Favorable neuroblastoma genes and molecular therapeutics of neuroblastoma.
OBJECTIVE
Neuroblastoma (NB) is a common pediatric solid tumor that exhibits a striking clinical bipolarity: favorable and unfavorable. Favorable NB genes (EPHB6, EFNB2, EFNB3, NTRK1, and CD44) are genes whose high-level expression predicts favorable NB outcome, and forced expression of these genes inhibits growth of unfavorable NB cells. In this study, we investigated whether favorable NB gene expression could be augmented in unfavorable NB cells by chemical compounds and whether an increased expression of these genes was associated with suppression of NB growth and metastasis.


RESULTS
We found that inhibitors of DNA methylation [5-aza-2'-deoxycytidine (5AdC)], histone deacetylase (HDAC) [4-phenylbutyrate (4PB)], and proteasome (MG262) enhanced the expression of favorable NB genes in NB cell lines and inhibited the growth of these cells in vitro (P < 0.0005). The growth-inhibitory effects of 5AdC and 4PB in vitro were in part due to caspase-dependent cell death and inhibition of DNA synthesis. Administration of 5AdC and/or 4PB also suppressed growth of subcutaneous NB xenografts in nude mice (P < 0.001), which was accompanied by enhanced favorable NB gene expression and an increase in apoptosis. Moreover, 4PB suppressed bone marrow and liver metastases of NB cells in severe combined immunodeficient/Beige mice (P = 0.007 and P = 0.008, respectively). The growth-suppressive activity of HDAC inhibitors on NB was further confirmed by the efficacy of trichostatin A, a potent and specific HDAC inhibitor.


CONCLUSIONS
Collectively, these observations further emphasize the link between the elevated favorable NB gene expression and a benign phenotype of NB.
Tang
Xao X
XX
Divisions of Neurology, Surgery Research, and Pathology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
Robinson
Marjorie E
ME
Riceberg
Justin S
JS
Kim
David Y
DY
Kung
Bing
B
Titus
Tracy B
TB
Hayashi
Satoshi
S
Flake
Alan W
AW
Carpentieri
David
D
Ikegaki
Naohiko
N
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D001897:Boronic Acids / Q000627:therapeutic use; D020169:Caspases / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors; D000077209:Decitabine; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000627:therapeutic use; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000235:genetics*; D009447:Neuroblastoma / Q000235:genetics*; D010654:Phenylbutyrates / Q000627:therapeutic use; D061988:Proteasome Inhibitors; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D001897:Boronic Acids; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C423917:MG 262; D009363:Neoplasm Proteins; D010654:Phenylbutyrates; D061988:Proteasome Inhibitors; C012589:trichostatin A; D000077209:Decitabine; C075773:4-phenylbutyric acid; D004247:DNA; D015254:DNA Modification Methylases; D020169:Caspases; D001374:Azacitidine