Triterpenoids from Ziziphus jujuba induce apoptotic cell death in human cancer cells through mitochondrial reactive oxygen species production. Issue 7 (3rd July 2018) - Shin, Minna
Abstract : Coumaroyl alphitolic acids induce apoptotic cell death in cancer cells via mitochondrial ROS production and ER stress. Abstract : Ziziphus jujuba var. inermis Rehder is an edible fruit-producing species of the Rhamnaceae family. In the present study, we isolated eight triterpenoids (1–8 ) from the fruits of Z. jujuba var. inermis and evaluated their apoptotic cell-death-inducing activities in human cancer cell lines (A549, PC-3, and MDA-MB-231). The structures of compounds1–8 were determined by spectroscopic methods. Among these, four isomers of coumaroyl alphitolic acid showed potent cytotoxic activities on these cancer cells: 3- O-cis-p -coumaroyl alphitolic acid (3 ), 3- O-trans-p -coumaroyl alphitolic acid (4 ), 2- O-trans-p -coumaroyl alphitolic acid (5 ), and 2- O-cis-p -coumaroyl alphitolic acid (6 ). Moreover, compounds3–6 induced apoptotic cell death in a concentration-dependent manner. We further investigated the apoptosis-inducing effects of compound4 in PC-3 cells which triggered the cleavage of procaspase-3, procaspase-7, procaspase-8, bid, and PARP. Compound4 increased both the mitochondrial reactive oxygen species (ROS) production and the phosphorylation of p38 MAPK (mitogen-activated protein kinase), but decreased the mitochondrial membrane potential. Pretreatment with Mito-TEMPO (a specific mitochondrial-targeted antioxidant) or a specific p38 inhibitor (SB203580) attenuated apoptotic cell death triggered by compound4 which suggests that compound4 may induce apoptotic cell death in these cancer cells by increasing the mitochondrial ROS production as well as the subsequent p38 MAPK activation. The study findings provide a rational base to use Ziziphus extracts for cancer treatments in traditional oriental medicine.