Abstract
Isoliensinine, liensinine and neferine are major bisbenzylisoquinoline alkaloids in the seed embryo of lotus (Nelumbo nucifera), and exhibit potential anti-cancer activity. Here, we explored the effects of these alkaloids on triple-negative breast cancer cells and found that among the three alkaloids isoliensinine possesses the most potent cytotoxic effect, primarily by inducing apoptosis. Interestingly, isoliensinine showed a much lower cytotoxicity against MCF-10A, a normal human breast epithelial cell line. Further studies showed that isoliensinine could significantly increase the production of reactive oxygen species (ROS) in triple-negative breast cancer cells, but not in MCF-10A cells. The isoliensinine-induced apoptosis could be attenuated by radical oxygen scavenger N-acetyl cysteine, suggesting that the cytotoxic effect of isoliensinine on cancer cells is at least partially achieved by inducing oxidative stress. We found that both p38 MAPK and JNK signaling pathways were activated by isoliensinine treatment and contributed to the induction of apoptosis. Furthermore, inhibitors or specific siRNAs of p38 MAPK and JNK could attenuate apoptosis induced by isoliensinine. However, only the p38 inhibitor or p38-specific siRNA blocked the elevation of ROS in isoliensinine-treated cells. Our findings thus revealed a novel antitumor effect of isoliensinine on breast cancer cells and may have therapeutic implications.
Highlights
IntroductionNeferine was shown to induce ROS generation leading to apoptosis in HepG2 cells[6]
To determine whether the isoliensinine-induced apoptosis in triple-negative breast cancer cells is mediated by elevated ROS level, we examined apoptosis induced by isoliensinine in cells pretreated with ROS scavenger N-acetyl cysteine (NAC)
We examined whether activation of p38 MAPK and JNK pathways was necessary for isoliensinine-induced apoptosis in MDA-MB-231 cells
Summary
Neferine was shown to induce ROS generation leading to apoptosis in HepG2 cells[6]. Isoliensinine and liensinine were shown to exhibit potent cytotoxic effect towards cancer cells (including MCF-7 cells) and function as an enhancer of autophagy in apoptosis-defective cells[8]. Excessive ROS can induce cell death including apoptosis, autophagy and necrosis[11,12]. Several studies have demonstrated that apoptotic cell death induced by ROS is mediated by p38 MAPK and JNK activation[13,14,15]. In the present study we assessed anti-cancer effects of isoliensinine, liensinine and neferine on triple-negative human breast cancer cells. We demonstrated that the pro-apoptotic effect of isoliensinine was mediated by an increase in ROS production and the activation of p38 MAPK and JNK pathways
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