Synthesis and Cytotoxicity against K562 Cells of 3-O-Angeloyl-20-O-acetyl Ingenol, a Derivative of Ingenol Mebutate

doi:10.3390/ijms17081348

	Synthesis and Cytotoxicity against K562 Cells of 3-O-Angeloyl-20-O-acetyl Ingenol, a Derivative of Ingenol Mebutate
	Liu, Ming 1; Chen, Fangling 1; Yu, Rilei 1; Zhang, Weiyi 1; Han, Mei 2; Liu, Fei 3,4; Wu, Jing 1; Zhao, Xingzeng 3,4; Miao, Jinlai 5
刊名	INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
	2016-08
卷号	17 期号:8
关键词	3-O-angeloyl-20-O-acetyl ingenol PEP008 20-O-acetyl-ingenol-3-angelate ingenol mebutat apoptosis chronic myeloid leukemia
ISSN号	1422-0067
DOI	10.3390/ijms17081348
英文摘要	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 C delta (PKC delta). 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 PKC delta 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 PKC delta/ERK, JAK/STAT3, and AKT signaling pathways. Our work suggests that AAI may be a new candidate of chemotherapeutic agent.
资助项目	Qingdao Entrepreneurship & Innovation Pioneers Program[15-10-3-15-(44)-zch]
WOS关键词	PROTEIN-KINASE-C ; ACTINIC KERATOSIS ; BCR-ABL ; CANCER ; ACTIVATOR ; ANGELATE ; DOCKING ; PEP005 ; DELTA
WOS研究方向	Biochemistry & Molecular Biology ; Chemistry
语种	英语
出版者	MDPI AG
WOS记录号	WOS:000382337900159
内容类型	期刊论文
源URL	[http://ir.fio.com.cn:8080/handle/2SI8HI0U/26084]
专题	自然资源部第一海洋研究所
通讯作者	Liu, Ming; Miao, Jinlai
作者单位	1.Ocean Univ China, Sch Med & Pharm, Minist Educ, Key Lab Marine Drugs, Qingdao 266003, Peoples R China 2.Qingdao Univ, Coll Med, Dept Pharmacol, Qingdao 266071, Peoples R China 3.Inst Bot, Nanjing 210014, Jiangsu, Peoples R China 4.Chinese Acad Sci, Nanjing Bot Garden, Mem Sun Yat Sen, Nanjing 210014, Jiangsu, Peoples R China 5.State Ocean Adm, Inst Oceanog 1, Key Lab Marine Bioact Subst, Qingdao 266061, Peoples R China
推荐引用方式 GB/T 7714	Liu, Ming,Chen, Fangling,Yu, Rilei,et al. Synthesis and Cytotoxicity against K562 Cells of 3-O-Angeloyl-20-O-acetyl Ingenol, a Derivative of Ingenol Mebutate[J]. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES,2016,17(8).
APA	Liu, Ming.,Chen, Fangling.,Yu, Rilei.,Zhang, Weiyi.,Han, Mei.,...&Miao, Jinlai.(2016).Synthesis and Cytotoxicity against K562 Cells of 3-O-Angeloyl-20-O-acetyl Ingenol, a Derivative of Ingenol Mebutate.INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES,17(8).
MLA	Liu, Ming,et al."Synthesis and Cytotoxicity against K562 Cells of 3-O-Angeloyl-20-O-acetyl Ingenol, a Derivative of Ingenol Mebutate".INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES 17.8(2016).