Abstract
The purpose of this work is to investigate the protein kinase inhibitory activity of constituents from Acacia auriculiformis stem bark. Column chromatography and NMR spectroscopy were used to purify and characterize betulin from an ethyl acetate soluble fraction of acacia bark. Betulin, a known inducer of apoptosis, was screened against a panel of 16 disease-related protein kinases. Betulin was shown to inhibit Abelson murine leukemia viral oncogene homolog 1 (ABL1) kinase, casein kinase 1ε (CK1ε), glycogen synthase kinase 3α/β (GSK-3 α/β), Janus kinase 3 (JAK3), NIMA Related Kinase 6 (NEK6), and vascular endothelial growth factor receptor 2 kinase (VEGFR2) with activities in the micromolar range for each. The effect of betulin on the cell viability of doxorubicin-resistant K562R chronic myelogenous leukemia cells was then verified to investigate its putative use as an anti-cancer compound. Betulin was shown to modulate the mitogen-activated protein (MAP) kinase pathway, with activity similar to that of imatinib mesylate, a known ABL1 kinase inhibitor. The interaction of betulin and ABL1 was studied by molecular docking, revealing an interaction of the inhibitor with the ABL1 ATP binding pocket. Together, these data demonstrate that betulin is a multi-target inhibitor of protein kinases, an activity that can contribute to the anticancer properties of the natural compound and to potential treatments for leukemia.
Highlights
Terrestrial plants are a crucial source of medicines, especially in developing countries
We demonstrate the effect of betulin on the viability of doxorubicin-resistant and -sensitive human leukemia cell lines
Preliminary kinase-based screening was carried out using Acacia auriculiformis stem bark extracts, and it was discovered that the ethyl acetate soluble fraction was the most active among the three fractions investigated, namely chloroform, ethyl acetate, and Nbutanol [23]
Summary
Terrestrial plants are a crucial source of medicines, especially in developing countries. Metabolites from plants are known to be a rich source of putative protein kinase inhibitors (e.g., flavonoid compounds that function as competitive inhibitors of ATP binding [13]). The genus Acacia belongs to the family Fabaceae and includes about 1400 species of trees and shrubs widespread throughout warm and semiarid regions of the world including subtropical and tropical Africa (e.g., Nigeria, Senegal, Egypt, and Mozambique) [14]. Within this vast genus, Acacia auriculiformis, commonly referred to as Black Wattle, is an important medicinal plant. We demonstrate the effect of betulin on the viability of doxorubicin-resistant and -sensitive human leukemia cell lines
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