Abstract
BackgroundIn the quest for new anti-cancer drugs, the drug discovery process has shifted to screening of active ingredients in traditional eastern medicine. Matrine is an active alkaloid isolated from plants of the Sophora genus used in traditional Chinese herbal medicine that exhibits a wide spectrum of biological properties and has a potential as an anti-proliferative agent. In this study, we investigated the anticancer property of MASM, ([(6aS, 10S, 11aR, 11bR, 11cS)210-Methylamino-dodecahydro-3a, 7a-diaza-benzo (de)anthracene-8-thione]), a potent derivative of matrine.MethodsFour epithelial cancer cell lines representing the dominant cancers, namely: A549 (non-small-cell lung cancer cell line), MCF-7 and MDA-MB-231 (breast cancer cell lines), and Hela (cervical cancer cell line) were employed, and the mechanistic underpinning of MASM-induced apoptosis was investigated using flow cytometry, western blot and immunofluorescence.ResultsMASM, induced apoptosis via caspase 3 dependent and independent pathways, and autophagy in all the four cancer cell lines, but post-EMT (epithelial mesenchymal transition) cells showed greater sensitivity to MASM. Scavenging reactive oxygen species using N-acetylcysteine rescued all cancer cell lines from apoptosis and autophagy. Mechanistic analysis revealed that MASM induced autophagy involves inhibition of Akt signaling and the activation of Erk and p38 signaling, and inhibition of autophagy further enhanced the apoptosis induced by MASM.ConclusionsThese results indicate that MASM possesses potency against cancer cells and modulating autophagy during MASM administration could be used to further enhance its therapeutic effects.
Highlights
In the quest for new anti-cancer drugs, the drug discovery process has shifted to screening of active ingredients in traditional eastern medicine
While there was no difference in LDH release in A549 and MCF-7 for the various MASM concentrations studied for up to 24 h (Additional file 1: Figure S1); in MDA-MB-231 and Hela cells, with an increase in the concentration of MASM to 90 μg/ml, there was a statistically significant increase in LDH release over 24 h in both MDA-MB-231 and HeLa cells (Fig. 1c)
Since we have shown that MASM induced autophagy occurs in part through the activation of Erk1/2 and p38, we wondered if inhibiting autophagy through Erk1/2 and p38 inhibition could influence the apoptosis induced by MASM
Summary
In the quest for new anti-cancer drugs, the drug discovery process has shifted to screening of active ingredients in traditional eastern medicine. Matrine is an active alkaloid isolated from plants of the Sophora genus used in traditional Chinese herbal medicine that exhibits a wide spectrum of biological properties and has a potential as an anti-proliferative agent. In 2015, there were 17.5 million incidents of cancer and 8.7 million cancer related deaths (15.7% of deaths) [1, 2]. In addition to surgery and radiotherapy, chemotherapy remains the major option for cancer therapy, especially for metastatic cancers [3]. The side-effects of chemotherapy and development of chemo-resistance in cancer cells are persistent challenges. Developing novel therapeutic agents and enhancing the therapeutic efficacy of anticancer drugs carries substantial clinical value
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