Abstract
β-Sitosterol (BS), a major bioactive constituent present in plants and vegetables has shown potent anticancer effect against many human cancer cells, but the underlying mechanism remain elusive on NSCLC cancers. We found that BS significantly inhibited the growth of A549 cells without harming normal human lung and PBMC cells. Further, BS treatment triggered apoptosis via ROS mediated mitochondrial dysregulation as evidenced by caspase-3 & 9 activation, Annexin-V/PI positive cells, PARP inactivation, loss of MMP, Bcl-2-Bax ratio alteration and cytochrome c release. Moreover, generation of ROS species and subsequent DNA stand break were found upon BS treatment which was reversed by addition of ROS scavenger (NAC). Indeed BS treatment increased p53 expression and its phosphorylation at Ser15, while silencing the p53 expression by pifithrin-α, BS induced apoptosis was reduced in A549 cells. Furthermore, BS induced apoptosis was also observed in NCI-H460 cells (p53 wild) but not in the NCI-H23 cells (p53 mutant). Down-regulation of Trx/Trx1 reductase contributed to the BS induced ROS accumulation and mitochondrial mediated apoptotic cell death in A549 and NCI-H460 cells. Taken together, our findings provide evidence for the novel anti-cancer mechanism of BS which could be developed as a promising chemotherapeutic drug against NSCLC cancers.
Highlights
Non-small cell lung cancer (NSCLC) is one of the common aggressive malignant tumor accounting for about 85% of human lung cancers[1]
Fluorescence images of the cells stained with propidium iodide (PI) revealed that increasing number of PI positive cells were observed during treatment with BS
The crucial factor which contributes for the current therapy failure includes the series of side effects and the emergence of multi-drug resistance to the conventional chemotherapy drugs[27,28,29]
Summary
Non-small cell lung cancer (NSCLC) is one of the common aggressive malignant tumor accounting for about 85% of human lung cancers[1]. The intake of higher dose of the drugs are incapable of improving the treatment efficiency, rather causes adverse side effects in non-targeted tissues. This has resulted in insistent need to explore new molecules which could combat NSCLC with potential anticancer efficiency along with significant safety and devoid of toxicity. In this study we have demonstrated for the first time that BS is effective against human NSCLC cells and the investigation of the molecular mechanism has revealed that BS promotes apoptotic cell death in A549 and NCI-H460 cells through ROS accumulation and loss of ΔΨ m via p53 activation. Our data revealed that BS inhibits the protein expression of Trx/TrxR1, which in turn triggers ROS accumulation in A549 and NCI-H460 cells and activation of apoptotic cell death
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