2. Academic Validation
  3. NOXA Accentuates Apoptosis Induction by a Novel Histone Deacetylase Inhibitor

NOXA Accentuates Apoptosis Induction by a Novel Histone Deacetylase Inhibitor

  • Cancers (Basel). 2023 Jul 17;15(14):3650. doi: 10.3390/cancers15143650.
Ramy Ashry 1 2,  Al-Hassan M Mustafa 1 3,  Kristin Hausmann 4,  Michael Linnebacher 5,  Susanne Strand 6,  Wolfgang Sippl 4,  Matthias Wirth 7 8 9,  Oliver H Krämer 1
Affiliations

Affiliations

  • 1 Institute of Toxicology, University Medical Centre Mainz, 55131 Mainz, Germany.
  • 2 Department of Oral Pathology, Faculty of Dentistry, Mansoura University, Mansoura 35516, Egypt.
  • 3 Department of Zoology, Faculty of Science, Aswan University, Aswan 81528, Egypt.
  • 4 Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther-University of Halle-Wittenberg, 06120 Halle (Saale), Germany.
  • 5 Clinic of General Surgery, Molecular Oncology and Immunotherapy, Rostock University Medical Center, 18057 Rostock, Germany.
  • 6 Department of Internal Medicine I, Molecular Hepatology, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.
  • 7 Department of Hematology, Oncology and Cancer Immunology, Charité-Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, Germany.
  • 8 Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, 37075 Göttingen, Germany.
  • 9 German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), 69120 Heidelberg, Germany.
PMID: 37509312 DOI: 10.3390/cancers15143650
Abstract

Epigenetic modifiers of the histone deacetylase (HDAC) family are often dysregulated in Cancer cells. Experiments with small molecule HDAC inhibitors (HDACi) have proven that HDACs are a vulnerability of transformed cells. We evaluated a novel hydroxamic acid-based HDACi (KH16; termed yanostat) in human pancreatic ductal adenocarcinoma (PDAC) cells, short- and long-term cultured colorectal Cancer (CRC) cells, and retinal pigment epithelial cells. We show that KH16 induces cell cycle arrest and Apoptosis, both time and dose dependently in PDAC and CRC cells. This is associated with altered expression of BCL2 family members controlling intrinsic Apoptosis. Recent data illustrate that PDAC cells frequently have an altered expression of the pro-apoptotic BH3-only protein NOXA and that HDACi induce an accumulation of NOXA. Using PDAC cells with a deletion of NOXA by CRISPR-Cas9, we found that a lack of NOXA delayed Apoptosis induction by KH16. These results suggest that KH16 is a new chemotype of hydroxamic acid HDACi with superior activity against solid tumor-derived cells. Thus, KH16 is a scaffold for future research on compounds with nanomolar activity against HDACs.

Keywords

HDAC; HDACi; NOXA; apoptosis; colon cancer; pancreatic cancer.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-155840
    98.62%, HDACi Inhibitor