Abstract
Phytochemicals from Pseuduvaria species have been reported to display a wide range of biological activities. In the present study, a known benzopyran derivative, (6E,10E) isopolycerasoidol (1), and a new benzopyran derivative, (6E,10E) isopolycerasoidol methyl ester (2), were isolated from a methanol extract of Pseuduvaria monticola leaves. The structures of the isolated compounds were elucidated by spectroscopic methods including 1D and 2D NMR, IR, UV, and LCMS-QTOF, and by comparison with previously published data. The anti-proliferative and cytotoxic effects of these compounds on human breast cancer cell-lines (MCF-7 and MDA-MB-231) and a human normal breast epithelial cell line (MCF-10A) were investigated. MTT results revealed both (1) and (2) were efficient in reducing cell viability of breast cancer cells. Flow cytometry analysis demonstrated that (1) and (2) induced cell death via apoptosis, as demonstrated by an increase in phosphotidylserine exposure. Both compounds elevated ROS production, leading to reduced mitochondrial membrane potential and increased plasma membrane permeability in breast cancer cells. These effects occurred concomitantly with a dose-dependent activation of caspase 3/7 and 9, a down-regulation of the anti-apoptotic gene BCL2 and the accumulation of p38 MAPK in the nucleus. Taken together, our data demonstrate that (1) and (2) induce intrinsic mitochondrial-mediated apoptosis in human breast cancer cells, which provides the first pharmacological evidence for their future development as anticancer agents.
Highlights
IntroductionMany active phytochemicals (glycosides, flavonoids, phenols, steroids, alkaloids and terpenoids) have been shown to exhibit a variety of biological properties [1, 2]
Many active phytochemicals have been shown to exhibit a variety of biological properties [1, 2]
The search for new anticancer agents from natural resources is an active area of research synthetic anticancer drugs such as doxorubicin and taxols are associated with serious side effects [3]
Summary
Many active phytochemicals (glycosides, flavonoids, phenols, steroids, alkaloids and terpenoids) have been shown to exhibit a variety of biological properties [1, 2]. The genus Pseuduvaria is a montane forest plant species which belongs to the family Annonaceae. Previous studies have identified isoquinoline alkaloids from Pseuduvaria species with interesting pharmacological properties such as cytotoxicity, antituberculosis and antimalarial activities, whereas ethyl acetate extracts of P. macrophylla exhibited broad spectrum antibacterial properties [7,8,9]. Monticola have not been extensively studies, methanolic extract of bark has been reported to contain oxoaporphine alkaloids and phenolic acids with potential anti-diabetic effects in rats with Type 2 diabetes [10]. Two benzopyran derivatives, namely (6E,10E) isopolycerasoidol (1) and a new derivative, (6E,10E) isopolycerasoidol methyl ester (2) were identified and isolated from methanol extracts of Pseuduvaria monticola leaves. We show that (1) and (2) induced mitochondrialmediated apoptosis in human breast cancer cell lines, which provides the first pharmacological evidence for their future development as anticancer agents
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