IN VITRO AND IN SILICO STUDIES ON LIGNAN SECOISOLARICIRESINOL DIGLUCOSIDE

Abstract

Objective: Lignans are important biologically active compounds in diphenolic structure. Secoisolariciresinol diglucoside (SDG) is a significant type of lignan known to have anti-cancer properties. This study aimed to investigate the antiproliferative activity properties of SDG on hepatocellular carcinoma cells (HepG2), colorectal cancer cells (DLD-1), lung carcinoma (A549), and prostate cancer (PC3) cell lines. Material and Method: Cell viability of cancer cells was determined by the MTT method after treatment with various concentrations of SDG at 48 or 72 hours. The DFT (Density Functional Theory) analysis of the SDG was performed using Spartan'10 and visualized. Drug-likeness and absorption, distribution, metabolism, excretion, and toxicity (ADME-Tox) properties of this compound were examined. Molecular docking was carried out to research the biological activity of SDG. Result and Discussion: Our results showed that SDG exhibited significant cytotoxicity only against DLD-1 cells with IC50 value of 37.45 µM, but inactive against other cancer cell lines as in vitro. 4UYA, which biomarker for colon cancer, is the crystal structure of the MLK4 kinase domain. The binding energy value for the SDG-MLK4 kinase domain was calculated as -6.1 kcal/mol. Anticancer potential was verified by in vitro assay and in silico molecular docking study. In conclusion, this study revealed the protective aspect of SDG against colon cancer and showed that it has promising anticancer activity.

Keywords

• Cancer
• cytotoxicity
• DFT
• molecular docking
• SDG

Project Number

TSG-2021-8458

LİGNAN SEKOİZOLARİSİRESİNOL DİGLUKOSİT ÜZERİNE İN VİTRO VE İN SİLİKO ÇALIŞMALAR

Abstract

Amaç: Lignanlar, difenolik yapıda biyolojik olarak aktif önemli bileşiklerdir. Sekoizolarisiresinol diglukosit. (SDG), kanser önleyici özelliklere sahip olduğu bilinen önemli bir lignan türüdür. Bu çalışmada SDG'nin hepatoselüler karsinom hücreleri (HepG2), kolorektal kanser hücreleri (DLD-1), akciğer karsinomu (A549) ve prostat kanseri (PC3) hücre hatları üzerindeki antiproliferatif aktivite özelliklerinin araştırılması amaçlanmıştır. Gereç ve Yöntem: Kanser hücrelerinin hücre canlılığı, 48 veya 72 saatte çeşitli SDG konsantrasyonları ile muamele edildikten sonra MTT yöntemiyle belirlendi. SDG’nin DFT (Yoğunluk Fonksiyonel Teorisi) analizi Spartan'10 kullanılarak yapıldı ve görselleştirildi. Bu bileşiğin ilaca benzerliği ve emilim, dağılım, metabolizma, atılım ve toksisite (ADME-Tox) özellikleri incelendi. SDG'nin biyolojik aktivitesini araştırmak için moleküler yerleştirme gerçekleştirildi. Sonuç ve Tartışma: Sonuçlarımız SDG'nin yalnızca IC50 değeri 37,45 µM olan DLD-1 hücrelerine karşı anlamlı sitotoksisite sergilediğini, diğer kanser hücre hatlarına karşı ise in vitro olarak inaktif olduğunu gösterdi. Kolon kanseri biyobelirteci olan 4UYA, MLK4 kinaz bölgesinin kristal yapısıdır. SDG-MLK4 kinaz alanına ait bağlanma enerjisi değeri -6,1 kcal/mol olarak hesaplandı. Antikanser potansiyeli in vitro analiz ve in silico moleküler yerleştirme çalışmasıyla doğrulandı. Sonuç olarak bu çalışma SDG’nin kolon kanserine karşı koruyucu yönünü ortaya koyarak umut verici antikanser etkinliğe sahip olduğunu göstermiştir.

