ITF2357 interferes with apoptosis and inflammatory pathways in the HL-60 model: a gene expression study

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Histone deacetylase inhibitors (HDACi) are emerging as a therapeutic strategy in cancer.
• ITF2355, an HDACi, has demonstrated cytotoxic and pro-apoptotic effects in acute myeloid leukemia (AML) cell lines.
• The precise molecular mechanisms underlying ITF2357's action in AML require further elucidation.

Purpose of the Study:

• To investigate the molecular mechanism of action of ITF2357 in acute myeloid leukemia HL-60 cells.
• To evaluate the impact of ITF2357 on cell proliferation, apoptosis, and key molecular pathways.
• To identify potential therapeutic targets and applications for ITF2357 in AML treatment.

Main Methods:

• Cell proliferation was assessed using the methyl thiazol tetrazolium bromide (MTT) assay.
• Apoptosis was measured by Annexin V staining and mitochondrial transmembrane potential using tetramethylrhodamine ethyl ester (TMRE).
• Gene expression profiling was performed using microarray and quantitative polymerase chain reaction (qPCR), alongside flow cytometry for functional assays.

Main Results:

• ITF2357 significantly inhibited cell proliferation and induced apoptosis in HL-60 cells.
• ITF2357 modulated the expression of apoptosis-related proteins, decreasing BCL-2, MCL-1, and BCL-X, while increasing BAK.
• Microarray analysis revealed deregulation of multiple pathways, including those involving interleukin-10, interleukin-6, epidermal growth factor, peroxisome proliferator-activated receptor (PPAR), and NF-κB.

Conclusions:

• ITF2357 exerts significant anti-leukemic effects by influencing both proliferation and apoptosis in HL-60 cells.
• The drug impacts critical inflammatory and cell survival pathways, highlighting its complex mechanism of action.
• These findings support the potential clinical utility of ITF2357 in the treatment of acute myeloid leukemia.