Immunomodulatory and Antiangiogenic Mechanisms of Polymolecular Botanical Drug Extract C5OSEW5050ESA OS Derived from Orthosiphon stamineus
Fouad Saleih R. Al-Suede1*, Mohamed B. Khadeer Ahamed1, Aman S. Abdul Majid2 Sultan Ayesh Mohammed Saghir3, Chern E. Oon4, Amin Malik Shah Abdul Majid1,5*
Journal of Angiotherapy 5(1) 194-206 https://doi.org/10.25163/angiotherapy.51211411913130321
Submitted: 19 January 2021 Revised: 13 March 2021 Published: 13 March 2021
Abstract
NuvastaticTM is a polymolecular botanical drug formulation containing a proprietary extract of a selected cultivar of Orthosiphon stamineus (OS) code name, C5OSEW5050ESA OS. The anti-angiogenic activity of C5OSEW5050ESA OS was explored by evaluating its activity towards a variety of angiogenesis modulators in vitro and in vivo. Multiplex immunoassays reveals that C5OSEW5050ESA OS inhibits Vascular Endothelial Growth factor (VEGF), Epidermal Growth Factor (EGF), Fibroblast Growth Factor (FGF), Interleukin 2 ( IL-2) & Interleukin 7 (IL-7), Nerve Growth Factor β (NGF-β) , Transforming Growth Factor -α (TGF-α) and Tumor Necrosis Factor- β (TNF-β). C5OSEW5050ESA OS also caused significant upregulation of interferon α (IFN-α), interferon β (IFN-β), interferon γ (IFN-γ) and Granulocyte-macrophage colony-stimulating factor (GM-CSF). C5OSEW5050ESA OS was found to inhibit endothelial cell proliferation and migration (92.6%) and disrupts the tube assembly (98.26%) for new blood vessel formation. The compound also inhibits neovascularisation in isolated rat aortic ring tissues (IC50 18.2 ± 2 µg/mL) and in chick chorioallantoic membrane assays (CAM) by 82.7%. In vivo matrigel plug assay treated with C5OSEW5050ESA OS shows inhibition of neovascularisation by 91.4± 3%. In conclusion, the study reveals that C5OSEW5050ESA OS has strong anti-angiogenic and immunomodulatory properties which may have significant clinical benefits in cancer therapy.
Key words: Nuvastatic, C5OSEW5050ESA OS, Orthosiphon stamineus; antiangiogenic, immunomudolutary; Matrigel plug, Chick Chorioallantoic Membrane VEGF, EGF, FGF, GM-CSF, IL-1, IL-7, IFNs and TNF-β.
References
Achen, M. G., & Stacker, S. A. (1998). The vascular endothelial growth factor family; proteins which guide the development of the vasculature. International Journal of Experimental Pathology, 79, 255-65.
https://doi.org/10.1046/j.1365-2613.1998.700404.x
Ahamed, M. B., Aisha, A. F., Nassar, Z. D., Siddiqui, J. M., Ismail, Z., Omari, S. M., et al. (2012). Cat's whiskers tea (Orthosiphon stamineus) extract inhibits growth of colon tumor in nude mice and angiogenesis in endothelial cells via suppressing VEGFR phosphorylation. Nutrition and Cancer, 64(1), 89-99.
https://doi.org/10.1080/01635581.2012.630160
Aisha, A. F. A., Majid, A. M. S. A., & Ismail, Z. (2014). Preparation and characterization of nano liposomes of Orthosiphon stamineus ethanolic extract in soybean phospholipids. BMC Biotechnology, 14, 23-23.
https://doi.org/10.1186/1472-6750-14-23
Akowuah, G. A., Zhari, I., Norhayati, I., Sadikun, A., & Khamsah, S. M. (2004). Sinensetin, eupatorin, 3′-hydroxy-5, 6, 7, 4′-tetramethoxyflavone and rosmarinic acid contents and antioxidative effect of Orthosiphon stamineus from Malaysia. Food Chemistry, 87(4), 559-566.
https://doi.org/10.1016/j.foodchem.2004.01.008
Akowuah, G., Ismail, Z., Norhayati, I., & Sadikun, A. (2005). The effects of different extraction solvents of varying polarities on polyphenols of Orthosiphon stamineus and evaluation of the free radical-scavenging activity. Food chemistry, 93, 311-317.
https://doi.org/10.1016/j.foodchem.2004.09.028
Al-Rawi, M. A., Watkins, G., Mansel, R. E., & Jiang, W. G. (2005). The effects of interleukin-7 on the lymphangiogenic properties of human endothelial cells. International Journal of Oncology, 27, 721-30.
