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

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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.

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Acknowledgements

This work was supported by Hungarian Research Fund Grant OTKA FK 124331 and GINOP 2.3.2-15-2016-00049.

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Authors and Affiliations

  1. Department of Radiology, Geisel School of Medicine, Dartmouth College, 1 Medical Center Drive, Lebanon, NH, 03756, USA

    Jesse M. Mast, Dan Tse, Kevin Shee, M. Lakshmi Kuppusamy, Maciej M. Kmiec & Periannan Kuppusamy

  2. Department of Institute of Organic and Medicinal Chemistry, Medical School, University of Pécs, Pécs, Hungary

    Tamás Kálai

  3. Department of Medicine, Geisel School of Medicine, Dartmouth College, 1 Medical Center Drive, Lebanon, NH, 03756, USA

    Periannan Kuppusamy

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  1. Jesse M. Mast
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Mast, J.M., Tse, D., Shee, K. et al. Diarylidenylpiperidones, H-4073 and HO-3867, Induce G2/M Cell-Cycle Arrest, Apoptosis and Inhibit STAT3 Phosphorylation in Human Pancreatic Cancer Cells. Cell Biochem Biophys 77, 109–119 (2019). https://doi.org/10.1007/s12013-019-00873-6

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