Abstract
BackgroundSyzygium campanulatum Korth (Myrtaceae) is an evergreen shrub rich in phenolics, flavonoid antioxidants, and betulinic acid. This study sought to investigate antiangiogenic and anti-colon cancer effects of S.C. standardized methanolic extract.MethodsBetulinic acid was isolated from methanolic extract by crystallization and chromatography techniques. S.C. methanolic extract was analyzed by UV-Vis spectrophotometry, FTIR, LC-MS, and HPLC. Antiangiogenic effect was studied on rat aortic rings, matrigel tube formation, cell proliferation and migration, and expression of vascular endothelial growth factor (VEGF). Antitumor effect was studied using a subcutaneous tumor model of HCT 116 colorectal carcinoma cells established in nude mice.ResultsAnalysis by HPLC, LC-MS and FTIR confirm presence of betulinic acid in S.C. methanolic extract. Quantitative analysis by HPLC indicates presence of betulinic acid in S.C. extract at 5.42 ± 0.09% (w/w). Antiangiogenesis study showed potent inhibition of microvessels outgrowth in rat aortic rings, and studies on normal and cancer cells did not show any significant cytotoxic effect. Antiangiogenic effect was further confirmed by inhibition of tube formation on matrigel matrix that involves human endothelial cells (IC50 = 17.6 ± 2.9 μg/ml). S.C. extract also inhibited migration of endothelial cells and suppressed expression of VEGF. In vivo antiangiogenic study showed inhibition of new blood vessels in chicken embryo chorioallantoic membrane (CAM), and in vivo antitumor study showed significant inhibition of tumor growth due to reduction of intratumor blood vessels and induction of cell death.ConclusionCollectively, our results indicate S. campanulatum as antiangiogenic and antitumor candidate, and a new source of betulinic acid.
Highlights
Syzygium campanulatum Korth (Myrtaceae) is an evergreen shrub rich in phenolics, flavonoid antioxidants, and betulinic acid
Ursolic acid (UA), oleanolic acid (OA), penicillin/streptomycin (PS) solution, XTT reagent with phenazine methosulfate (PMS), suramin, amphotericin B, aprotinin, 6-aminocaproic acid, L-glutamine, thrombin, human insulin, epidermal growth factor, and gentamicin were obtained from Sigma–Aldrich (Kuala Lumpur, Malaysia)
In this study effect on vascular endothelial growth factor (VEGF) expression in endothelial cells was investigated as a possible mechanism of S.C. extract antiangiogenic effect; the results showed significant suppression of VEGF expression in HUVECs lysates at 100 μg/ml (12 ± 1.8 pg/ml) compared to untreated cells (26 ± 2.7 pg/ml), P = 0.001
Summary
Syzygium campanulatum Korth (Myrtaceae) is an evergreen shrub rich in phenolics, flavonoid antioxidants, and betulinic acid. Angiogenesis is a critical process in various physiological conditions such as wound healing, female reproductive system, and embryonic development. There has been a great interest in angiogenesis modulators for therapy of several angiogenesis related disorders In this context, several plant-derived compounds have shown promising antiangiogenic and antitumor effects such as ursolic acid [5], oleanolic acid [6], lupeol [7], betulinic acid [8], green tea catechins [9], resveratrol from grapes [10], quercetin [11], rosmarinic acid [12], genistein [13] and curcumin [14]
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