NOXA Accentuates Apoptosis Induction by a Novel Histone Deacetylase Inhibitor

被引：3

作者：

Ashry, Ramy ^{[1
,2
]}

Mustafa, Al-Hassan M. ^{[1
,3
]}

Hausmann, Kristin ^{[4
]}

Linnebacher, Michael ^{[5
]}

Strand, Susanne ^{[6
]}

Sippl, Wolfgang ^{[4
]}

Wirth, Matthias ^{[7
,8
,9
,10
,11
]}

Kraemer, Oliver H. ^{[1
]}

机构：

[1] Univ Med Ctr Mainz, Inst Toxicol, D-55131 Mainz, Germany

[2] Mansoura Univ, Fac Dent, Dept Oral Pathol, Mansoura 35516, Egypt

[3] Aswan Univ, Fac Sci, Dept Zool, Aswan 81528, Egypt

[4] Martin Luther Univ Halle Wittenberg, Inst Pharm, Dept Med Chem, D-06120 Halle, Germany

[5] Rostock Univ, Med Ctr, Clin Gen Surg Mol Oncol & Immunotherapy, D-18057 Rostock, Germany

[6] Johannes Gutenberg Univ Mainz, Univ Med Ctr, Dept Internal Med 1, Mol Hepatol, D-55131 Mainz, Germany

[7] Charite Univ Med Berlin, Freie Univ Berlin, Dept Hematol Oncol & Canc Immunol, D-10117 Berlin, Germany

[8] Humboldt Univ, D-10117 Berlin, Germany

[9] Univ Med Ctr Gottingen, Dept Gen Visceral & Pediat Surg, D-37075 Gottingen, Germany

[10] German Canc Res Ctr, D-69120 Heidelberg, Germany

[11] German Canc Consortium DKTK, D-69120 Heidelberg, Germany

来源：

CANCERS | 2023年 / 15卷 / 14期

关键词：

apoptosis; colon cancer; HDAC; HDACi; NOXA; pancreatic cancer; HDAC INHIBITORS; MECHANISMS;

D O I：

10.3390/cancers15143650

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Simple Summary Tumors in the pancreas and colon are still too often an unmet clinical problem. Cells from these cancers and normal cells have different gene expression profiles. Such dysregulation can be exploited with novel drugs that modulate the acetylation of proteins. We present KH16, a novel compound that causes protein hyperacetylation and shifts the balance of protein expression towards cell death. Promisingly, KH16 kills tumor cells but not normal cells. Moreover, KH16 is more effective than clinically well-established and currently tested drugs with a similar mode of action. Future research can focus on KH16 and compounds with a similar chemotype for anti-cancer therapy. 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.

引用

页数：18