Al-Salahi, O. S. A., Kit Lam, C., Majid, A. M. S. A., Al-Suede, F. S. R., Mohammed Saghir, S. A., Abdullah, W. Z., Ahamed, M. B. K., & Yusoff, N. M.( 2013). Anti-angiogenic quassinoid-rich fraction from Eurycoma longifolia modulates endothelial cell function. Microvascular Research, 90, 30-39.
https://doi.org/10.1016/j.mvr.2013.07.007
Alshawsh, M. A., Abdulla, M. A., Ismail, S., & Amin, Z. A.( 2011). Hepatoprotective Effects of Orthosiphon stamineus Extract on Thioacetamide-Induced Liver Cirrhosis in Rats. Evidence-Based Complementary and Alternative Medicine, 2011, 6.
https://doi.org/10.1155/2011/103039
Al-Suede, F. S. R., Elham, F., Mohamed B. Khadeer Ahamed, Z. Ismail, Majid, A. S. A., & A. M. S. Abdul Majid. (2014a). Marked antitumor activity of cat's whiskers tea (Orthosiphon stamineus) extract in orthotopic model of human colon tumor in nude mice. Journal of Biochemical Technology, 3(5), S 170-176.
Al-Suede, F. S R., Majid, A. S. A., Ismail, Z., Kadir, M., & Majid, A. M. S. A. (2013). Abstract B87: Antiangiogenic and antimetastatic activities of cat's whiskers tea (Orthosiphon stamineus) extract against colon cancer cell line. Cancer Research, 73(3 Supplement), B87-B87.
https://doi.org/10.1158/1538-7445.TIM2013-B87
Al-Suede, F. S. R., Khadeer Ahamed, M. B., Abdul Majid, A. S., Baharetha, H. M., Hassan, L. E., Kadir, M. O. A., ... & Abdul Majid, A. (2014). Optimization of cat's whiskers tea (orthosiphon stamineus) using supercritical carbon dioxide and selective chemotherapeutic potential against prostate cancer cells. Evidence-Based Complementary and Alternative Medicine, 2014b.
https://doi.org/10.1155/2014/396016
Badroon, N., Abdul Majid, N., Al-Suede, F. S. R., Nazari V, M., Giribabu, N., Abdul Majid, A. M. S., & Alshawsh, M. A. (2020). Cardamonin Exerts Antitumor Effect on Human Hepatocellular Carcinoma Xenografts in Athymic Nude Mice through Inhibiting NF-κβ Pathway. Biomedicines, 8(12), 586.
https://doi.org/10.3390/biomedicines8120586
Bae, J., Park, D., Lee, Y. S., & Jeoung, D. (2008). Interleukin-2 promotes angiogenesis by activation of Akt and increase of ROS. Journal of microbiology and biotechnology, 18, 377-382.
Birner, P., Obermair, A., Schindl, M., Kowalski, H., Breitenecker, G., & Oberhuber, G. (2001). Selective immunohistochemical staining of blood and lymphatic vessels reveals independent prognostic influence of blood and lymphatic vessel invasion in early-stage cervical cancer. Clin Cancer Res, 7(1), 93-97.
Eubank, T. D., Roberts, R. D., Khan, M., Curry, J. M., Nuovo, G. J., Kuppusamy, P., & Marsh, C. B. (2009). Gm-csf inhibits breast cancer growth and metastasis.
