Subditine, a New Monoterpenoid Indole Alkaloid from Bark of Nauclea subdita (Korth.) Steud. Induces Apoptosis in Human Prostate Cancer Cells

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.

Cytisine exerts anti-tumour effects on lung cancer cells by modulating reactive oxygen species-mediated signalling pathways

“…Sophoridine significantly induces apoptosis in BRL-3A rat liver cells with associated accumulation of ROS [28]. Subditine, a quinolizidine alkaloid from the bark of nauclea subdita, induces apoptosis in human prostate cancer cells by promoting ROS production [29]. In this study, we found that cytisine induced ROS generation in A549 cells in a dose-dependent manner ( Figure 6A).…”

Oxygenated monoterpenes citral and carvacrol cause oxidative damage in Escherichia coli without the involvement of tricarboxylic acid cycle and Fenton reaction

“…The oxidation of particular cell components, in addition to direct damages, results in the formation of several toxic by-products, such as different ROS-derived aldehydes that cause damage to different cellular components (Esterbauer et al, 1991). Citral and carvacrol actually promote intracellular ROS production, as described for other monoterpenoids (Liew et al, 2014;Su et al, 2013). In addition, mechanisms of E. coli inactivation by citral and carvacrol were studied under anaerobic conditions to prevent oxygen from being an electron acceptor, thus avoiding the formation of ROS through the electron transport chain (Imlay, 2013).…”

Effect of erythrinaline alkaloids from Erythrina lysistemon on human recombinant caspase-3

“…Author(s) agree that this article remain permanently open access under the terms of the Creative Commons Attribution License 4.0 International License process, therefore, is a significant therapeutic target for the effective elimination of androgen-dependent and androgen-independent prostate cancer cells (Nicholson et al, 1995;Bruckheimer et al, 2000;Griffin et al, 2011;Liew et al, 2014). Prostate cancer is only next to lung cancer, the second leading cause of cancer-related deaths of men in the United States (Jemal et al, 2004;Alam et al, 2014;Siegel et al, 2016).…”

“…Prostate cancer is only next to lung cancer, the second leading cause of cancer-related deaths of men in the United States (Jemal et al, 2004;Alam et al, 2014;Siegel et al, 2016). Anticancer effects of plant-based alkaloids against prostate cancer have been reported (Adhami et al, 2004;Griffin et al, 2011;Christodoulou et al, 2014;Liew et al, 2014). Activation of caspase-3, the apoptosis executioner/effector (Chang and Yang, 2000;Liew et al, 2014) could force cancer cells to undergo apoptosis.…”

“…Anticancer effects of plant-based alkaloids against prostate cancer have been reported (Adhami et al, 2004;Griffin et al, 2011;Christodoulou et al, 2014;Liew et al, 2014). Activation of caspase-3, the apoptosis executioner/effector (Chang and Yang, 2000;Liew et al, 2014) could force cancer cells to undergo apoptosis. Indeed proteolytic activation of caspase-3 is a common event leading to apoptosis of prostate cancer (LNCaP) cells (Marcelli et al, 1999;Liew et al, 2016).…”