The anti-leukemic effect of a novel histone deacetylase inhibitor MCT-1 and 5-aza-cytidine involves augmentation of Nur77 and inhibition of MMP-9 expression

H B Liu; M T Voso; D Gumiero; J Duong; J J McKendrick; A E Dear

The anti-leukemic effect of a novel histone deacetylase inhibitor MCT-1 and 5-aza-cytidine involves augmentation of Nur77 and inhibition of MMP-9 expression

Int J Oncol. 2009 Feb;34(2):573-9.

Authors

H B Liu¹, M T Voso, D Gumiero, J Duong, J J McKendrick, A E Dear

Affiliation

¹ Australian Centre for Blood Diseases, Eastern Clinical Research Unit, Monash University, and Department of Oncology, Box Hill Hospital, Melbourne, Victoria, Australia.

PMID: 19148494

Abstract

A combination of demethylating agents and histone deacetylase inhibitors (HDACi) has been proposed as a novel therapy in leukemia and myelodysplasia. In HL-60 cells azacytidine (AZA) and Metacept-1 (MCT-1), a novel HDACi augmented inhibition of cell growth and increased apoptosis. In identifying a molecular mechanism responsible for these effects MCT-1 alone and in combination with AZA induced p15INK4b, p21WAF1/CIP1 and Caspase-3 whilst attenuating Bcl-XL expression. Interestingly, MCT-1 in combination with AZA significantly induced the recently identified suppressor of leukemogenesis Nur77 and attenuated AZA-induced MMP-9 expression. The combination of MCT-1 and AZA is more effective in inhibiting leukemic cell growth and induction of apoptosis. Regulation of a recently identified tumour suppressor gene together with cell cycle, apoptosis and matrix degrading proteases may underpin the molecular mechanism responsible for these effects.

MeSH terms

Antimetabolites, Antineoplastic / therapeutic use*
Apoptosis / drug effects
Azacitidine / therapeutic use*
Cyclin-Dependent Kinase Inhibitor p15 / genetics
DNA-Binding Proteins / genetics*
Gene Expression Regulation, Enzymologic
Gene Expression Regulation, Neoplastic
HL-60 Cells / drug effects
Histone Deacetylase Inhibitors*
Humans
Hydroxamic Acids / therapeutic use*
Leukemia / drug therapy*
Matrix Metalloproteinase 9 / genetics*
Nuclear Receptor Subfamily 4, Group A, Member 1
RNA, Messenger / genetics
RNA, Neoplasm / genetics
RNA, Neoplasm / isolation & purification
Receptors, Steroid / genetics*
Reverse Transcriptase Polymerase Chain Reaction
Sulfonamides / therapeutic use*

Substances

Antimetabolites, Antineoplastic
CDKN2B protein, human
Cyclin-Dependent Kinase Inhibitor p15
DNA-Binding Proteins
Histone Deacetylase Inhibitors
Hydroxamic Acids
NR4A1 protein, human
Nuclear Receptor Subfamily 4, Group A, Member 1
RNA, Messenger
RNA, Neoplasm
Receptors, Steroid
Sulfonamides
metacept-1
Matrix Metalloproteinase 9
Azacitidine