Induction of differentiation and suppression of malignant phenotype of human neuroblastoma BE(2)-C cells by valproic acid: enhancement by combination with interferon-alpha.
Valproic acid (VPA) has been shown to induce growth-arrest and differentiation of human neuroectodermal tumors similarly to several other fatty acids. In the present study, we show that continuous VPA treatment together with Interferon-alpha (INF-alpha) synergistically inhibited cell growth of a well-established model of neuroblastoma (NB) differentiation using the human N-myc amplified cell line BE(2)-C. Suppression of tumor growth was accompanied by morphological features of neuronal differentiation and inhibition of histone deacetylase activity. Furthermore, induction of differentiation was concomitant with altered expression of genes related to malignant phenotype such as down-regulation of N-myc, induction of bcl-2 and neural cell adhesion molecule. Production of inhibitors of angiogenesis like thrombospondin-1 and activin A was up-regulated in differentiated NB cells. Treatment with VPA alone decreased the ability of BE(2)-C cells to adhere to and penetrate human endothelium. All these effects of VPA were significantly enhanced when combined with INF-alpha which on its own had little or no effect. These results suggest that combination of VPA and INF-alpha may provide a novel therapeutic strategy for NB due to enhanced inhibition of tumor cell growth, induction of tumor differentiation and suppression of malignant biology by reduced angiogenic and decreased metastatic potentials.
Cinatl
Jindrich
J
Institute for Medical Virology, Johann Wolfgang Goethe-University Medical Center, D-60596 Frankfurt am Main, Germany. cinatl@em.uni-frankfurt.de
Kotchetkov
Rouslan
R
Blaheta
Roman
R
Driever
Pablo Hernáiz
PH
Vogel
Jens Uwe
JU
Cinatl
Jaroslav
J
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D017931:DNA Primers / Q000737:chemistry; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D024202:Electrophoretic Mobility Shift Assay; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D007124:Immunoenzyme Techniques; D016898:Interferon-alpha / Q000627:therapeutic use*; D009363:Neoplasm Proteins / Q000378:metabolism; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014635:Valproic Acid / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D017931:DNA Primers; D004791:