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.
Highlights
Esophageal squamous cell carcinoma (ESCC) is esophageal cancer’s dominate pathologic subtype with remarkable geographic variation in incidence
DS2 treatment at 4 μM concentration for 24 h or 48 h resulted in about 33% or 48%, 30% or 50%, 32% or 70% and 40% or 80% growth inhibition of MGC-803, PC-3, EC9706 and EC109 cells
We investigated DS2, a novel diterpenoid analog, the potential anti-proliferation activity using a few of human cancer cell lines, and found that DS2 displayed more potent anti-proliferation properties in a tumorselective manner than oridonin
Summary
Esophageal squamous cell carcinoma (ESCC) is esophageal cancer’s dominate pathologic subtype with remarkable geographic variation in incidence. Isodon rubescens (“Donglingcao” in Chinese) is a significant source of a traditional Chinese herbal medicine that has been widely used for esophageal and cardia cancer’s treatment for many years in China [6, 7]. Many ent-kaurane diterpenoids were isolated from this herb, such as Oridonin [8], Jaridonin [9] and Eriocalyxin B [10]. From Isodon rubescens, another new ent-kaurene diterpenoid was isolated by us, named Jaridonin. Expeditious synthetic methods that were based on the Jaridonin scaffold were successfully built by our group to access a series of disulfide bond-substituted derivatives with improved anticancer activity, among them, DS2 (the synthesis and the structure identification of DS2 are shown in Supplementary Figures S1, S2 and S3) suggesting that disulfide bond-substituted modifications seem to be tolerated for producing biologically interesting molecules
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