Stabilized Peptide HDAC Inhibitors Derived from HDAC1 Substrate H3K56 for the Treatment of Cancer Stem-Like Cells In Vivo.

Abstract

FDA-approved HDAC inhibitors exhibit dose-limiting adverse effects; thus, we sought to improve the therapeutic windows for this class of drugs. In this report, we describe a new class of peptide-based HDAC inhibitors derived from the HDAC1-specific substrate H3K56 with improved nonspecific toxicity compared with traditional small-molecular inhibitors. We showed that our designed peptides exerted superior antiproliferation effects on cancer stem-like cells with minimal toxicity to normal cells compared with the small-molecular inhibitor SAHA, which showed nonspecific toxicity to normal and cancer cells. These peptide inhibitors also inactivated cellular HDAC1 and HDAC6 and disrupted the formation of the HDAC1, LSD1, and CoREST complex. In ovarian teratocarcinoma (PA-1) and testicular embryonic carcinoma (NTERA-2) cell xenograft animal models (5 mice/group, 50 mg/kg, every other day, intraperitoneal injection), these peptides inhibited tumor growth by 80% to 90% with negligible organ (heart, liver, spleen, lung, kidney, brain) lesions. These results represent the first attempt to design chemically stabilized peptide inhibitors to investigate HDAC inhibition in cancer stem-like cells. These novel peptide inhibitors have significantly enhanced therapeutic window and offer promising opportunities for cancer therapy. SIGNIFICANCE: Selective antiproliferative effects of stabilized peptide HDAC inhibitors toward cancer stem-like cells provide a therapeutic alternative that avoids high nonspecific toxicity of current drugs.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/8/1769/F1.large.jpg.

• Authors: Dongyuan Wang, Wenjun Li, Rongtong Zhao, Longjian Chen, Na Liu, Yuan Tian, Hui Zhao, Mingsheng Xie, Fei Lu, Qi Fang, Wei Liang, Feng Yin, Zigang Li
• Journal: Cancer research (Cancer Res) Vol. 79 Issue 8 Pg. 1769-1783 (04 15 2019) ISSN: 1538-7445 [Electronic] United States
• PMID: 30842103 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2019 American Association for Cancer Research.

Chemical References

• Histone Deacetylase Inhibitors
• Histones
• Peptide Fragments
• HDAC1 protein, human
• Histone Deacetylase 1
• Lysine

Topics

• Animals
• Apoptosis
• Cell Cycle
• Cell Movement
• Cell Proliferation
• Female
• Histone Deacetylase 1 (antagonists & inhibitors)
• Histone Deacetylase Inhibitors (chemistry, pharmacology)
• Histones (chemistry, metabolism)
• Humans
• Lysine (chemistry, metabolism)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Neoplasms (drug therapy, enzymology, pathology)
• Neoplastic Stem Cells (drug effects, enzymology, pathology)
• Peptide Fragments (chemistry, pharmacology)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays