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-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.

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Involvement of mitogen-activated protein kinase in signal transducer and activator of transcription-1 mediated differentiation induced by bortezomib in acute myeloid leukemia cells

Molecular Carcinogenesis ◽

10.1002/mc.20873 ◽

2011 ◽

Vol 52 (1) ◽

pp. 18-28 ◽

Cited By ~ 5

Author(s):

Xinglu Zhou ◽

Yanfen Fang ◽

Hui Jing ◽

Like Zhong ◽

Peihua Luo ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Protein Kinase ◽

Myeloid Leukemia ◽

Mitogen Activated Protein Kinase ◽

Leukemia Cells ◽

Signal Transducer ◽

Mitogen Activated Protein ◽

Acute Myeloid Leukemia Cells ◽

Acute Myeloid

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KIT exon 8 mutations associated with core-binding factor (CBF)–acute myeloid leukemia (AML) cause hyperactivation of the receptor in response to stem cell factor

Blood ◽

10.1182/blood-2004-06-2068 ◽

2005 ◽

Vol 105 (8) ◽

pp. 3319-3321 ◽

Cited By ~ 66

Author(s):

Tobias M. Kohl ◽

Susanne Schnittger ◽

Joachim W. Ellwart ◽

Wolfgang Hiddemann ◽

Karsten Spiekermann

Keyword(s):

Acute Myeloid Leukemia ◽

Stem Cell ◽

Stem Cell Factor ◽

Myeloid Leukemia ◽

Apoptotic Cell ◽

Mitogen Activated Protein Kinase ◽

Core Binding Factor ◽

Binding Factor ◽

Mitogen Activated Protein ◽

Acute Myeloid

AbstractKIT exon 8 mutations are located in the extracellular portion of the receptor and are strongly associated with core-binding factor (CBF)-acute myeloid leukemia (AML). To characterize the functional role of these mutants, we analyzed the proproliferative and antiapoptotic potential of 3 KIT exon 8 mutations in interleukin 3 (IL-3)-dependent Ba/F3 cells. All KIT exon 8 mutants induced receptor hyperactivation in response to stem cell factor (SCF) stimulation in terms of proliferation and resistance toward apoptotic cell death. A representative KIT exon 8 mutant showed spontaneous receptor dimerization, phosphorylation of mitogen-activated protein kinase (MAPK), and conferred IL-3-independent growth to Ba/F3 cells. MAPK and phosphatidylinositol 3-kinase (PI3-kinase) activation was essential for the phenotype of this mutant. Additionally, imatinib inhibited proliferation of KIT exon 8 mutant-expressing Ba/F3 cells. Our data show that KIT exon 8 mutations represent gain-of-function mutations and might represent a new molecular target for treatment of CBF leukemias. (Blood. 2005;105:3319-3321)

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Withanolide Metabolites Inhibit PI3K/AKT and MAPK Pro-Survival Pathways and Induce Apoptosis in Acute Myeloid Leukemia Cells

Biomedicines ◽

10.3390/biomedicines8090333 ◽

2020 ◽

Vol 8 (9) ◽

pp. 333

Author(s):

Nosheen Akhtar ◽

Muhammad Waleed Baig ◽

Ihsan-ul Haq ◽

Vinothini Rajeeve ◽

Pedro Rodriguez Cutillas

Keyword(s):

Acute Myeloid Leukemia ◽

Protein Kinase ◽

Myeloid Leukemia ◽

Therapeutic Potential ◽

Mammalian Target Of Rapamycin ◽

Enrichment Analysis ◽

Label Free ◽

Anticancer Activities ◽

Acute Myeloid Leukemia Cells ◽

Acute Myeloid

Acute myeloid leukemia (AML) is an aggressive disease and, despite advances, its treatment remains challenging. Therefore, it remains important to identify new agents for the management of this disease. Withanolides, a group of steroidal lactones found in Solanaceae plants are of potential interest due to their reported anticancer activities in different settings. In this study we investigated the anti-proliferative effects and mode of action of Solanaceae-derived withanolides in AML cell models; these metabolites include withametelin (WTH) and Coagulansin A (CoA) isolated from Datura innoxia and Withania coagluanse, respectively. Both withanolides inhibited the proliferation of AML cells and induced cell death, with WTH being more potent than CoA in the AML models tested. Quantitative label-free proteomics and phosphoproteomics were employed to define the mechanism of action of the studied withanolides. We identified and quantified 5269 proteins and 17,482 phosphosites in cells treated with WTH, CoA or vehicle control. Withanolides modulated the expression of proteins involved in regulating key cellular processes including cell cycle, metabolism, signaling, protein degradation and gene expression. Enrichment analysis of the phosphoproteomics data against kinase substrates, kinase-kinase relationships and canonical pathways showed that the withanolides decreased the activity of kinases such as phosphoinositide 3-kinase (PI3K), protein kinase B (PKB; also known as RAC-alpha serine/threonine-protein kinase or AKT), mammalian target of rapamycin (mTOR), extracellular signal-regulated protein kinase 1 and 2 (ERK1/2) and the serine/threonine-protein kinase A-Raf (ARAF), while increasing the activation of DNA repair kinases. These results indicate that withanolide metabolites have pleiotropic effects in the modulation of oncogenic pro-survival and pro-apoptotic signaling pathways that regulate the induction of apoptosis. Withanolide mediated apoptosis was confirmed by immunoblotting showing increased expression of cleaved PARP and Caspases 3, 8 and 9 as a result of treatment. Overall, our results suggest that WTH and CoA have therapeutic potential against AML with WTH exhibiting more potent effects and should be explored further.

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