Diarylidenylpiperidones, H-4073 and HO-3867, Induce G2/M Cell-Cycle Arrest, Apoptosis and Inhibit STAT3 Phosphorylation in Human Pancreatic Cancer Cells.

Abstract

Pancreatic cancer has a 5-year survival rate below 10% and the treatment options are limited. Signal transducer and activator of transcription (STAT3) is a constitutively expressed protein in human pancreatic cancers and is associated with their poor prognosis. Targeting of STAT3 signaling using novel therapeutic agents is a potential strategy for pancreatic cancer treatment. Diarylidenylpiperidone (DAP) compounds, such as H-4073 and HO-3867, have been shown to be STAT3 inhibitors in several human ovarian cancers. Particularly, HO-3867 is an N-hydroxypyrroline derivative of DAP that has targeted cytotoxicity toward cancer cells without affecting healthy cells. In the present study, we evaluated the anticancer efficacy of H-4073 and HO-3867 in a human pancreatic cell line (AsPC-1). We found that both the compounds exhibited potential cytotoxicity to AsPC-1 cells by inducing G2/M cell-cycle arrest, apoptosis, and cell death, by mitochondrial damage and inhibition of STAT3 phosphorylation. In summary, H-4073 and HO-3867 are cytotoxic to AsPC-1 cells and seem to act through similar mechanisms, including STAT3 inhibition, cell-cycle arrest, and apoptosis.

• Authors: Jesse M Mast, Dan Tse, Kevin Shee, M Lakshmi Kuppusamy, Maciej M Kmiec, Tamás Kálai, Periannan Kuppusamy
• Journal: Cell biochemistry and biophysics (Cell Biochem Biophys) Vol. 77 Issue 2 Pg. 109-119 (Jun 2019) ISSN: 1559-0283 [Electronic] United States
• PMID: 31089934 (Publication Type: Journal Article)

Chemical References

• (3,5-bis((4-fluorophenyl)methylidene)-1-((1-hydroxy-2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrol-3-yl)methyl)piperidin-4-one)
• Biomarkers, Tumor
• Piperidones
• Reactive Oxygen Species
• STAT3 Transcription Factor
• Cyclin D1
• Proto-Oncogene Proteins c-akt

Topics

• Apoptosis (drug effects)
• Biomarkers, Tumor (metabolism)
• Cell Line, Tumor
• Cyclin D1 (metabolism)
• G2 Phase Cell Cycle Checkpoints (drug effects)
• Humans
• M Phase Cell Cycle Checkpoints (drug effects)
• Mitochondria (drug effects, metabolism)
• Pancreatic Neoplasms (metabolism, pathology)
• Phosphorylation (drug effects)
• Piperidones (chemistry, pharmacology)
• Proto-Oncogene Proteins c-akt (metabolism)
• Reactive Oxygen Species (metabolism)
• STAT3 Transcription Factor (antagonists & inhibitors, metabolism)