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The Curcumin Analogue, EF-24, Triggers p38 MAPK-Mediated Apoptotic Cell Death via Inducing PP2A-Modulated ERK Deactivation in Human Acute Myeloid Leukemia Cells
- Source :
- Cancers, Vol 12, Iss 2163, p 2163 (2020), Cancers, Volume 12, Issue 8
- Publication Year :
- 2020
- Publisher :
- MDPI AG, 2020.
-
Abstract
- 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 (IC50) than DMC. We found that EF-24 treatment induces several features of apoptosis, including an increase in the sub-G1 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.
- Subjects :
- 0301 basic medicine
MAPK/ERK pathway
Cancer Research
p38 mitogen-activated protein kinases
Population
acute myeloid leukemia
lcsh:RC254-282
Article
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
education
Protein kinase A
EF-24
education.field_of_study
Chemistry
protein phosphatase 2 a
apoptosis
Myeloid leukemia
p38 mitogen-activated protein kinase
Protein phosphatase 2
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
030104 developmental biology
Oncology
Apoptosis
030220 oncology & carcinogenesis
Cancer research
Curcumin
extracellular-regulated protein kinase
Subjects
Details
- Language :
- English
- ISSN :
- 20726694
- Volume :
- 12
- Issue :
- 2163
- Database :
- OpenAIRE
- Journal :
- Cancers
- Accession number :
- edsair.doi.dedup.....2679069c72c4cd78f7028ece38630b7b