In-Vitro and In-Silico Approach Distinguish ER-α and HER-2 Antagonistic Properties of Indian Herbal Formulation on Breast Cancer
Abstract
Objectives: The anticancer effect of an Indian herbal preparation was studied under a cancer cell line, as well as the in silico computational methods that explain the probability of protein ligands binding to ER- α and HER-2 receptors.
Method: The in vitro anticancer activity of Body Revival® suspension (BR) was determined using cytotoxicity tests, cell invasion and migration assays, and metastatic protein expression assays using MCF-7 breast cancer cells. The computational predictive biological method was applied to find out the pharmacodynamic and pharmacokinetic interactions between the active molecules present in the BR and ER- α/and HER-2 of breast cancer.
Results: BR showed significant and dose dependent cytotoxic effects on MCF-7 cells. The 50% effective cytotoxic dose of BR was 34.27µl/ml. It restricted invasion (26%) and migration (28%) of cancer cells than BSA control. MMP-9 and IL-6 concentration were reduced significantly (p<0.001) after treatment. Cucurbitacin B had maximum in silico binding energy score (-7.8) with ER-α, while symconoside B had with HER-2 (-8.4); but, among the other interactions between the two ligands and receptors, withaferin A had the highest affinity (-15.3). Additionally, withaferin A, symconoside A, and symconoside B curcurbitacin A demonstrated bioavailability and fulfilled safety standards.
Conclusion: Body Revival® showed as a powerful multi-target inhibitor of ER- α and HER-2 that has prospective anticancer action without side effects, and may be useful in the therapy management following a successful trial in breast cancer patients.
Keywords: Breast cancer, Cytotoxicity, MCF-7, ER- α, HER-2, Herbs, In Silico
Keywords:
Breast cancer, Cytotoxicity, MCF-7, ER-alpha, HER-2, Herbs, In SilicoDOI
https://doi.org/10.22270/jddt.v13i11.6274References
American Cancer Society, 2021. https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2021/cancer-facts-and-figures-2021.pdf
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021; 71:209-249. https://doi.org/10.3322/caac.21660 PMid:33538338
Cardoso F, Spence D, Mertz S, Corneliussen-James D, Sabelko K, Gralow J et al. Global analysis of advanced/metastatic breast cancer: Decade report (2005-2015). The Breast 2018; 39:131-138. https://doi.org/10.1016/j.breast.2018.03.002 PMid:29679849
Kumar SK, Chaturvedi M, Das P, Stephen S, Mathur P. Cancer incidence estimates for 2022 and projection for 2025: Result from National Cancer Registry Programme, India. Indian J Med Res 2022; 156(4&5):598-607. https://doi.org/10.4103/ijmr.ijmr_1821_22 PMid:36510887 PMCid:PMC10231735
Riaz M, van Jaarsveld MT, Hollestelle A, Prager-van der Smissen WJ, Heine AA, Boersma AW, et al. miRNA expression profiling of 51 human breast cancer cell lines reveals subtype and driver mutation-specific miRNAs. Breast Cancer Res BCR. 2013; 15: R33. https://doi.org/10.1186/bcr3415 PMid:23601657 PMCid:PMC3672661
Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011; 144:646-74. https://doi.org/10.1016/j.cell.2011.02.013 PMid:21376230
IARC. WHO classification of tumours of the breast. Eds. Lakhani S, Ellis I, Schnitt S, Tan PH, van de Vijver MJ. 4th ed. Lyon, IARC Press, 2012.
