Tehranolide inhibits proliferation of MCF-7 human breast cancer cells by inducing G0/G1 arrest and apoptosis
Zuhair M. Hassan
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Tehranolide, a novel natural sesquiterpene lactone with an endoperoxide group, bears a structural similarity to artemisinin and has been shown to inhibit cell growth. However, the underlying mechanisms of these activities remain obscure. The purpose of this study was to investigate the fundamental mechanisms by which tehranolide inhibits growth in MCF-7 cells. Cell growth was determined by using the MTT viability assay and counting cells. Apoptosis and cell-cycle progression were evaluated by means of Hoechst 33258 staining, flow cytometry with annexin-V/propidium iodide double staining, and ROS formation. The protein expression of Bax and Bcl-2 was demonstrated by Western blotting. Moreover, to determine the molecular mechanism whereby tehranolide mediates G0/G1 arrest, the expression of PI3K, p-PI3K, Akt, p-Akt, p27kip1, cyclin D1, and CDK4 was monitored. Cell proliferation was significantly inhibited by tehranolide in a dose- and time-dependent manner. This compound inhibited cell proliferation and induced G0/G1 arrest through the PI3K/Akt/cyclin D1 pathway. It also induced apoptosis and an increase in ROS. In addition, an increase in cytochrome c and Bax, as well as a decrease in Bcl-2, was observed. Moreover, blocking the CD95 receptor with an anti-CD95 antibody (ZB4) had no effect on tehranolide-mediated apoptosis. This study has yielded promising results, which show for the first time that tehranolide does inhibit the growth of cancer cells. The selective inhibition of cancer cell growth, the apoptosis induction via the mitochondrial pathway, and the G0/G1 arrest by modulating the PI3K/AKT signaling pathway and downregulating cyclin D1, which leads to the release of p27kip1 and the association of this inhibitor with the cyclin E/CDK2 complex, ultimately preventing cell-cycle progression from G1 to S phase, all serve to provide support for further studies of tehranolide as a possible anticancer drug in the clinical treatment of cancer. © 2012 Elsevier Inc. All rights reserved.