Induction of the mitochondria-mediated apoptosis in human esophageal cancer cells by DS2, a newly synthetic diterpenoid analog, is regulated by Bax and caused by generation of reactive oxygen species

Abstract

Ent-kaurane diterpene compounds have attracted considerable attention in recent years due to its antitumor, antibacterial, and antiviral activities. However, the clinical development of natural kaurane diterpenes, for example, oridonin for cancer therapy has been hampered by its relatively moderate potency, limited bioavailability. Herein, we report a newly synthetic analog of natural ent-kaurane diterpene, DS2, which exhibits significantly improved activity of antiproliferation against various cancer cell lines relative to oridonin. DS2 treatment triggers the mitochondria-mediated apoptosis and cell cycle arrest in human esophageal cancer cell lines (EC9706, EC109). Interestingly, normal human esophageal epithelial cells (HEECs) and normal human liver cells (HL-7702) are both significantly more resistant to the growth inhibition by DS2 compared with esophageal cancer cells. The DS2-induced apoptosis in EC9706 cells correlated with the drop of mitochondrial membrane potential (MMP), release of cytochrome c into the cytosol and activation of caspase-9 and -3. The induction of proapoptotic proteins p21 and Bax were also observed in DS2-treated cells. The DS2-induced apoptosis was significantly attenuated by knockdown of Bax proteins. Meanwhile, the DS2 treatment caused generation of reactive oxygen species (ROS) in human esophageal cancer cells, but not in HEECs, which was attenuated by pretreatment with ROS scavenger N-acetylcysteine (NAC). More interestingly, the antioxidants pretreatment completely attenuated DS2 mediated loss of the MMP and apoptosis, as well as Bax expression and growth inhibition. In conclusion, the present study reveals that the mitochondria-mediated cell death by DS2 is associated with Bax regulation and ROS generation, and understanding the function and mechanism of DS2 will help us to design better anti-cancer drugs.

Amifostine Pretreatment Attenuates Myocardial Ischemia/Reperfusion Injury by Inhibiting Apoptosis and Oxidative Stress

“…We found that amifostine could reduce ROS and increase SOD2 expression in TBHP-treated H9c2 cells. Mitochondria has been identified as a major source of ROS, and accumulation of ROS will cause abnormal ΔΨ m [31]. We found that amifostine was effective in preventing a decrease in ΔΨ m in TBHP-induced H9c2 cells.…”

Quinalizarin Induces Apoptosis through Reactive Oxygen Species (ROS)-Mediated Mitogen-Activated Protein Kinase (MAPK) and Signal Transducer and Activator of Transcription 3 (STAT3) Signaling Pathways in Colorectal Cancer Cells

“…ROS are mainly produced by mitochondria and act as second messengers to control various cellular processes such as apoptosis and cell proliferation [ 35 ]. The overproduction of intracellular ROS generally causes mitochondrial dysfunction and leads to cellular oxidative stress-induced apoptosis [ 36 , 37 ]. Our study investigated the role of ROS production and the induction of apoptosis in quinalizarin-treated SW480 cells, showing that the generation of ROS influenced quinalizarin-induced cell apoptosis, MAPK, and STAT3 phosphorylation.…”

The role of oxidative stress-mediated apoptosis in the pathogenesis of uric acid nephropathy

“…Then, centrifuged the sediment in 200 μL mitochondrial extract (add DTT and protease inhibitors), and rapidly blended the mitochondrial proteins. The p53, Bax and caspase-9/-3 proteins were detected by immunoblot [7].…”