@CS-NP imposes its therapeutic impact by hormonal adjustments, downregulating proteins involved in inflammation and cellular proliferation, and thereby promotes apoptosis by impeding apoptotic inhibitors.

Downloads

Download data is not yet available.

References

Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209-49. doi: 10.3322/caac.21660, PMID 33538338.

Manobharathi V, Kalaiyarasi D, Mirunalini S. A concise critique on breast cancer: a historical and scientific perspective. Res J Biotech. 2021;16(7):220-30. doi: 10.25303/167rjbt22021.

Perez Soto E, Estanislao Gomez CC, Perez Ishiwara DG, Ramirez Celis C, del Consuelo Gomez Garcia M. Cytotoxic effect and mechanisms from some plant-derived compounds in breast cancer. In: Cytotoxicity 2019;6:1-24.

Korsh J, Shen A, Aliano K, Davenport T. Polycyclic aromatic hydrocarbons and breast cancer: a review of the literature. Breast Care (Basel). 2015;10(5):316-8. doi: 10.1159/ 000436956, PMID 26688678.

Vinothini G, Murugan RS, Nagini S. Evaluation of molecular markers in a rat model of mammary carcinogenesis. Oncol Res. 2009;17(10):483-93. doi: 10.3727/096504009789735459, PMID 19725228.

Karimi B, Ashrafi M, Shomali T, Yektaseresht A. Therapeutic effect of simvastatin on DMBA‐induced breast cancer in mice. Fundam Clin Pharmacol. 2019;33(1):84-93. doi: 10.1111/fcp.12397, PMID 29962034.

Port Louis LR, Varshney KC, Nair MG. An immunohistochemical study on the expression of sex steroid receptors in canine mammary tumors. Int Sch Res Not. 2012;1:1-7.

Alvarado A, Lopes AC, Faustino-Rocha AI, Cabrita AMS, Ferreira R, Oliveira PA, Colaço B. Prognostic factors in MNU and DMBA-induced mammary tumors in female rats. Pathol Res Pract. 2017;213(5):441-6. doi: 10.1016/j.prp.2017.02.014, PMID 28285967.

Vinothkumar V, Manoharan S, Sindhu G, Nirmal MR, Vetrichelvi V. Geraniol modulates cell proliferation, apoptosis, inflammation, and angiogenesis during 7, 12-dimethylbenz [a] anthracene-induced hamster buccal pouch carcinogenesis. Mol Cell Biochem. 2012;369(1-2):17-25. doi: 10.1007/s11010-012-1364-1, PMID 22729742.

Lengare PV, Sinai Khandeparkar SG, Joshi AR, Gogate BP, Solanke SG, Gore SH. Immunohistochemical expression of cyclin D1 in invasive breast carcinoma and its correlation with clinicopathological parameters. Indian J Pathol Microbiol. 2020;63(3):376-81. doi: 10.4103/IJPM.IJPM_106_20, PMID 32769325.

Wang W, Nag SA, Zhang R. Targeting the NFκB signaling pathways for breast cancer prevention and therapy. Curr Med Chem. 2015;22(2):264-89. doi: 10.2174/0929867321666141106124315, PMID 25386819.

Zhou XL, Fan W, Yang G, Yu MX. The clinical significance of PR, ER, NF- κ B, and TNF- α in breast cancer. Dis Markers. 2014;2014:494581. doi: 10.1155/2014/494581. PMID 24864130.

Luo JL, Kamata H, Karin M. IKK/NF-kappaB signaling: balancing life and death--a new approach to cancer therapy. J Clin Invest. 2005;115(10):2625-32. doi: 10.1172/JCI26322, PMID 16200195.

Purushothaman A, Nandhakumar E, Shanthi P, Sachidanandam TP. Antiproliferative and apoptotic effects of Shemamruthaa, a herbal preparation 7, 12-dimethylbenz (a) anthracene-induced breast cancer rats. J Evid Based Complementary Altern Med 2015;20:259-68. doi: 10.1177/2156587215580434, PMID 25888591

Mitra S, Dash R. Natural products for the management and prevention of breast cancer. Evid Based Complement Alternat Med 2018;1:1-23. DOI: 10.1155/2018/8324696, PMID 29681985

Xu XH, Li T, Fong CM, Chen X, Chen XJ, Wang YT, Huang MQ, Lu JJ. Saponins from Chinese medicines as anticancer agents. Molecules. 2016;21(10):1-27. doi: 10.3390/molecules21101326, PMID 27782048.

Manobharathi V, Mirunalini S. Pharmacological characteristics of a phyto steroidal food saponin: Diosgenin. Afr J Biol Sci. 2020;2:77. doi: 10.33472/AFJBS.2.2.2020.77-87.

