Anti-Tumor Study Of Scopoletin And Rubbing-Mercapto-Nitrile From Nicotiana Glauca
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Date
2016-03
Authors
Mahfooth, Yasser Tabana
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Publisher
Universiti Sains Malaysia
Abstract
Nicotiana glauca (Solanaceae) has been traditionally used as a folk remedy to treat infections and cancer. It has been reported as a rich source of beneficial phytochemicals. In the present study, two anti-tumor compounds derived from n-hexane extract of N. glauca namely scopoletin and, a novel compound, Rubbing-Mercapto-Nitrile (RMN) have been isolated. Antiangiogenesis-guided isolation of scopoletin was conducted using an extract from the stem of N. glauca. The anti-angiogenic activity of scopoletin was investigated using ex vivo and in vivo angiogenesis models. The antitumorigenic efficacy of scopoletin was studied in human colorectal tumor xenografts using athymic nude mice. Scopoletin caused significant suppression of microvessel sprouting in rat aortic explants with IC50 of 34 μg/ml. Scopoletin (100 and 200 mg/kg) strongly inhibited (59.72% and 89.4%, respectively) vascularization in matrigel plugs implanted in nude mice. In a tumor xenograft model, scopoletin showed potent inhibition of tumor growth (34.2% and 94.7% at 100 and 200 mg/kg, respectively). Tumor histology reveals a drastic decline of vascularization. In silico studies suggest that scopoletin strongly inhibit protein kinase (ERK1), vascular endothelial growth factor A (VEGF-A), and fibroblast growth factor 2 (FGF-2). A novel anti-cancer compound Rubbing-Mercapto-Nitrile (RMN) was also isolated from N. glauca and characterized. RMN has potent but selective cytotoxic activity towards HCT-116 colorectal cancer cells. The compound stimulates strong apoptosis in the neoplastic tissue with a high selective index (SI = 4.3). It causes nuclear condensation, chromatin degradation, and damage to the mitochondrial membrane. RMN also causes down-regulation of the TGF and HIF signaling pathways, and up-regulation of the WNT, NOTCH, NF-κB, ERK, P53, and JNK signaling pathways in vitro. Overall, in this study, two anticancer compounds were isolated and identified from N. glauca and the antitumor activity of Scopoletin was verified ex vivo and in vivo and the RMN activity was confirmed in vitro with their molecular targets identified.
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Keywords
Nicotiana glauca