Cargando…
The Curcumin Analogue, EF-24, Triggers p38 MAPK-Mediated Apoptotic Cell Death via Inducing PP2A-Modulated ERK Deactivation in Human Acute Myeloid Leukemia Cells
Curcumin (CUR) has a range of therapeutic benefits against cancers, but its poor solubility and low bioavailability limit its clinical use. Demethoxycurcumin (DMC) and diphenyl difluoroketone (EF-24) are natural and synthetic curcumin analogues, respectively, with better solubilities and higher anti...
Autores principales: | , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464750/ https://www.ncbi.nlm.nih.gov/pubmed/32759757 http://dx.doi.org/10.3390/cancers12082163 |
_version_ | 1783577435404500992 |
---|---|
author | Hsiao, Pei-Ching Chang, Jer-Hwa Lee, Wei-Jiunn Ku, Chia-Chi Tsai, Meng-Ying Yang, Shun-Fa Chien, Ming-Hsien |
author_facet | Hsiao, Pei-Ching Chang, Jer-Hwa Lee, Wei-Jiunn Ku, Chia-Chi Tsai, Meng-Ying Yang, Shun-Fa Chien, Ming-Hsien |
author_sort | Hsiao, Pei-Ching |
collection | PubMed |
description | Curcumin (CUR) has a range of therapeutic benefits against cancers, but its poor solubility and low bioavailability limit its clinical use. Demethoxycurcumin (DMC) and diphenyl difluoroketone (EF-24) are natural and synthetic curcumin analogues, respectively, with better solubilities and higher anti-carcinogenic activities in various solid tumors than CUR. However, the efficacy of these analogues against non-solid tumors, particularly in acute myeloid leukemia (AML), has not been fully investigated. Herein, we observed that both DMC and EF-24 significantly decrease the proportion of viable AML cells including HL-60, U937, and MV4-11, harboring different NRAS and Fms-like tyrosine kinase 3 (FLT3) statuses, and that EF-24 has a lower half maximal inhibitory concentration (IC(50)) than DMC. We found that EF-24 treatment induces several features of apoptosis, including an increase in the sub-G(1) population, phosphatidylserine (PS) externalization, and significant activation of extrinsic proapoptotic signaling such as caspase-8 and -3 activation. Mechanistically, p38 mitogen-activated protein kinase (MAPK) activation is critical for EF-24-triggered apoptosis via activating protein phosphatase 2A (PP2A) to attenuate extracellular-regulated protein kinase (ERK) activities in HL-60 AML cells. In the clinic, patients with AML expressing high level of PP2A have the most favorable prognoses compared to various solid tumors. Taken together, our results indicate that EF-24 is a potential therapeutic agent for treating AML, especially for cancer types that lose the function of the PP2A tumor suppressor. |
format | Online Article Text |
id | pubmed-7464750 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-74647502020-09-04 The Curcumin Analogue, EF-24, Triggers p38 MAPK-Mediated Apoptotic Cell Death via Inducing PP2A-Modulated ERK Deactivation in Human Acute Myeloid Leukemia Cells Hsiao, Pei-Ching Chang, Jer-Hwa Lee, Wei-Jiunn Ku, Chia-Chi Tsai, Meng-Ying Yang, Shun-Fa Chien, Ming-Hsien Cancers (Basel) Article Curcumin (CUR) has a range of therapeutic benefits against cancers, but its poor solubility and low bioavailability limit its clinical use. Demethoxycurcumin (DMC) and diphenyl difluoroketone (EF-24) are natural and synthetic curcumin analogues, respectively, with better solubilities and higher anti-carcinogenic activities in various solid tumors than CUR. However, the efficacy of these analogues against non-solid tumors, particularly in acute myeloid leukemia (AML), has not been fully investigated. Herein, we observed that both DMC and EF-24 significantly decrease the proportion of viable AML cells including HL-60, U937, and MV4-11, harboring different NRAS and Fms-like tyrosine kinase 3 (FLT3) statuses, and that EF-24 has a lower half maximal inhibitory concentration (IC(50)) than DMC. We found that EF-24 treatment induces several features of apoptosis, including an increase in the sub-G(1) population, phosphatidylserine (PS) externalization, and significant activation of extrinsic proapoptotic signaling such as caspase-8 and -3 activation. Mechanistically, p38 mitogen-activated protein kinase (MAPK) activation is critical for EF-24-triggered