Anti-leukemia activity of chaetocin via death receptor-dependent apoptosis and dual modulation of the histone methyl-transferase SUV39H1.

Abstract

Epigenetic deregulation is involved in acute myeloid leukemia (AML) pathogenesis and epigenetic targeting drugs are in clinical trial. Since the first results with histone-deacetylase inhibitors in AML are controversial, novel single and combined treatments need to be explored. It is tempting to combine chromatin-targeting drugs. SUV39H1, the main methyl-transferase for lysine 9 tri-methylation on histone H3, interacts with oncogenes involved in AML and acts as a transcriptional repressor for hematopoietic differentiation and immortalization. We report here that pharmacological inhibition of SUV39H1 by chaetocin induces apoptosis in leukemia cell lines in vitro and primary AML cells ex vivo, and that it interferes with leukemia growth in vivo. Chaetocin treatment upregulates reactive oxygen species (ROS) production as well as the transcription of death-receptor-related genes, in a ROS-dependent manner, leading to death receptor-dependent apoptosis. In addition to its direct inhibition by chaetocin, SUV39H1 is indirectly modulated by chaetocin-induced ROS. Accordingly, chaetocin potentiates other anti-AML drugs, in a ROS-dependent manner. The decryption of a dual mechanism of action against AML involving both direct and indirect SUV39H1 modulation represents an innovative read-out for the anticancer activity of chaetocin and for its synergy with other anti-AML drugs, suggesting new therapeutic combination strategies in AML.

• Authors: H Chaib, A Nebbioso, T Prebet, R Castellano, S Garbit, A Restouin, N Vey, L Altucci, Y Collette
• Journal: Leukemia (Leukemia) Vol. 26 Issue 4 Pg. 662-74 (Apr 2012) ISSN: 1476-5551 [Electronic] England
• PMID: 21979880 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Piperazines
• Reactive Oxygen Species
• Receptors, Death Domain
• Repressor Proteins
• chaetocin
• SUV39H1 protein, human
• Methyltransferases
• Caspases

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Caspases (physiology)
• Humans
• Leukemia, Myeloid, Acute (drug therapy, pathology)
• Methyltransferases (antagonists & inhibitors)
• Mice
• Piperazines (pharmacology)
• Reactive Oxygen Species (metabolism)
• Receptors, Death Domain (physiology)
• Repressor Proteins (antagonists & inhibitors)
• U937 Cells
• Xenograft Model Antitumor Assays