Sains Malaysiana 53(3)(2024): 653-665

http://doi.org/10.17576/jsm-2024-5303-13

 

Formation of Inclusion Complex of Curcumin and Tetrahydrocurcumin Prevents Angiogenesis by Inhibiting VEGF Activity: An in-silico Study

(Pembentukan Kompleks Rangkuman Kurkumin dan Tetrahidrokurkumin Menghalang Angiogenesis dengan Merencat Aktiviti VEGF: Suatu Kajian in silico)

 

FIRLI RAHMAH PRIMULA DEWI1,*, ULIE VIANISSA DWIUTAMI TAMBUNAN1, PUTRI AMATUL BARI1, MUHAMMAD ARDIANSYAH FARID1, NADIRA AISHA ANJANI1, SRI PUJI ASTUTI WAHYUNINGSIH1, AMY YI HSAN SAIK2, YONG YOKE KEONG3, VUANGHAO LIM4, WEN NEE TAN5 & MOHAMMED ABDULLAH MAHDI ALSHAWSH6

 

1Department of Biology, Faculty of Science and Technology, Universitas Airlangga, Indonesia

2Department of Pre-Clinical Sciences, M. Kandiah Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Sungai Long City Campus, Bandar Sungai Long, Cheras, 43000 Kajang, Selangor, Malaysia

3Department of Human Anatomy, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia

4School of Advanced Medical and Dental Institute, Universiti Sains Malaysia, Bertam, 13200 Kepala Batas, Pulau Pinang, Malaysia

5Chemical Sciences Programme, School of Distance Education, Universiti Sains Malaysia, 11800 USM Penang, Pulau Pinang, Malaysia

6Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia

 

Received: 17 July 2023/Accepted: 6 February 2024

 

Abstract

Curcumin and tetrahydrocurcumin (THC) are known for their anticancer properties, but limited solubility in water hinders their effectiveness against cancer. In this study, we conducted an in silico exploration of β-cyclodextrin's potential to form inclusion complexes with curcumin or THC. The aim of this study was to assess the potential of curcumin and THC inclusion complexes to inhibit vascular endothelial growth factor (VEGF) signaling pathway, a key element in carcinogenesis. The in silico analysis involved multiple stages, such as bioactive compound preparation, biological activity prediction, 3D structure retrieval of VEGF and VEGFR, protein-ligand docking, and visualization. The results of the study demonstrated that both the curcumin- and THC-inclusion complexes exhibit a lower requirement for binding free energy to interact with VEGFR compared to curcumin or THC molecules alone. When VEGFR binds with curcumin, the curcumin-inclusion complex, or the THC-inclusion complex before interacting with VEGF, there is a notable increase in the binding free energy for the VEGF-VEGFR interaction. Specifically, the presence of THC-inclusion complex demonstrates the highest binding free energy for the VEGF-VEGFR interaction. The molecular dynamic simulation study shows that when VEGFR binds with curcumin, curcumin-inclusion complex, or THC-inclusion complex, the fluctuation of amino acid residues in VEGFR decreases compared to the VEGFR protein structure before binding with these molecules. In conclusion, this study suggests that the formation of inclusion complexes holds considerable promise for enhancing the anticancer potential of curcumin and THC by augmenting their anti-angiogenic activity.

 

Keywords: Angiogenesis; cancer; curcumin; inclusion complex; tetrahydrocurcumin

 

