The curcumin analogue, ef-24, triggers p38 mapkmediated apoptotic cell death via inducing pp2amodulated erk deactivation in human acute myeloid leukemia cells

Pei Ching Hsiao, Jer Hwa Chang, Wei Jiunn Lee, Chia Chi Ku, Meng Ying Tsai, Shun Fa Yang, Ming Hsien Chien

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

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 extracellularregulated 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.

Original languageEnglish
Article number2163
Pages (from-to)1-17
Number of pages17
JournalCancers
Volume12
Issue number8
DOIs
Publication statusPublished - Aug 2020

Keywords

  • Acute myeloid leukemia
  • Apoptosis
  • EF-24
  • Extracellular-regulated protein kinase
  • P38 mitogenactivated protein kinase
  • Protein phosphatase 2 a

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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