Ferrara, N. (2001). Role of vascular endothelial growth factor in regulation of physiological angiogenesis. American journal of physiology Cell physiology, 280, C1358-66.
https://doi.org/10.1152/ajpcell.2001.280.6.C1358
Ferrari, G., Cook, B. D., Terushkin, V., Pintucci, G., & Mignatti, P. (2009). Transforming Growth Factor-Beta 1 (TGF-Β1) Induces Angiogenesis Through Vascular Endothelial Growth Factor (VEGF)-Mediated Apoptosis. Journal of cellular physiology, 219, 449-458.
https://doi.org/10.1002/jcp.21706
Folkman, J., & Shing, Y. (1992). Angiogenesis. Journal of Biological Chemistry, 267, 10931-10934.
https://doi.org/10.1016/S0021-9258(19)49853-0
Gringhuis, S. I., de Leij, L. F., Verschuren, E. W., Borger, P., & Vellenga, E. (1997). Interleukin-7 upregulates the interleukin-2-gene expression in activated human T lymphocytes at the transcriptional level by enhancing the DNA binding activities of both nuclear factor of activated T cells and activator protein-1. Blood, 90, 2690-700.
https://doi.org/10.1182/blood.V90.7.2690
Hagemann, T., Robinson, S. C., Schulz, M., Trumper, L., Balkwill, F. R. & Binder, C. (2004). Enhanced invasiveness of breast cancer cell lines upon co-cultivation with macrophages is due to TNF-alpha dependent up-regulation of matrix metalloproteases. Carcinogenesis, 25, 1543.
https://doi.org/10.1093/carcin/bgh146
Haller, O., Kochs, G., & Weber, F. (2007). Interferon, Mx, and viral countermeasures. Cytokine & growth factor reviews, 18(5-6), 425-433.
https://doi.org/10.1016/j.cytogfr.2007.06.001
Horvat, R., Hovorka, A., Dekan, G., Poczewski, H., & Kerjaschki, D. (1986). Endothelial cell membranes contain podocalyxin--the major sialoprotein of visceral glomerular epithelial cells. J Cell Biol, 102(2), 484-491.
https://doi.org/10.1083/jcb.102.2.484
Hussain, K., Ismail, Z., Sadikun, A., Shah, A. M. A. M., Latif, A., & Hashmi, F. K. (2012). Antiangiogenic Activity and Bioassay-guided Isolation of Aqueous Extract of Orthosiphon stamineus. Journal of the Chinese Chemical Society, 59(9), 1137-1143.
https://doi.org/10.1002/jccs.201100753
Karamysheva, A. F. (2008). Mechanisms of angiogenesis. Biochemistry (Moscow), 73, 751-62
https://doi.org/10.1134/S0006297908070031
Kottakis, F., Polytarchou, C., Foltopoulou, P., Sanidas, I., Kampranis, S. C., & Tsichlis, P. N. (2011). FGF-2 regulates cell proliferation, migration, and angiogenesis through an NDY1/KDM2B-miR-101-EZH2 pathway. Molecular Cell, 43, 285-98
https://doi.org/10.1016/j.molcel.2011.06.020
Kragh, M., Hjarnaa, P., Bramm, E., Kristjansen, P., Rygaard, J., & & Binderup, L. (2003). In vivo chamber angiogenesis assay: An optimized Matrigel plug assay for fast assessment of anti-angiogenic activity. International Journal of Oncology, 22(2), 305-311.
https://doi.org/10.3892/ijo.22.2.305
Ledermann, J. A. (1999). Antiangiogenic Agents in Cancer Therapy. Journal of the Royal Society of Medicine, 92, 603-603.
https://doi.org/10.1177/014107689909201122
Losso, J. N. (2003). Targeting excessive angiogenesis with functional foods and nutraceuticals. Trends in Food Science & Technology, 14, 455-468.
https://doi.org/10.1016/S0924-2244(03)00156-0
Mohamed, E. A. H., Yam, M. F., Ang, L. F., Mohamed, A. J., & Asmawi, M. Z. (2013). Antidiabetic Properties and Mechanism of Action of Orthosiphon stamineus Benth Bioactive Sub-fraction in Streptozotocin-induced Diabetic Rats. Journal of Acupuncture and Meridian Studies, 6, 31-40.
https://doi.org/10.1016/j.jams.2013.01.005
Nicosia, R. F., Bonanno, E., & Villaschi, S. (1992). Large-vessel endothelium switches to a microvascular phenotype during angiogenesis in collagen gel culture of rat aorta. Atherosclerosis, 95, 191-199.
https://doi.org/10.1016/0021-9150(92)90022-9
Nicosia, R. F., Lin, Y. J., Hazelton, D., & Qian, X. (1997). Endogenous regulation of angiogenesis in the rat aorta model. Role of vascular endothelial growth factor. American Journal of Pathology, 151, 1379-86.