ABSTRAK

Kurkumin dan tetrahidrokurkumin (THC) terkenal dengan sifat antikansernya, tetapi keterlarutan terhad dalam air menghalang keberkesanannya terhadap kanser. Dalam kajian ini, kami menjalankan penyelidikan in silico terhadap potensi β-siklodekstrin untuk membentuk kompleks rangkuman dengan kurkumin atau THC. Matlamat kajian ini adalah untuk menilai potensi kompleks rangkuman kurkumin dan THC untuk menghalang laluan isyarat faktor pertumbuhan endoteliaum vaskular (VEGF), unsur utama dalam karsinogenesis. Analisis in silico melibatkan pelbagai peringkat seperti penyediaan sebatian bioaktif, ramalan aktiviti biologi, struktur 3D temuan semulaVEGF dan VEGFR, dok protein-ligan dan visualisasi. Hasil kajian menunjukkan bahawa kedua-dua kompleks rangkuman kurkumin dan THC menunjukkan keperluan yang lebih rendah untuk mengikat tenaga bebas untuk berinteraksi dengan VEGFR berbanding dengan molekul kurkumin atau THC sahaja. Apabila VEGFR diikat dengan kurkumin sebelum kompleks rangkuman kurkumin atau kompleks rangkuman THC berinteraksi dengan VEGF, terdapat peningkatan ketara dalam tenaga bebas pengikat untuk interaksi VEGF-VEGFR. Khususnya, kehadiran kompleks rangkuman THC menunjukkan tenaga bebas pengikat tertinggi untuk interaksi VEGF-VEGFR. Kajian simulasi dinamik molekul menunjukkan bahawa apabila VEGFR mengikat dengan kurkumin, kompleks rangkuman kurkumin atau kompleks rangkuman THC, turun naik sisa asid amino dalam VEGFR berkurangan berbanding dengan struktur protein VEGFR sebelum diikat dengan molekul ini. Kesimpulannya, kajian ini mencadangkan bahawa pembentukan kompleks rangkuman berpotensi untuk meningkatkan potensi antikanser kurkumin dan THC dengan menambah aktiviti anti-angiogenik mereka.

Kata kunci: Angiogenesis; kanser; kurkumin; kompleks rangkuman; tetrahidrokurkumin

References

Aggarwal, B.B., Deb, L. & Prasad, S. 2015. Curcumin differs from tetrahydrocurcumin for molecular targets, signaling pathways and cellular responses. Molecules 20: 185-205.

Binion, D.G., Otterson, M.F. & Rafiee, P. 2008. Curcumin inhibits VEGF-mediated angiogenesis in human intestinal microvascular endothelial cells through COX-2 and MAPK inhibition. Gut 57: 1509-1517.

Chan, H.K. & Ismail, S. 2014. Side effects of chemotherapy among cancer patients in a Malaysian General Hospital: Experiences, perceptions and informational needs from clinical pharmacists. Asian Pacific Journal of Cancer Prevention 15: 5305-5309.

Chaudhary, V.B. & Patel, J.K. 2013. Cyclodextrin inclusion complex to enhance solubility of poorly water-soluble drugs: A review. International Journal Pharmaceutical Sciences and Research 4: 68-76.

Cheirsilp, B. & Rakmai, J. 2016. Inclusion complex formation of cyclodextrin with its guest and their applications. Biology, Engineering and Medicine 2: 2-6.

Cheng, F., Li, W., Zhou, Y., Shen, J., Wu, Z., Liu, G., Lee, P.W. & Tang, Y. 2012. admetSAR: A comprehensive source and free tool for assessment of chemical ADMET properties. J. Chem. Inf. Model. 52: 3099-3105.

Cid-Samamed, A., Rakmai, J., Mejuto, J.C., Simal-Gandara, J. & Astray, G. 2022.  Cyclodextrins inclusion complex: Preparation methods, analytical techniques and food industry applications. Food Chemistry 384: 132467.

Dewi, F.R.P., Ahmar, R.F., Alifiyah, N.I.I., Shoukat, N. & Wahyuningsih, S.P.A. 2021. The potential of A. muricata bioactive compounds to inhibit HIF1α expression via disruption of tyrosine kinase receptor activity: An in silico study. Acta Informatica Medica 29: 176.

Ferrara, N. 2005. VEGF as a therapeutic target in cancer. Oncology 69: 11-16.

Fu, Z., Chen, X., Guan, S., Yan, Y., Lin, H. & Hua, Z.C. 2015. Curcumin inhibits angiogenesis and improves defective hematopoiesis induced by tumor-derived VEGF in tumor model through modulating VEGF-VEGFR2 signaling pathway. Oncotarget 14: 19469-19482.

Han, X., Deng, S., Wang, N., Liu, Y. & Yang, X. 2016. Inhibitory effects and molecular mechanisms of tetrahydrocurcumin against human breast cancer MCF-7 cells. Food & Nutrition Research 60: 30616.

Hanahan, D. & Weinberg, R.A. 2011. Hallmarks of cancer: The next generation. Cell 144: 646-674.

