Abstract
Xanthatin, a natural sesquiterpene lactone, has significant antitumor activity against a variety of cancer cells, yet little is known about its anticancer mechanism. In this study, we demonstrated that xanthatin had obvious dose-/time-dependent cytotoxicity against the human non-small-cell lung cancer (NSCLC) cell line A549. Flow cytometry analysis showed xanthatin induced cell cycle arrest at G2/M phase. Xanthatin also had pro-apoptotic effects on A549 cells as evidenced by Hoechst 33258 staining and annexin V-FITC staining. Mechanistic data revealed that xanthatin downregulated Chk1, Chk2, and phosphorylation of CDC2, which contributed to the cell cycle arrest. Xathatin also increased total p53 protein levels, decreased Bcl-2/Bax ratio and expression of the downstream factors procaspase-9 and procaspase-3, which triggered the intrinsic apoptosis pathway. Furthermore, xanthatin blocked phosphorylation of NF-κB (p65) and IκBα, which might also contribute to its pro-apoptotic effects on A549 cells. Xanthatin also inhibited TNFα induced NF-κB (p65) translocation. We conclude that xanthatin displays significant antitumor effects through cell cycle arrest and apoptosis induction in A549 cells. These effects were associated with intrinsic apoptosis pathway and disrupted NF-κB signaling. These results suggested that xanthatin may have therapeutic potential against NSCLC.
Highlights
Cancer remains a leading cause of death worldwide
We demonstrated that xanthatin potently inhibited cell viability and induced cell cycle arrest at G2/M checkpoint and apoptosis in A549 cells
To determine the cytotoxic effects of xanthatin on A549 cells, we first evaluated the alterations in cell morphology
Summary
Cancer remains a leading cause of death worldwide. Chemotherapy as a systemic drug-based approach is still irreplaceable in clinical contexts. Many SLs such as artemisinin, thapsigargin and parthenolide and many of their derivatives are emerging as potent anticancer agents in cancer chemotherapy and chemoprevention [3,4] They are found to be selective toward tumors by targeting specific signaling pathways, making them lead compounds in cancer clinical investigations [4]. We demonstrated that xanthatin potently inhibited cell viability and induced cell cycle arrest at G2/M checkpoint and apoptosis in A549 cells These effects were associated with activation of p53 and inhibition of NF-κB signaling, leading to decreased Bcl-2/Bax ratio and activated caspase cascade. These results indicated that xanthatin could be exploited as a promising candidate for treatment of lung cancer
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