Keywords

• DFT
• kanser
• moleküler yerleştirme
• SDG
• sitotoksisite

Project Number

TSG-2021-8458

References

1. 1. Touré, A., Xueming, X. (2010). Flaxseed Lignans: source, biosynthesis, metabolism, antioxidant activity, bio-active components, and health benefits. Comprehensive Reviews in Food Science and Food Safety, 9(3), 261-269. [CrossRef]
2. 2. Moree, S.S., Rajesha, J. (2011). Secoisolariciresinol Diglucoside: A potent multifarious bioactive phytoestrogen of flaxseed. Research and Reviews in Biomedicine and Biotechnology, 2(3), 1-24.
3. 3. Kezimana, P., Dmitriev, A.A., Kudryavtsava, A.V., Romanova, E.V., Melnikova, N.V. (2018). Secoisolariciresinol Diglucoside of flaxseed and its metabolites: Biosynthesis and potential for nutraceuticals. Frontiers in Genetics, 9, 641. [CrossRef]
4. 4. Imran, M., Ahmad, N., Anjum, F.M., Khan, M.K., Muhstaq, Z., Nadeem, M., Hussain, S. (2015). Potential protective properties of flax lignan secoisolariciresinol diglucoside. Nutrition Journal, 14, 71.
5. 5. Adolphe, J.L., Whiting, S.J., Juurlink, B.H.J., Thorpe, L.U., Alcorn, J. (2010). Health effects with consumption of the flax lignan secoisolariciresinol diglucoside. British Journal of Nutrition, 103(7), 929-938. [CrossRef]
6. 6. Fabian, C.J., Kimler, B.F., Zalles, C.M., Klemp, J.R., Petroff, B.K., Khan, Q.J., Sharma, P., Setchell, K.D.R., Zhao, X., Phillips, T.A., Metheny, T., Hughes, J.R., Yeh, H.W., Johnson, K.A. (2010). Reduction in Ki-67 in Benign Breast Tissue of High-Risk Women with the Lignan Secoisolariciresinol Diglycoside. Cancer Prevention Research, 3(10), 1342-1350. [CrossRef]
7. 7. Bowers, L.W., Lineberger, C.G., Ford, N.A., Rossi, E.L., Punjala, A., Camp, K.K., Kimler, B.K., Fabian, C.J., Hursting, S.D. (2019). The flaxseed lignan secoisolariciresinol diglucoside decreases local inflammation, suppresses NFκB signaling, and inhibits mammary tumor growth. Breast Cancer Research and Treatment, 173(3), 545-557. [CrossRef]
8. 8. Mali, A.V., Wagh, U.V., Hegde, M.V., Chandorkar, S.S., Surve, S.V., Patole, M.V. (2012). In vitro anti-metastatic activity of enterolactone, a mammalian lignan derived from flax lignan, and down-regulation of matrix metalloproteinases in MCF-7 and MDA MB 231 cell lines. Indian Journal of Cancer, 49(1), 181-187. [CrossRef]

