Investigation Of Molecular Mechanisms Underlying The Anti-Tumor And Anti-Angiogenic Activities Of Orthosiphon Stamineus Towards Colorectal Cancer
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Date
2016-09
Authors
Alsuede, Fouad Saleih Resq
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Abstract
Orthosiphon stamineus Benth. (Lamiaceae) tea is widely consumed traditionally for its vast medicinal value. Recent studies revealed that 50% ethanolic extract of Orthosiphon stamineus (EOS) and its active compound, rosmarinic acid (RA), displayed significant anti-angiogenic, anti-inflammatory and anti-tumor effects in various experimental models. However, the mechanisms underlying these properties have not been fully evaluated. The present work aims to further evaluate the molecular mechanisms underlying its anti-tumour and anti-angiogenic properties. In migration, proliferation and tube formation assay, both EOS and its active RA caused significant inhibition of human endothelial cell (HUVECs) functions crucial for promotion of angiogenesis. Both in vitro and in vivo studies revealed significant suppression of neovascularisation in rat aortic ring, CAM and matrigel plug. Multiplex array studies showed reduction of key growth factors for pro-angiogenic cascade and tumor development i.e. Vascular endothelial growth factor (VEGF), basic fibroblast growth factor (b-FGF), transforming growth factor alpha (TGF-α), tumor necrosis factor (TNF-β) and interleukin-1, 2, 7. Induction of anti-tumor agents i.e. interferon (IFN-α, β) and granulocyte macrophage colony stimulating factor (GM-CSF) both in vitro and in vivo was also noted. In addition, EOS and RA also caused a marked reduction of pro-angiogenic inflammatory mediators, cyclooxygenase (COX) enzyme, TNF-α, IL-1 and nitric oxide (NO) level vital for tumorigenesis. Moreover, EOS and RA significantly inhibited the genes expression
in colorectal tumor tissue including HIF-α, WNT, KDR and COX2. Furthermore, EOS extensively inhibited invasion and tumor aggregation evidenced by fluorescent molecular tomography (FMT) in vivo imaging and histopathological analysis. These findings coincide with its inhibitory effects on tumor promoting angiogenesis factors in nude mice xenograft. In silico molecular interaction simulations on EOS active biomarkers confirms good binding affinity and strong modulatory effect towards the angiogenic and tumorigenesis factors. It is likely the high phenolic and flavonoids content in EOS also exert a significant anti-tumor effect via modulating pro-inflammatory and angiogenesis mediators through their significant free radicals scavenging effect. In conclusion, overall results strongly substantiates EOS and RA anti-angiogenic and anti-tumor properties evidenced by their significant modulatory effect on key associated growth-factors and mediators.
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Further evaluate the molecular mechanisms underlying its , anti-tumour and anti-angiogenic properties.