apoptosis via activating protein phosphatase 2A (PP2A) to attenuate extracellular-regulated protein kinase (ERK) activities in HL-60 AML cells. In the clinic, patients with AML expressing high level of PP2A have the most favorable prognoses compared to various solid tumors. Taken together, our results indicate that EF-24 is a potential therapeutic agent for treating AML, especially for cancer types that lose the function of the PP2A tumor suppressor. MDPI 2020-08-04 /pmc/articles/PMC7464750/ /pubmed/32759757 http://dx.doi.org/10.3390/cancers12082163 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Hsiao, Pei-Ching Chang, Jer-Hwa Lee, Wei-Jiunn Ku, Chia-Chi Tsai, Meng-Ying Yang, Shun-Fa Chien, Ming-Hsien The Curcumin Analogue, EF-24, Triggers p38 MAPK-Mediated Apoptotic Cell Death via Inducing PP2A-Modulated ERK Deactivation in Human Acute Myeloid Leukemia Cells |
title | The Curcumin Analogue, EF-24, Triggers p38 MAPK-Mediated Apoptotic Cell Death via Inducing PP2A-Modulated ERK Deactivation in Human Acute Myeloid Leukemia Cells |
title_full | The Curcumin Analogue, EF-24, Triggers p38 MAPK-Mediated Apoptotic Cell Death via Inducing PP2A-Modulated ERK Deactivation in Human Acute Myeloid Leukemia Cells |
title_fullStr | The Curcumin Analogue, EF-24, Triggers p38 MAPK-Mediated Apoptotic Cell Death via Inducing PP2A-Modulated ERK Deactivation in Human Acute Myeloid Leukemia Cells |
title_full_unstemmed | The Curcumin Analogue, EF-24, Triggers p38 MAPK-Mediated Apoptotic Cell Death via Inducing PP2A-Modulated ERK Deactivation in Human Acute Myeloid Leukemia Cells |
title_short | The Curcumin Analogue, EF-24, Triggers p38 MAPK-Mediated Apoptotic Cell Death via Inducing PP2A-Modulated ERK Deactivation in Human Acute Myeloid Leukemia Cells |
title_sort | curcumin analogue, ef-24, triggers p38 mapk-mediated apoptotic cell death via inducing pp2a-modulated erk deactivation in human acute myeloid leukemia cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464750/ https://www.ncbi.nlm.nih.gov/pubmed/32759757 http://dx.doi.org/10.3390/cancers12082163 |
work_keys_str_mv | AT hsiaopeiching thecurcuminanalogueef24triggersp38mapkmediatedapoptoticcelldeathviainducingpp2amodulatederkdeactivationinhumanacutemyeloidleukemiacells AT changjerhwa thecurcuminanalogueef24triggersp38mapkmediatedapoptoticcelldeathviainducingpp2amodulatederkdeactivationinhumanacutemyeloidleukemiacells AT leeweijiunn thecurcuminanalogueef24triggersp38mapkmediatedapoptoticcelldeathviainducingpp2amodulatederkdeactivationinhumanacutemyeloidleukemiacells AT kuchiachi thecurcuminanalogueef24triggersp38mapkmediatedapoptoticcelldeathviainducingpp2amodulatederkdeactivationinhumanacutemyeloidleukemiacells AT tsaimengying thecurcuminanalogueef24triggersp38mapkmediatedapoptoticcelldeathviainducingpp2amodulatederkdeactivationinhumanacutemyeloidleukemiacells AT yangshunfa thecurcuminanalogueef24triggersp38mapkmediatedapoptoticcelldeathviainducingpp2amodulatederkdeactivationinhumanacutemyeloidleukemiacells AT chienminghsien thecurcuminanalogueef24triggersp38mapkmediatedapoptoticcelldeathviainducingpp2amodulatederkdeactivationinhumanacutemyeloidleukemiacells AT hsiaopeiching curcuminanalogueef24triggersp38mapkmediatedapoptoticcelldeathviainducingpp2amodulatederkdeactivationinhumanacutemyeloidleukemiacells AT changjerhwa curcuminanalogueef24triggersp38mapkmediatedapoptoticcelldeathviainducingpp2amodulatederkdeactivationinhumanacutemyeloidleukemiacells AT leeweijiunn curcuminanalogueef24triggersp38mapkmediatedapoptoticcelldeathviainducingpp2amodulatederkdeactivationinhumanacutemyeloidleukemiacells AT kuchiachi curcuminanalogueef24triggersp38mapkmediatedapoptoticcelldeathviainducingpp2amodulatederkdeactivationinhumanacutemyeloidleukemiacells AT tsaimengying curcuminanalogueef24triggersp38mapkmediatedapoptoticcelldeathviainducingpp2amodulatederkdeactivationinhumanacutemyeloidleukemiacells AT yangshunfa curcuminanalogueef24triggersp38mapkmediatedapoptoticcelldeathviainducingpp2amodulatederkdeactivationinhumanacutemyeloidleukemiacells AT chienminghsien curcuminanalogueef24triggersp38mapkmediatedapoptoticcelldeathviainducingpp2amodulatederkdeactivationinhumanacutemyeloidleukemiacells |