Hashem, S., Tayyiba, A.A., Sabah, A., Sabah, N., Geetanjali, S., Shahid, A., Sharefa, A.M., Therachiyil, L., Mir, R., Elfaki, I., Mir, M.M., Jamal, F., Masoodi, T., Uddin, S., Singh, M., Haris, M., Macha, M. & Bhat, A.A. 2022. Targeting cancer signaling pathways by natural products: Exploring promising anti-cancer agents. Biomedicine & Pharmacotherapy 150: 113054.

Kamalakkannan, V., Puratchikody, A., Masilamani, K. & Senthilnathan, B. 2010. Solubility enhancement of poorly soluble drugs by solid dispersion technique. Journal of Pharmacy Research 3: 2314-2321.

Kooti, W., Servatyari, K., Behzadifar, M., Asadi-Samani, M., Sadeghi, F., Nouri, B. & Zare, M.H. 2017. Effective medicinal plant in cancer treatment, part 2: Review study. Journal of Evidence-Based Complementary & Alternative Medicine 22: 982-995.

Kuhn, M., von Mering, C., Campillos, M., Jensen, L.J. & Bork, P. 2008. STITCH: Interaction networks of chemicals and proteins. Nucleic Acids Res. 36(Database issue): D684-688.

Laskowski, R.A. & Swindells, M.B. 2011. LigPlot+: Multiple Ligand–Protein interaction diagrams for drug discovery. Journal of Chemical Information and Modeling 51: 2778-2786.

Leclercq, L. 2016. Interactions between cyclodextrins and cellular components: Towards greener medical applications. Beilstein Journal of Organic Chemistry 12: 2644-2662.

Lee, W.H., Loo, C.Y., Bebawy, M., Luk, F., Mason, R.S. & Rohanizadeh, R. 2013. Curcumin and its derivatives: Their application in neuropharmacology and neuroscience in the 21st century. Curr. Neuropharmacol. 11: 338-378.

Liu, W., Zhang, Z., Lin, G., Luo, D., Chen, H., Yang, H., Liang, J., Liu, Y., Xie, J., Su, Z. & Cao, H. 2017. Tetrahydrocurcumin is more effective than curcumin in inducing the apoptosis of H22 cells via regulation of a mitochondrial apoptosis pathway in ascites tumor-bearing mice. Food & Function 8(9): 3120-3129.

Low, Z.X., Teo, M.Y.M., Nordin, F.J., Dewi, F.R.P., Palanirajan, V.K. & In, L.L.A. 2022. Biophysical evaluation of water-soluble curcumin encapsulated in β-cyclodextrins on colorectal cancer cells. International Journal of Molecular Sciences 23: 12866.

Lugano, R., Ramachandran, M. & Dimberg, A. 2020. Tumor angiogenesis: Causes, consequences, challenges and opportunities. Cellular and Molecular Life Sciences 77: 1745-1770.

Macindoe, G., Mavridis, L., Venkatraman, V., Devignes, M.D. & Ritchie, D.W. 2010. HexServer: An FFT-based protein docking server powered by graphics processors. Nucleic Acids Research 38: W445-W449.

Martin-Del Valle, E.M. 2004. Cyclodextrins and their uses: A review. Process Biochemistry 39: 1033-1046.

Minder, P., Zajac, E., Quigley, J.P. & Deryugina, E.I. 2015. EGFR regulates the development and microarchitecture of intratumoral angiogenic vasculature capable of sustaining cancer cell intravasation. Neoplasia 17: 634-649.

Muninggar, L., Widjiati, W., Yuliati, I., Askandar, B. & Hartono, P. 2019. Effects of curcumin on vascular endothelial growth factor expression on Rattus norvegicus cervical cancer xenograft model. Indonesian Journal of Cancer 12(3): 95.

Niu, G. & Chen, X. 2010. Vascular endothelial growth factor as an anti-angiogenic target for cancer therapy. Curr. Drug Targets 11: 1000-1017.

Paramera, E.I., Konteles, S.J. & Karathanos, V.T. 2011. Stability and release properties of curcumin encapsulated in Saccharomyces cerevisiae, β-cyclodextrin and modified starch. Food Chemistry 125: 913-922.

Patel, M., Chilton, M.L., Sartini, A., Gibson, L., Barber, C., Covey-Crump, L., Przybylak, K.R., Cronin, M.T.D. & Madden, J.C. 2018. Assessment and reproducibility of quantitative structure-activity relationship models by the nonexpert. J. Chem. Inf. Model. 58: 673-682.