Sengal AT, Mukhtar NS, Elhaj AM, Bedri S, Kantelhardt EJ, Mohamedani AA, et al. Immunohistochemistry defined subtypes of breast cancer in 678 Sudanese and Eritrean women; Hospitals based case series. BMC Cancer 2017;17:804. https://doi.org/10.1186/s12885-017-3805-4 PMid:29191181 PMCid:PMC5710067
Chand P, Garg A, Singla V, Rani N. Evaluation of immune histochemical profile of breast cancer for prognostics and therapeutic use. Niger J Surg 2018; 24:100-106. https://doi.org/10.4103/njs.NJS_2_18 PMid:30283220 PMCid:PMC6158994
Shawarby MA, Al-Tamimi DM, Ahmed A. Molecular classification of breast cancer: An overview with emphasis on ethnic variations and future perspectives. Saudi J Med Med Sci 2013; 1:14-9. https://doi.org/10.4103/1658-631X.112908
NIH, National Cancer Institute. Side Effects of Cancer Treatment. 2023. https://www.cancer.gov/about-cancer/treatment/side-effects
American Cancer Society, Chemotherapy Side Effects. 2023. https://www.cancer.org/content/dam/CRC/PDF/Public/8419.00.pdf
CDC: Cancer Survivors, Side Effects of Cancer Treatment. 2023. https://www.cdc.gov/cancer/survivors/patients/side-effects-of-treatment.htm
Yin SY, Wei WC, Jian FY, Yang NS. Therapeutic applications of herbal medicines for cancer patients. eCAM 2012; 302426. https://doi.org/10.1155/2013/302426 PMid:23956768 PMCid:PMC3727181
Subramaniam S, Selvaduray KR, Radhakrishnan AK. Bioactive compounds: natural defence against cancer. Biomol 2019; 9:758-768. https://doi.org/10.3390/biom9120758 PMid:31766399 PMCid:PMC6995630
Sinha K, Som Chaudhury S, Ruidas B, Majumder R, Pal T, Sur TK et al. Role of modern biological techniques in evidence-based validation of Ayurvedic herbometallic preparations. In: Evidence Based Validation of Traditional Medicines: A Comprehensive Approach. Eds. Mondal SC, Chakraborty R, Sen S. Springer Nature, Singapore, 2021. pp. 313. https://doi.org/10.1007/978-981-15-8127-4_16
Khan M, Pandit S, Saha A, Joshi V, Biswas TK, Sur TK. Perspective of using Indian polyherbal medicine in the treatment of cancer. Curr Res Compl Alter Med 2022; 6:165 https://doi.org/10.29011/2577-2201.100065
Khan M, Somani R, Sur TK. Assessment of immunopotentiation action of standardized Indian herbal formulation (Body Revival). Eur J Med Health Sci 2020; 2:1-6. https://doi.org/10.24018/ejmed.2020.2.2.229
Sur TK, Auddy B, Bhattacharyya D. Effects of Body Revival (herbal formulation) on human platelet aggregation and myocardial ischemia in rats. Zhong Xi Yi Jie He Xue Bao 2011; 9:746-51. https://doi.org/10.3736/jcim20110708 PMid:21749825
Joshi V, Khan M, Somani R, Pandit S, Sur TK. Indian medicine can improve quality of life in breast cancer patients: case studies. Nat Ayurvedic Med 2023; 7: 000395. DOI: https://doi.org/10.23880/jonam-16000395
Ruidas B, Sur TK, Das Mukhopadhyay C, Sinha K, Som Chaudhury S, Sharma P, et al. Quercetin: Silent retarder of fatty acid oxidation in breast cancer metastasis through steering of mitochondrial CPT1. Breast Cancer. 2022; 29:748-760. https://doi.org/10.1007/s12282-022-01356-y PMid:35511410
Ruidas B, Sur TK, Pal K, Som Chaudhury S, Prasad P, Das Mukhopadhyay C. Herbometallic nano-drug inducing metastatic growth inhibition in breast cancer through intracellular energy depletion. Mol Biol Rep 2020; 47:3745-3763. https://doi.org/10.1007/s11033-020-05467-7 PMid:32361897
CASTp web server. http://sts.bioe.uic.edu/castp/index.html?2011
Hazra AK, Ghosh C, Chatterjee S, Biswas TK, Pandit S, Sur TK. In silico studies of essential oil components from Indian herbal formulation against RdRp enzyme in Covid-19 virus. J Analytical Pharmaceutic Res 2022; 11:95-100.
Cai C, Wu Q, Hong H, He L, Liu Z, Gu Y, et al., In silico identification of natural products from Traditional Chinese Medicine for cancer immunotherapy. Scientific Reports 2021; 11:3332. https://doi.org/10.1038/s41598-021-82857-2 PMid:33558586 PMCid:PMC7870934
Yadav B, Bajaj A, Saxena M, Saxena AK. In vitro anticancer activity of the root, stem and leaves of Withania somnifera against various human cancer cell lines. Indian J Pharm Sci 2010; 72:659-663. https://doi.org/10.4103/0250-474X.78543 PMid:21695006 PMCid:PMC3116319
Chan KT, Li K, Liu SL, Chu KH, Toh M, Xie WD. Cucurbitacin B inhibits STAT3 and the Raf/MEK/ERK pathway in leukemia cell line K562. Cancer Lett 2010; 289:46-52. https://doi.org/10.1016/j.canlet.2009.07.015 PMid:19700240
Acharya N, Shah U, Hingorani L, Acharya S. Antioxidant and anticancer potential of Symplocos racemosa bark against Hep3b cell line. Int J Pharm Sci Res 2015; 6:4529-4533.
