title: 13-Oxyingenol dodecanoate, a cytotoxic ingenol derivative, induces mitochondrial apoptosis and caspase-dependent Akt decrease in K562 cells.
abstract: 13-Oxyingenol dodecanoate (13OD) is an ingenol derivative prepared from Chinese traditional medicine Euphorbia kansui without any report about its bioactivity. The present study demonstrated for the first time that 13OD displayed potent cytotoxicity against chronic myeloid leukemia K562 cells in vitro. 13OD inhibited proliferation, induced G2/M phase arrest, and exhibited potent apoptotic activity in K562 cells. In K562 cells, 13OD disrupted the mitochondrial membrane potential and induced high level of ROS, which played an indispensable role in 13OD-induced apoptosis. Further investigations on the molecular mechanisms revealed that total Akt protein level was decreased in a caspase-dependent way after treatment with 13OD; in addition, ERK was activated by 13OD, and this activation played a protective role in 13OD stimulation. Altogether, these results revealed that the cytotoxic ingenol derivative 13OD induced apoptosis with novel mechanisms for the proapoptotic function in cancer cells, and suggested that 13OD may serve as a lead template for rational drug design and for future anticancer agent development.
authors.affiliation: Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Liu
authors.affiliation: Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China.
authors.forename: Weiyi
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China.
authors.forename: Genzhu
authors.initials: G
authors.lastname: Wang
authors.affiliation: Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Song
authors.affiliation: Institute of Botany, Jiangsu Province and Chinese Academy of Sciences (Nanjing Botanical Garden, Mem. Sun Yat-sen), Nanjing, 210014, China.
authors.forename: Xingzeng
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Nanjing Spring & Autumn Biological Engineering Co., Ltd, China, Nanjing, 210014, China.
authors.forename: Xiangyun
authors.initials: X
authors.lastname: Wang
authors.affiliation: Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Qi
authors.affiliation: Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China. ljlilac@163.com.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D004224:Diterpenes / Q000008:administration & dosage*; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C559803:13-oxyingenol; D004224:Diterpenes; D051057:Proto-Oncogene Proteins c-akt; D020169:Caspases
keywords: 13-Oxyingenol dodecanoate; Akt; Apoptosis; Euphorbia kansui; mTOR