title: Synthesis and Cytotoxicity against K562 Cells of 3-O-Angeloyl-20-O-acetyl Ingenol, a Derivative of Ingenol Mebutate.
abstract: Ingenol mebutate possesses significant cytotoxicity and is clinically used to treat actinic keratosis. However, ingenol mebutate undergoes acyl migration which affects its bioactivity. Compound 3-O-angeloyl-20-O-acetyl ingenol (AAI, also known as 20-O-acetyl-ingenol-3-angelate or PEP008) is a synthetic derivative of ingenol mebutate. In this work, we report the AAI synthesis details and demonstrate AAI has higher cytotoxicity than ingenol mebutate in a chronic myeloid leukemia K562 cell line. Our data indicate that the increased activity of AAI originates from the improved intracellular stability of AAI rather than the increased binding affinity between AAI and the target protein protein kinase Cδ (PKCδ). AAI inhibits cell proliferation, induces G2/M phase arrest, disrupts the mitochondrial membrane potential, and stimulates apoptosis, as well as necrosis in K562 cells. Similar to ingenol mebutate, AAI activates PKCδ and extracellular signal regulated kinase (ERK), and inactivates protein kinase B (AKT). Furthermore, AAI also inhibits JAK/STAT3 pathway. Altogether, our studies show that ingenol derivative AAI is cytotoxic to K562 cells and modulates PKCδ/ERK, JAK/STAT3, and AKT signaling pathways. Our work suggests that AAI may be a new candidate of chemotherapeutic agent.
authors.affiliation: Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China. lmouc@hotmail.com.
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. Chenfangling0410@hotmail.com.
authors.forename: Fangling
authors.initials: F
authors.lastname: Chen
authors.affiliation: Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China. rileiyu2010@hotmail.com.
authors.forename: Rilei
authors.initials: R
authors.lastname: Yu
authors.affiliation: Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China. 13070868219@163.com.
authors.forename: Weiyi
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Medical College Qingdao University, Qingdao 266071, China. maviswga@163.com.
authors.forename: Mei
authors.initials: M
authors.lastname: Han
authors.affiliation: Institute of Botany, Jiangsu Province and Chinese Academy of Sciences (Nanjing Botanical Garden, Mem Sun Yat-sen), Nanjing 210014, China. liufeiseu@163.com.
authors.forename: Fei
authors.initials: F
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. 6151504014@vip.jiangnan.edu.cn.
authors.forename: Jing
authors.initials: J
authors.lastname: Wu
authors.affiliation: Institute of Botany, Jiangsu Province and Chinese Academy of Sciences (Nanjing Botanical Garden, Mem Sun Yat-sen), Nanjing 210014, China. zhaoxingzeng@hotmail.com.
authors.forename: Xingzeng
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Key Laboratory of Marine Bioactive Substance, The First Institute of Oceanography, State Oceanic Administration, Qingdao 266061, China. miaojinlai@163.com.
authors.forename: Jinlai
authors.initials: J
authors.lastname: Miao
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004224:Diterpenes / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C486592:3-ingenyl angelate; D000970:Antineoplastic Agents; D004224:Diterpenes; D048049:Extracellular Signal-Regulated MAP Kinases; C008125:ingenol
keywords: 20-O-acetyl-ingenol-3-angelate; 3-O-angeloyl-20-O-acetyl ingenol; PEP008; apoptosis; chronic myeloid leukemia; ingenol mebutat