Albini A. Tumor and endothelial cell invasion of basement membranes: The matrigel chemoinvasion assay as a tool for dissecting molecular mechanisms. Pathol Oncol Res 1998; 4:230-241. https://doi.org/10.1007/BF02905254 PMid:9761943
Radu CG, Yang LV, Riedinger M, Au M, Witte ON. T cell chemotaxis to lysophosphatidylcholine through the G2A receptor. Proc. Natl Acad Sci 2004;101:245-250. https://doi.org/10.1073/pnas.2536801100 PMid:14681556 PMCid:PMC314170
Akhouri V, Kumari M, Kumar A. Therapeutic effect of Aegle marmelos fruit extract against DMBA induced breast cancer in rats. Scientific Rep 2020; 10:18016. https://doi.org/10.1038/s41598-020-72935-2 PMid:33093498 PMCid:PMC7581526
Farina AR, Mackay AR. Gelatinase b/MMP-9 in tumour pathogenesis and progression. Cancers 2014; 6:240-296. https://doi.org/10.3390/cancers6010240 PMid:24473089 PMCid:PMC3980597
Leifler KS, Svensson S, Abrahamsson A, Bendrik C, Robertson J, Gauldie J, et al. Inflammation induced by MMP-9 enhances tumor regression of experimental breast cancer. J Immunol 2013; 190: 4420-4430. doi: 10.4049/jimmunol.1202610. Epub 2013 Mar 15. https://doi.org/10.4049/jimmunol.1202610 PMid:23509357 PMCid:PMC3619527
Yousef EM, Tahir MR, St-Pierre Y, Gaboury LA. MMP-9 expression varies according to molecular subtypes of breast cancer. BMC Cancer 2014; 14: 609. https://doi.org/10.1186/1471-2407-14-609 PMid:25151367 PMCid:PMC4150970
Huang H. Matrix metalloproteinase-9 (MMP-9) as a cancer biomarker and MMP-9 biosensors: Recent advances. Sensors 2018: 18, 3249. https://doi.org/10.3390/s18103249 PMid:30262739 PMCid:PMC6211011
Lee DH, Lim IH, Sung EG, Kim JY, Song IH, Park YK, Lee TJ. Withaferin A inhibits matrix metalloproteinase-9 activity by suppressing the Akt signaling pathway. Oncol Rep. 2013; 30:933-938. https://doi.org/10.3892/or.2013.2487 PMid:23708780
Ahmed OI, Adel AM, Diab DR, Gobran NS. Prognostic value of serum level of Interleukin-6 and Interleukin-8 in metastatic breast cancer Patients. Egypt J Immunol 2006; 13:61-68. PMID: 18689272.
Wolfe AR, Trenton NJ, Debeb BG, Larson R, Ruffell B, Chu K, et al. Mesenchymal stem cells and macrophages interact through IL-6 to promote inflammatory breast cancer in pre-clinical models. Oncotarget 2016; 7:82482-82492 https://doi.org/10.18632/oncotarget.12694 PMid:27756885 PMCid:PMC5347707
Tawara K, Scott H, Emathinger J, Wolf C, LaJoie D, Hedeen D, et al. High expression of OSM and IL-6 are associated with decreased breast cancer survival: synergistic induction of IL-6 secretion by OSM and IL-1b. Oncotarget 2019; 10:2068-2085. https://doi.org/10.18632/oncotarget.26699 PMid:31007849 PMCid:PMC6459341
Chen J, Wei Y, Yang W, Huang Q, Chen Y, Zeng K, Chen J. IL-6: The link between inflammation, immunity and breast cancer. Front Oncol 2022; 12:903800. https://doi.org/10.3389/fonc.2022.903800 PMid:35924148 PMCid:PMC9341216
Manore SG, Doheny DL, Wong GL, Lo HW. IL-6/JAK/STAT3 signaling in breast cancer metastasis: biology and treatment. Front Oncol 2022; 12:866014. https://doi.org/10.3389/fonc.2022.866014 PMid:35371975 PMCid:PMC8964978
Chung SS, Wu Y, Okobi Q, Adekoya D, Atefi M, Clarke O, et al. Proinflammatory cytokines IL-6 and TNF-α increased telomerase activity through NF-κB/STAT1/STAT3 activation, and Withaferin A inhibited the signaling in colorectal cancer cells. Mediators Inflamm 2017; 2017:5958429. https://doi.org/10.1155/2017/5958429 PMid:28676732 PMCid:PMC5476880
Rajagopal K, Kalusalingam A, Bharathidasa AR, Sivaprakash A, Shanmugam K, Sundaramoorth M. In silico drug design of anti-breast cancer agents. Molecules 2023; 28:4175. https://doi.org/10.3390/molecules28104175 PMid:37241915 PMCid:PMC10223712
Hahm ER, Lee J, Huang Y, Singh SV. Withaferin A suppresses estrogen receptor-α expression in human breast cancer cells. Mol Carcinog 2011; 50:614-24. https://doi.org/10.1002/mc.20760 PMid:21432907 PMCid:PMC3129407
Carpenter TS, Kirshner DA, Lau EY, Wong SE, Nilmeier JP, Lightstone FC. A method to predict blood-brain barrier permeability of drug-like compounds using molecular dynamics simulations. Biophys J 2014: 5;107:630-641. https://doi.org/10.1016/j.bpj.2014.06.024 PMid:25099802 PMCid:PMC4129472
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