A novel histone deacetylase inhibitor exhibits antitumor activity via apoptosis induction, F-actin disruption and gene acetylation in lung cancer.

Abstract

BACKGROUND:

Lung cancer is the leading cause of cancer mortality worldwide, yet the therapeutic strategy for advanced non-small cell lung cancer (NSCLC) is limitedly effective. In addition, validated histone deacetylase (HDAC) inhibitors for the treatment of solid tumors remain to be developed. Here, we propose a novel HDAC inhibitor, OSU-HDAC-44, as a chemotherapeutic drug for NSCLC.

METHODOLOGY/PRINCIPAL FINDINGS:

The cytotoxicity effect of OSU-HDAC-44 was examined in three human NSCLC cell lines including A549 (p53 wild-type), H1299 (p53 null), and CL1-1 (p53 mutant). The antiproliferative mechanisms of OSU-HDAC-44 were investigated by flow cytometric cell cycle analysis, apoptosis assays and genome-wide chromatin-immunoprecipitation-on-chip (ChIP-on-chip) analysis. Mice with established A549 tumor xenograft were treated with OSU-HDAC-44 or vehicle control and were used to evaluate effects on tumor growth, cytokinesis inhibition and apoptosis. OSU-HDAC-44 was a pan-HDAC inhibitor and exhibits 3-4 times more effectiveness than suberoylanilide hydroxamic acid (SAHA) in suppressing cell viability in various NSCLC cell lines. Upon OSU-HDAC-44 treatment, cytokinesis was inhibited and subsequently led to mitochondria-mediated apoptosis. The cytokinesis inhibition resulted from OSU-HDAC-44-mediated degradation of mitosis and cytokinesis regulators Auroroa B and survivin. The deregulation of F-actin dynamics induced by OSU-HDAC-44 was associated with reduction in RhoA activity resulting from srGAP1 induction. ChIP-on-chip analysis revealed that OSU-HDAC-44 induced chromatin loosening and facilitated transcription of genes involved in crucial signaling pathways such as apoptosis, axon guidance and protein ubiquitination. Finally, OSU-HDAC-44 efficiently inhibited A549 xenograft tumor growth and induced acetylation of histone and non-histone proteins and apoptosis in vivo.

CONCLUSIONS/SIGNIFICANCE:

OSU-HDAC-44 significantly suppresses tumor growth via induction of cytokinesis defect and intrinsic apoptosis in preclinical models of NSCLC. Our data provide compelling evidence that OSU-HDAC-44 is a potent HDAC targeted inhibitor and can be tested for NSCLC chemotherapy.

• Authors: Yen-An Tang, Wei-Ling Wen, Jer-Wei Chang, Tzi-Tang Wei, Yi-Hung Carol Tan, Santosh Salunke, Chien-Tien Chen, Ching-Shih Chen, Yi-Ching Wang
• Journal: PloS one (PLoS One) Vol. 5 Issue 9 Pg. e12417 (Sep 14 2010) ISSN: 1932-6203 [Electronic] United States
• PMID: 20856855 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 4-(2,2-dimethyl-4-phenylbutyrylamino)-N-hydroxybenzamide
• Actins
• Antineoplastic Agents
• Benzamides
• Histone Deacetylase Inhibitors
• Hydroxamic Acids

Topics

• Acetylation (drug effects)
• Actins (metabolism)
• Animals
• Antineoplastic Agents (administration & dosage)
• Apoptosis (drug effects)
• Benzamides (administration & dosage)
• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics, metabolism, physiopathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Disease Models, Animal
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Histone Deacetylase Inhibitors (administration & dosage)
• Humans
• Hydroxamic Acids (administration & dosage)
• Lung Neoplasms (drug therapy, genetics, metabolism, physiopathology)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Xenograft Model Antitumor Assays