9. 9. Bigdeli, B., Goliaei, B., Masoudi-Khoram, N., Jooyan, N., Nikoofar, A., Rouhani, M., Haghparast, A., Mamashli, F. (2016). Enterolactone: A novel radiosensitizer for human breast cancer cell lines through impaired DNA repair and increased apoptosis. Toxicology and Applied Pharmacology, 313, 180-194. [CrossRef]
10. 10. Alphonse, P.A.S., Aluko, R.E. (2015). Anti-carcinogenic and anti-metastatic effects of flax seed lignan secolariciresinol diglucoside (SDG). Discovery Phytomedicine, 2, 12-17.
11. 11. Dobrowolska, K., Regulska-Ilow, B. (2021). The legitimacy of using dietary supplement diglycoside secoisolariciresinol (sdg) from flaxseed in cancer. National Institute of Public Health, 72(1), 9-20. [CrossRef]
12. 12. Ayella, A., Lim, S., Jiang, Y., Iwamoto, T., Lin, D., Tomich, J., Wang, W. (2010). Cytostatic inhibition of cancer cell growth by lignan secoisolariciresinol diglucoside. Nutrition Research, 30, 762-769. [CrossRef]
13. 13. Rom, S., Zuluaga-Ramirez, V., Reichenbach, N.L., Erickson, M.A., Winfield, M., Gajghate, S., Christofidou-Solomidou, M., Jordan-Sciutto, K.L., Persidsky, Y. (2018). Secoisolariciresinol diglucoside is a bloodbrain barrier protective and antiinflammatory agent: implications for neuroinflammation. Journal of Neuroinflammation, 15(1), 25. [CrossRef]
14. 14. Saggar, J.K., Chen, J., Corey, P., Thompson, L.U. (2010). The effect of Secoisolariciresinol Diglucoside and Flaxseed oil, alone and in combination, on MCF-7 tumor growth and signaling pathways. Nutrition and Cancer, 62(4), 533-542. [CrossRef]
15. 15. Di, Y., De Silva, F., Krol, E.S., Alcorn, J. (2018). Flaxseed lignans enhance the cytotoxicity of chemotherapeutic agents against breast cancer cell lines MDA-MB-231 and SKBR3. Nutrition and Cancer, 70(2), 306-315. [CrossRef]
16. 16. Tannous, S., Haykal, T., Dhaini, J., Hodroj, M.H., Rizk, S. (2020). The anti-cancer effect of flaxseed lignan derivatives on different acute myeloid leukemia cancer cells. Biomedicine Pharmacotherapie, 132, 110884. [CrossRef]
17. 17. Akkoç, S., Gök, Y., İlhan, İ.Ö., Kayser, V. (2016). N-Methylphthalimide substituted benzimidazolium salts and PEPPSI Pd-NHC complexes: synthesis, characterization and catalytic activity in carbon-carbon bond forming reactions. Beilstein Journal of Organic Chemistry, 12, 81-88. [CrossRef]
18. 18. Akkoç, S. (2019). Derivatives of 1-(2-(Piperidin-1-yl)ethyl)-1H-benzo[d]imidazole: Synthesis, characterization, determining of electronic properties and cytotoxicity studies. ChemistrySelect, 4(17), 4938-4943. [CrossRef]
19. 19. Onlu, S., Sacan, M.T. (2018). Toxicity of contaminants of emerging concern to Dugesia japonica: QSTR modeling and toxicity relationship with Daphnia magna. Journal of Hazardous Materials, 351, 20-28. [CrossRef]
20. 20. Bouzzine S.M., Bouzakraoui S., Bouachrine M., Hamidi M. (2005). Density functional theory (B3LYP/6-31G*) study of oligothiophenes in their aromatic and polaronic states. Journal of Molecular Structure: THEOCHEM, 726(1-3), 271-276. [CrossRef]
21. 21. Daina, A., Michielin, O., Zoete, V. (2017). SwissADME. A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Scientific Reports, 7, 1-13.
22. 22. Banerjee, P., Eckert, A.O., Schrey, A.K., Preissner, R. (2018). ProTox-II: A webserver for the prediction of toxicity of chemicals. Nucleic Acids Research, 46 (1), 257-263.
23. 23. Daina, A., Michielin, O., Zoete, V. (2019). Swiss Target Prediction: Updated data and new features for efficient prediction of protein targets of small molecules. Nucleic Acids Research, 47(1), 357-364.
24. 24. Yavuz, S.Ç. (2023). Molecular docking studies and structural&electronic analysis of gefarnate. Journal of the Indian Chemical Society, 100(4), 100971. [CrossRef]
25. 25. Özgöçmen, M., Bayram, D., Türel, G.Y., Toğay, V.A., Calapoğlu, N.Ş. (2021). Secoisolariciresinol diglucoside induces caspase-3- mediated apoptosis in monolayer and spheroid cultures of human colon carcinoma cells. Journal of Food Biochemistry, 45(5), e13719. [CrossRef]
26. 26. Chen, T., Wang, Z., Zhong, J., Zhang, L., Zhang, H., Zhang, D., Xu, X., Zhong, X., Wang, J., Li, H. (2022). Secoisolariciresinol diglucoside induces pyroptosis by activating caspase-1 to cleave GSDMD in colorectal cancer cells. Drug Development Research, 83(5), 1152-1166. [CrossRef]
27. 27. Zhuo, L.G., Liao, W., Yu, Z.X. (2012). A frontier molecular orbital theory approach to understanding the Mayr equation and to quantifying nucleophilicity and electrophilicity by using HOMO and LUMO energies. Asian Journal of Organic Chemistry, 1(4), 336-345. [CrossRef]
28. 28. Altürk, S., Tamer, Ö., Avcı, D., Atalay, Y. (2015). Synthesis, spectroscopic characterization, second and third-order nonlinear optical properties, and DFT calculations of a novel Mn (II) complex. Journal of Organometallic Chemistry, 797, 110-119. [CrossRef]
29. 29. Sahin S., Dege N. (2021). A newly synthesized small molecule: the evaluation against Alzheimer's Disease by in silico drug design and computational structure analysis methods. Journal of Molecular Structure, 1236, 130337-130349. [CrossRef]
30. 30. Anand G., Sivasubramanian M., Manimehan I., Ruby A., Abinayashri R., Asmitha R.K. (2023). Synthesis, spectroscopic elucidation (FT-IR, FT-Raman, UV–vis), quantum chemical computation (PES, FMO, HOMO–LUMO, MEP, NLO, Hirshfeld) and molecular docking studies on 2-thiophenecarboxamide crystal. Journal of Molecular Structure, 1286, 135586-135598. [CrossRef]
31. 31. Yıldız, C.B., Azizoglu, A. (2013). Computational investigations on the electronic and structural properties of germacyclopropylidenoids. Computational and Theoretical Chemistry, 1023, 24-28. [CrossRef]
32. 32. Swarnamughi P., Kumar M., Manikandan P., Chithra S., Jeelani A., Khaled J.M., Abbas G. Muthu, S. (2023). Solvent impact on electronic, photochemical, molecular structure, topology studies, and the antihistamine activity of 2-(2-Benzylphenoxy)-N,N-dimethylethanamine. Journal of Molecular Liquids, 390, 123077-123089. [CrossRef]
33. 33. Benhander, G.M., Abdusalam, A.A.A. (2022). Identification of potential inhibitors of SARS-CoV-2 main protease from Allium roseum L. molecular docking study. Chemistry Africa, 5(1), 57-67. [CrossRef]
34. 34. Shen, J., Cheng, F., Xu, Y., Li, W., Tang, Y. (2010). Estimation of ADME properties with substructure pattern recognition. Journal of chemical information and modeling, 50(6), 1034-1041. [CrossRef]
35. 35. Lipinski C.A., Lombardo F., Dominy B.W., Feeney P.J. (1997). Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Advanced Drug Delivery Reviews, 23(1), 3-25. [CrossRef]