Related Experiment Video
Updated: Jun 12, 2026
Assays for Validating Histone Acetyltransferase Inhibitors
Published on: August 6, 2020
Histone Deacetylase Inhibitor M344 Inhibits Cell Proliferation and Induces Apoptosis in Human THP-1 Leukemia Cells
1Department of Internal medicine and Karmanos Cancer Institute, Wayne State University School of Medicine, 550 E. Canfield, Detroit, MI 48201.
Abstract:
Histone acetylation plays an important role in the silencing and activation of genes involved in tumoregenesis. Trichostatin A, originally identified as an anti-fungal drug, is a potent inhibitor of histone deacetylase (HDAC) with potential anti-tumor activity. In this study, we investigated the effect of M344, an amide analogues of trichostatin A, on the growth and differentiation of THP-1 human leukemia cells. We showed that at low doses, (< 0.2 muM), M344 could inhibit the growth of THP-1 cells at G1 phase in vitro with low cytotoxic effect. Low dose of M344 exerted some differentiating effect on THP-1 cells as judged by the expression of c-fms proto-oncogene (M-CSF receptor) and appearance of adherent cells. Growth arrest induced by M344 is associated with increased levels of cyclin-dependent protein kinase inhibitor p21 and cyclin E, in agreement with G1 phase arrest. At higher doses (2 muM), M344 could induce THP-1 cells to undergo apoptosis, which was associated with the cleavage of PARP, cytochrome c release and activation of both caspases-8, -9, followed by the activation of caspase-3. In addition, M344 could increase the levels of pro-apoptotic protein Bax but decreased the levels of anti-apoptotic protein XIAP. M344 is a potent activator of NF-kappaB transcription factor. RT-PCR assay showed that the M344 could transiently increase IL-1 expression yet markedly decreased TNF-alpha expression. Our results show that M344 is a potent growth inhibitor and inducer of apoptosis in human leukemia cells and suggest potential therapeutic strategies of HDAC inhibitors for patients with leukemias.
Insights
M344, a histone deacetylase inhibitor, effectively inhibits leukemia cell growth and induces apoptosis. This compound shows potential as a therapeutic strategy for leukemia patients.
Area of Science:
- Epigenetics and Cancer Biology
- Molecular Oncology
- Pharmacology
Background:
- Histone acetylation regulates gene expression in tumoregenesis.
- Histone deacetylase (HDAC) inhibitors, like Trichostatin A, show anti-tumor potential.
- M344 is an amide analog of Trichostatin A, investigated for its effects on leukemia.
Purpose of the Study:
- To investigate the effects of M344 on the growth and differentiation of THP-1 human leukemia cells.
- To determine the mechanisms by which M344 affects leukemia cell proliferation and survival.
- To explore the therapeutic potential of M344 as an HDAC inhibitor for leukemia treatment.
Main Methods:
- Cell culture of THP-1 human leukemia cells.
- Treatment with varying doses of M344 (low dose < 0.2 muM, high dose 2 muM).
- Analysis of cell cycle progression (G1 arrest), differentiation markers (c-fms), apoptosis (PARP cleavage, cytochrome c release, caspase activation), gene expression (Bax, XIAP, IL-1, TNF-alpha), and transcription factor activation (NF-kappaB).
Main Results:
- Low-dose M344 inhibited THP-1 cell growth at G1 phase with low cytotoxicity and induced differentiation.
- High-dose M344 induced apoptosis through intrinsic and extrinsic pathways, involving caspase activation and altered expression of apoptosis-related proteins (Bax, XIAP).
- M344 activated NF-kappaB, transiently increased IL-1, and decreased TNF-alpha expression.
Conclusions:
- M344 is a potent inhibitor of human leukemia cell growth and a strong inducer of apoptosis.
- M344 demonstrates therapeutic potential for leukemia treatment through its effects on cell cycle arrest, differentiation, and apoptosis.
- HDAC inhibitors like M344 represent promising therapeutic strategies for patients with leukemias.
Related Concept Videos
01:31The Intrinsic Apoptotic Pathway
02:34Inhibition of Cdk Activity
02:23Abnormal Proliferation