NOXA Accentuates Apoptosis Induction by a Novel Histone Deacetylase Inhibitor
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 h...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-07-01
|
| Series: | Cancers |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6694/15/14/3650 |
| _version_ | 1797589895380729856 |
|---|---|
| author | Ramy Ashry Al-Hassan M. Mustafa Kristin Hausmann Michael Linnebacher Susanne Strand Wolfgang Sippl Matthias Wirth Oliver H. Krämer |
| author_facet | Ramy Ashry Al-Hassan M. Mustafa Kristin Hausmann Michael Linnebacher Susanne Strand Wolfgang Sippl Matthias Wirth Oliver H. Krämer |
| author_sort | Ramy Ashry |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T01:13:36Z |
| format | Article |
| id | doaj.art-66b873db16c94c1489496d35ed6e0587 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-11T01:13:36Z |
| publishDate | 2023-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-66b873db16c94c1489496d35ed6e05872023-11-18T18:42:11ZengMDPI AGCancers2072-66942023-07-011514365010.3390/cancers15143650NOXA Accentuates Apoptosis Induction by a Novel Histone Deacetylase InhibitorRamy Ashry0Al-Hassan M. Mustafa1Kristin Hausmann2Michael Linnebacher3Susanne Strand4Wolfgang Sippl5Matthias Wirth6Oliver H. Krämer7Institute of Toxicology, University Medical Centre Mainz, 55131 Mainz, GermanyInstitute of Toxicology, University Medical Centre Mainz, 55131 Mainz, GermanyDepartment of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther-University of Halle-Wittenberg, 06120 Halle (Saale), GermanyClinic of General Surgery, Molecular Oncology and Immunotherapy, Rostock University Medical Center, 18057 Rostock, GermanyDepartment of Internal Medicine I, Molecular Hepatology, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, GermanyDepartment of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther-University of Halle-Wittenberg, 06120 Halle (Saale), GermanyDepartment of Hematology, Oncology and Cancer Immunology, Charité—Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, GermanyInstitute of Toxicology, University Medical Centre Mainz, 55131 Mainz, GermanyEpigenetic 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.https://www.mdpi.com/2072-6694/15/14/3650apoptosiscolon cancerHDACHDACiNOXApancreatic cancer |
| spellingShingle | Ramy Ashry Al-Hassan M. Mustafa Kristin Hausmann Michael Linnebacher Susanne Strand Wolfgang Sippl Matthias Wirth Oliver H. Krämer NOXA Accentuates Apoptosis Induction by a Novel Histone Deacetylase Inhibitor Cancers apoptosis colon cancer HDAC HDACi NOXA pancreatic cancer |
| title | NOXA Accentuates Apoptosis Induction by a Novel Histone Deacetylase Inhibitor |
| title_full | NOXA Accentuates Apoptosis Induction by a Novel Histone Deacetylase Inhibitor |
| title_fullStr | NOXA Accentuates Apoptosis Induction by a Novel Histone Deacetylase Inhibitor |
| title_full_unstemmed | NOXA Accentuates Apoptosis Induction by a Novel Histone Deacetylase Inhibitor |
| title_short | NOXA Accentuates Apoptosis Induction by a Novel Histone Deacetylase Inhibitor |
| title_sort | noxa accentuates apoptosis induction by a novel histone deacetylase inhibitor |
| topic | apoptosis colon cancer HDAC HDACi NOXA pancreatic cancer |
| url | https://www.mdpi.com/2072-6694/15/14/3650 |
| work_keys_str_mv | AT ramyashry noxaaccentuatesapoptosisinductionbyanovelhistonedeacetylaseinhibitor AT alhassanmmustafa noxaaccentuatesapoptosisinductionbyanovelhistonedeacetylaseinhibitor AT kristinhausmann noxaaccentuatesapoptosisinductionbyanovelhistonedeacetylaseinhibitor AT michaellinnebacher noxaaccentuatesapoptosisinductionbyanovelhistonedeacetylaseinhibitor AT susannestrand noxaaccentuatesapoptosisinductionbyanovelhistonedeacetylaseinhibitor AT wolfgangsippl noxaaccentuatesapoptosisinductionbyanovelhistonedeacetylaseinhibitor AT matthiaswirth noxaaccentuatesapoptosisinductionbyanovelhistonedeacetylaseinhibitor AT oliverhkramer noxaaccentuatesapoptosisinductionbyanovelhistonedeacetylaseinhibitor |