Synthesis and Cytotoxicity against K562 Cells of 3-O-Angeloyl-20-O-acetyl Ingenol, a Derivative of Ingenol Mebutate
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 synthe...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2016-08-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | http://www.mdpi.com/1422-0067/17/8/1348 |
| _version_ | 1811207631819243520 |
|---|---|
| author | Ming Liu Fangling Chen Rilei Yu Weiyi Zhang Mei Han Fei Liu Jing Wu Xingzeng Zhao Jinlai Miao |
| author_facet | Ming Liu Fangling Chen Rilei Yu Weiyi Zhang Mei Han Fei Liu Jing Wu Xingzeng Zhao Jinlai Miao |
| author_sort | Ming Liu |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T04:07:56Z |
| format | Article |
| id | doaj.art-cad5d18d9c2c48bba4b58f15134992ac |
| institution | Directory Open Access Journal |
| issn | 1422-0067 |
| language | English |
| last_indexed | 2024-04-12T04:07:56Z |
| publishDate | 2016-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-cad5d18d9c2c48bba4b58f15134992ac2022-12-22T03:48:35ZengMDPI AGInternational Journal of Molecular Sciences1422-00672016-08-01178134810.3390/ijms17081348ijms17081348Synthesis and Cytotoxicity against K562 Cells of 3-O-Angeloyl-20-O-acetyl Ingenol, a Derivative of Ingenol MebutateMing Liu0Fangling Chen1Rilei Yu2Weiyi Zhang3Mei Han4Fei Liu5Jing Wu6Xingzeng Zhao7Jinlai Miao8Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, ChinaKey Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, ChinaKey Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, ChinaKey Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, ChinaDepartment of Pharmacology, Medical College Qingdao University, Qingdao 266071, ChinaInstitute of Botany, Jiangsu Province and Chinese Academy of Sciences (Nanjing Botanical Garden, Mem Sun Yat-sen), Nanjing 210014, ChinaKey Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, ChinaInstitute of Botany, Jiangsu Province and Chinese Academy of Sciences (Nanjing Botanical Garden, Mem Sun Yat-sen), Nanjing 210014, ChinaKey Laboratory of Marine Bioactive Substance, The First Institute of Oceanography, State Oceanic Administration, Qingdao 266061, ChinaIngenol 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.http://www.mdpi.com/1422-0067/17/8/13483-O-angeloyl-20-O-acetyl ingenolPEP00820-O-acetyl-ingenol-3-angelateingenol mebutatapoptosischronic myeloid leukemia |
| spellingShingle | Ming Liu Fangling Chen Rilei Yu Weiyi Zhang Mei Han Fei Liu Jing Wu Xingzeng Zhao Jinlai Miao Synthesis and Cytotoxicity against K562 Cells of 3-O-Angeloyl-20-O-acetyl Ingenol, a Derivative of Ingenol Mebutate International Journal of Molecular Sciences 3-O-angeloyl-20-O-acetyl ingenol PEP008 20-O-acetyl-ingenol-3-angelate ingenol mebutat apoptosis chronic myeloid leukemia |
| title | Synthesis and Cytotoxicity against K562 Cells of 3-O-Angeloyl-20-O-acetyl Ingenol, a Derivative of Ingenol Mebutate |
| title_full | Synthesis and Cytotoxicity against K562 Cells of 3-O-Angeloyl-20-O-acetyl Ingenol, a Derivative of Ingenol Mebutate |
| title_fullStr | Synthesis and Cytotoxicity against K562 Cells of 3-O-Angeloyl-20-O-acetyl Ingenol, a Derivative of Ingenol Mebutate |
| title_full_unstemmed | Synthesis and Cytotoxicity against K562 Cells of 3-O-Angeloyl-20-O-acetyl Ingenol, a Derivative of Ingenol Mebutate |
| title_short | Synthesis and Cytotoxicity against K562 Cells of 3-O-Angeloyl-20-O-acetyl Ingenol, a Derivative of Ingenol Mebutate |
| title_sort | synthesis and cytotoxicity against k562 cells of 3 o angeloyl 20 o acetyl ingenol a derivative of ingenol mebutate |
| topic | 3-O-angeloyl-20-O-acetyl ingenol PEP008 20-O-acetyl-ingenol-3-angelate ingenol mebutat apoptosis chronic myeloid leukemia |
| url | http://www.mdpi.com/1422-0067/17/8/1348 |
| work_keys_str_mv | AT mingliu synthesisandcytotoxicityagainstk562cellsof3oangeloyl20oacetylingenoladerivativeofingenolmebutate AT fanglingchen synthesisandcytotoxicityagainstk562cellsof3oangeloyl20oacetylingenoladerivativeofingenolmebutate AT rileiyu synthesisandcytotoxicityagainstk562cellsof3oangeloyl20oacetylingenoladerivativeofingenolmebutate AT weiyizhang synthesisandcytotoxicityagainstk562cellsof3oangeloyl20oacetylingenoladerivativeofingenolmebutate AT meihan synthesisandcytotoxicityagainstk562cellsof3oangeloyl20oacetylingenoladerivativeofingenolmebutate AT feiliu synthesisandcytotoxicityagainstk562cellsof3oangeloyl20oacetylingenoladerivativeofingenolmebutate AT jingwu synthesisandcytotoxicityagainstk562cellsof3oangeloyl20oacetylingenoladerivativeofingenolmebutate AT xingzengzhao synthesisandcytotoxicityagainstk562cellsof3oangeloyl20oacetylingenoladerivativeofingenolmebutate AT jinlaimiao synthesisandcytotoxicityagainstk562cellsof3oangeloyl20oacetylingenoladerivativeofingenolmebutate |