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Int. J. Mol. Sci. 2016, 17(8), 1348; doi:10.3390/ijms17081348

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

1
Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China
2
Department of Pharmacology, Medical College Qingdao University, Qingdao 266071, China
3
Institute of Botany, Jiangsu Province and Chinese Academy of Sciences (Nanjing Botanical Garden, Mem Sun Yat-sen), Nanjing 210014, China
4
Key Laboratory of Marine Bioactive Substance, The First Institute of Oceanography, State Oceanic Administration, Qingdao 266061, China
*
Authors to whom correspondence should be addressed.
Academic Editor: David Arráez-Román
Received: 1 June 2016 / Revised: 11 August 2016 / Accepted: 12 August 2016 / Published: 19 August 2016
(This article belongs to the Section Bioactives and Nutraceuticals)
View Full-Text   |   Download PDF [4737 KB, uploaded 19 August 2016]   |  

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. View Full-Text
Keywords: 3-O-angeloyl-20-O-acetyl ingenol; PEP008; 20-O-acetyl-ingenol-3-angelate; ingenol mebutat; apoptosis; chronic myeloid leukemia 3-O-angeloyl-20-O-acetyl ingenol; PEP008; 20-O-acetyl-ingenol-3-angelate; ingenol mebutat; apoptosis; chronic myeloid leukemia
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Liu, M.; Chen, F.; Yu, R.; Zhang, W.; Han, M.; Liu, F.; Wu, J.; Zhao, X.; Miao, J. Synthesis and Cytotoxicity against K562 Cells of 3-O-Angeloyl-20-O-acetyl Ingenol, a Derivative of Ingenol Mebutate. Int. J. Mol. Sci. 2016, 17, 1348.

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