O'Reilly, M. S., Boehm, T., Shing, Y., Fukai, N., Vasios, G., Lane, W. S., Flynn, E., Birkhead, J. R., Olsen, B. R., & Folkman, J. (1997). Endostatin: An Endogenous Inhibitor of Angiogenesis and Tumor Growth. Cell, 88, 277-
https://doi.org/10.1016/S0092-8674(00)81848-6
Özcetin, A., Aigner, A., & Bakowsky, U. (2013). A chorioallantoic membrane model for the determination of anti-angiogenic effects of imatinib. European Journal of Pharmaceutics and Biopharmaceutics, 85(3 PART A), 711-715.
https://doi.org/10.1016/j.ejpb.2013.07.010
Parkin, J., & Cohen, B. (2001). An overview of the immune system. The Lancet, 357(9270), 1777-1789.
https://doi.org/10.1016/S0140-6736(00)04904-7
Ribatti, D. (2008). Chick embryo chorioallantoic membrane as a useful tool to study angiogenesis. International Review of Cell And Molecular Biology, 270, 181-224.
https://doi.org/10.1016/S1937-6448(08)01405-6
Sagar, S. M., Yance, D., & Wong, R. K. (2006). Natural health products that inhibit angiogenesis: a potential source for investigational new agents to treat cancer Part 1. Current Oncology, 13, 14-26.
https://doi.org/10.3747/co.v13i1.77
Saidan, N. H., Aisha, A. F., Hamil, M. S. R., Majid, A. M. S. A., & Ismail, Z. (2015a). A novel reverse phase high-performance liquid chromatography method for standardization of Orthosiphon stamineus leaf extracts. Pharmacognosy research, 7(1), 23.
https://doi.org/10.4103/0974-8490.147195
Tabana, Y. M., Al-Suede, F. S. R., Ahamed, M. B. K., Dahham, S. S., Hassan, L. E. A., Khalilpour, S., & Majid, A. M. S. A. (2016). Cat's whiskers (Orthosiphon stamineus) tea modulates arthritis pathogenesis via the angiogenesis and inflammatory cascade. BMC complementary and alternative medicine, 16(1), 480.
https://doi.org/10.1186/s12906-016-1467-4
Turner, N., & Grose, R. (2010). Fibroblast growth factor signalling: from development to cancer. Nature Reviews Cancer, 10, 116-129.
https://doi.org/10.1038/nrc2780
Umar, M. I., Asmawi, M. Z., Sadikun, A., Majid, A. M., Al-Suede, F. S., Hassan, L. E., et al. (2014). Ethyl-p-methoxycinnamate isolated from Kaempferia galanga inhibits inflammation by suppressing interleukin-1, tumor necrosis factor-alpha, and angiogenesis by blocking endothelial functions. Clinics (Sao Paulo), 69(2), 134-144.
https://doi.org/10.6061/clinics/2014(02)10
West, D. C., Thompson, W. D., Sells, P. G., & Burbridge, M. F. (2001). Angiogenesis assays using chick chorioallantoic membrane. Methods in Molecular Medicine, 46, 107-29.
https://doi.org/10.1385/1-59259-143-4:107
Wu, W. B., Hung, D. K., Chang, F. W., Ong, E. T., & Chen, B. H. (2012). Anti-inflammatory and anti-angiogenic effects of flavonoids isolated from Lycium barbarum Linnaeus on human umbilical vein endothelial cells. Food Function, 3, 1068-81.
https://doi.org/10.1039/c2fo30051f
Yance, D. R., & Sagar, S. M. (2006). Targeting angiogenesis with integrative cancer therapies. Integrative Cancer Therapies, 5(1), 9-29.
https://doi.org/10.1177/1534735405285562
View Dimensions
View Altmetric
Save
Citation
View
Share