Abstract
In this study, a new apoptotic monoterpenoid indole alkaloid, subditine (1), and four known compounds were isolated from the bark of Nauclea subdita. Complete 1H- and 13C- NMR data of the new compound were reported. The structures of isolated compounds were elucidated with various spectroscopic methods such as 1D- and 2D- NMR, IR, UV and LCMS. All five compounds were screened for cytotoxic activities on LNCaP and PC-3 human prostate cancer cell-lines. Among the five compounds, the new alkaloid, subditine (1), demonstrated the most potent cell growth inhibition activity and selective against LNCaP with an IC50 of 12.24±0.19 µM and PC-3 with an IC50 of 13.97±0.32 µM, compared to RWPE human normal epithelial cell line (IC50 = 30.48±0.08 µM). Subditine (1) treatment induced apoptosis in LNCaP and PC-3 as evidenced by increased cell permeability, disruption of cytoskeletal structures and increased nuclear fragmentation. In addition, subditine (1) enhanced intracellular reactive oxygen species (ROS) production, as reflected by increased expression of glutathione reductase (GR) to scavenge damaging free radicals in both prostate cancer cell-lines. Excessive ROS could lead to disruption of mitochondrial membrane potential (MMP), release of cytochrome c and subsequent caspase 9, 3/7 activation. Further Western blot analyses showed subditine (1) induced down-regulation of Bcl-2 and Bcl-xl expression, whereas p53 was up-regulated in LNCaP (p53-wild-type), but not in PC-3 (p53-null). Overall, our data demonstrated that the new compound subditine (1) exerts anti-proliferative effect on LNCaP and PC-3 human prostate cancer cells through induction of apoptosis.
Highlights
The Rubiaceae family (Madder family) is one of the largest of the angiosperms with more than 637 genera and almost 10,700 species [1]
The dichloromethane extract of the bark of Nauclea subdita was subjected to column chromatography over silica gel 60 with gradient elution system of dichloromethane (CH2Cl2) and methanol (MeOH), giving 15 fractions
The nuclear intensity, corresponding to apoptotic chromatin changes were significantly increased following subditine (1) treatment in LNCaP and PC-3 cells (Figure 4, P,0.05). These results suggest that subditine (1) treatment induced apoptosis in LNCaP and PC-3 prostate cancer cells
Summary
The Rubiaceae family (Madder family) is one of the largest of the angiosperms with more than 637 genera and almost 10,700 species [1]. Is a tropical plant that grows in lowland to hill forests, in swampy places and frequently along streams and rivers [4]. It is a small or medium tree to 25 m tall and 60 cm girth [3]. The plants from this genus are known to produce interesting monoterpenoid indole alkaloids with high structural diversity such as naucline [5], nauclealines B [6] and naufoline [7]. Many of them exhibited significant biological activities; anti-convulsant [8], anti-proliferative [9] and vasorelaxant activities [5]
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