Poerwosusanta, H., Utomo, D.H., Noor, Z., Oktaviyanti, I.K., Mintaroem, K., Pardjianto, B., Widodo, M.A. & Widjajanto, E. 2019. Eleutherine americana Merr. extract regulates mitochondrial calcium homeostasis in intra-abdominal adhesion: A computational study. Drug Invention Today 11: 526-530.

Quintero-Fabián, S., Arreola, R., Becerril-Villanueva, E., Torres-Romero, J.C., Arana-Argáez, V., Lara-Riegos, J., Ramírez-Camacho, M.A. & Alvarez-Sánchez, M.E. 2019. Role of matrix metalloproteinases in angiogenesis and cancer. Front Oncol. 9: 1370.

Rege, S.A., Varshneya, M.A. & Momin, S.A. 2021. A mini-review: Comparison between curcumin and tetrahydrocurcumin based on their activities. Croatian Journal of Food Science and Technology 13: 128-132.

Rege, S.A., Momin, S.A., Bhowmick, D.N. & Pratap, A.P. 2012. Stabilization of emulsion and butter like products containing essential fatty acids using kalonji seeds extract and curcuminoids. J. Oleo Sci. 61(1): 11-16.

Shanmugam, M.K., Lee, J.H., Chai, E.Z.P., Kanchi, M.M., Kar, S., Arfuso, F., Dharmarajan, A., Prem Kumar, A., Samy Ramar, P., Looi, C.Y., Mustafa, M.R., Tergaonkar, V., Bishayee, A., Ahn, K.S. & Sethi, G. 2016. Cancer prevention and therapy through the modulation of transcription factors by bioactive natural compounds. Seminars in Cancer Biology 40-41: 35-47.

Shibuya, M. 2011. Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) signaling in angiogenesis: A crucial target for anti- and pro-angiogenic therapies. Genes Cancer 2: 1097-1105.

Simons, M. 2012. An inside view: VEGF receptor trafficking and signaling. Physiology 27(4): 213-222.

Sopo, M., Anttila, M., Hämäläinen, K., Kivela, A., Ylä-Herttuala, S., Kosma, V., Keski-Nisula, L. & Sallinen, H. 2019. Expression profiles of VEGF-A, VEGF-D and VEGFR1 are higher in distant metastases than in matched primary high grade epithelial ovarian cancer. BMC Cancer 19: 584.

Tomeh, M.A., Hadianamrei, R. & Zhao, X. 2019. A review of curcumin and its derivatives as anticancer agents. International Journal of Molecular Sciences 20: 1033.

Wadood, A., Ahmed, N., Shah, L., Ahmad, A., Hassan, H. & Shams, S. 2013. In-silico drug design: An approach which revolutionarised the drug discovery process. OA Drug Des. Deliv. 1(1): 3.

Wahyuningsih, S.P.A., Dewi, F.R.P., Hsan, A.S.Y., Lee, M.L., Lim, V., Aun, L.I.L., Ling, T.C. & Marviella, S.T. 2022. The regulation of hypoxia inducible factor (HIF) 1α expression by quercetin: An in silico study. Acta Informatica Medica 30: 96.

Wang, T.Y. & Chen, J.X. 2019. Effects of curcumin on vessel formation insight into the pro- and antiangiogenesis of curcumin. Evid. Based Complement Alternat. Med. 2019: 1390795.

World Health Organization (WHO). 2020. Cancer. https://www.who.int/news-room/fact-sheets/detail/cancer Accessed on 24 January 2023.

Wilken, R., Veena, M.S., Wang, M.B. & Srivatsan, E.S. 2011. Curcumin: A review of anti-cancer properties and therapeutic activity in head and neck squamous cell carcinoma. Mol. Cancer 10: 12.

Yang, H., Lou, C., Sun, L., Li, J., Cai, Y., Wang, Z., Li, W., Liu, G. & Tang, Y. 2019. admetSAR 2.0: web-service for prediction and optimization of chemical ADMET properties. Bioinformatics 35(6): 1067-1069.

 

*Corresponding author; email: firli.rahmah@fst.unair.ac.id

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

previous