Arulmozhi V, Pandian K, Mirunalini S. Ellagic acid encapsulated chitosan nanoparticles for drug delivery system in human oral cancer cell line (KB). Colloids Surf B Biointerfaces. 2013;110:313-20. doi: 10.1016/j.colsurfb.2013.03.039, PMID 23732810.

Isabella S, Mirunalini S, Pandiyan K. 3,3’-Diindolylmethane Encapsulated Chitosan Nanoparticles Accelerates Inflammatory Markers, ER/PR, Glycoprotein and Mast Cells Population During Chemical Carcinogen Induced Mammary Cancer in Rats. Indian J Clin Biochem. 2018;33(4):397-405. doi: 10.1007/ s12291-017-0701-2, PMID 30319185.

Jagadeesan J, Nandakumar N, Rengarajan T, Balasubramanian MP. Diosgenin, a steroidal saponin, exhibits anticancer activity by attenuating lipid peroxidation via enhancing antioxidant defense system during NMU-induced breast carcinoma. J Environ Pathol Toxicol Oncol. 2012;31(2):121-9. doi: 10.1615/JEnvironPatholToxicolOncol.v31.i2.40.

Kumar BNP, Puvvada N, Rajput S, Sarkar S, Das SK, Emdad L, Sarkar D, Venkatesan P, Pal I, Dey G, Konar S, Brunt KR, Rao RR, Mazumdar A, Kundu SC, Pathak A, Fisher PB, Mandal M. Sequential release of drugs from hollow manganese ferrite nanocarriers for breast cancer therapy. J Mater Chem B. 2015;3(1):90-101. doi: 10.1039/c4tb01098a, PMID 32261929.

Isabella S, Mirunalini S. 3, 3’-diindolylmethane-encapsulated chitosan nanoparticles accelerate molecular events during chemical carcinogen-induced mammary cancer in Sprague Dawley rats. Breast Cancer. 2019;26(4):499-509. doi: 10.1007/s12282-019-00950-x, PMID 30684233.

Morris GM, Goodsell DS, Pique ME, Lindstrom WL, Huey R, Forli S. AutoDock 4.2 user guide. Scripps Research Institute; 2009. p. 1-66.

Younas M, Hano C, Giglioli-Guivarc’h N, Abbasi BH. Mechanistic evaluation of phytochemicals in breast cancer remedy: current understanding and future perspectives. RSC Adv. 2018;8(52):29714-44. doi: 10.1039/C8RA04879G.

Sethi G, Shanmugam MK, Warrier S, Merarchi M, Arfuso F, Kumar AP, Bishayee A. Pro-apoptotic and anti-cancer properties of diosgenin: a comprehensive and critical review. Nutrients. 2018;10(5):1-12. doi: 10.3390/nu10050645, PMID 29783752.

Kalaiyarasi D, Manobharathi V, Mirunalini S. Development of nano drugs: A promising avenue for cancer treatment. Res J Biotechnol. 2021;16:234-44.

Ferreira LG, Dos Santos RN, Oliva G, Andricopulo AD. Molecular docking and structure-based drug design strategies. Molecules. 2015;20(7):13384-421. doi: 10.3390/molecules200713384, PMID 26205061.

Shishodia S, Aggarwal BB. Diosgenin inhibits osteoclastogenesis, invasion, and proliferation through the downregulation of Akt, I κ B kinase activation and NF-κ B-regulated gene expression. Oncogene. 2006;25(10):1463-73. doi: 10.1038/sj.onc.1209194, PMID 16331273.

Thangarasu R, Pachaiappan P, Subbaiyan T. Anti-estrogenic and anti-cell proliferative effect of allyl isothiocyanate in chemoprevention of chemically induced mammary carcinogenesis in rats. Pathol Oncol Res. 2020;26(2):913-25. doi: 10.1007/s12253-019-00638-9, PMID 30895454.

Tang P, Tse GM. Immunohistochemical surrogates for molecular classification of breast carcinoma: a 2015 update. Arch Pathol Lab Med. 2016;140(8):806-14. doi: 10.5858/arpa.2015-0133-RA, PMID 27472239.

Beresford MJ, Wilson GD, Makris A. Measuring proliferation in breast cancer: practicalities and applications. Breast Cancer Res. 2006;8(6):216. doi: 10.1186/bcr1618, PMID 17164010.

Martins GR, Gelaleti GB, Moschetta MG, Maschio-Signorini LB, Zuccari DA. Proinflammatory and anti-inflammatory cytokines mediated by NF-κB factor as prognostic markers in mammary tumors. Mediators Inflamm. 2016;2016:9512743. doi: 10.1155/2016/9512743, PMID 26989335.

Kumaraguruparan R, Prathiba D, Nagini S. Of humans and canines: Immunohistochemical analysis of PCNA, Bcl-2, p53, cytokeratin and ER in mammary tumours. Res Vet Sci. 2006;81(2):218-24. doi: 10.1016/j.rvsc.2005.08.002, PMID 16740286.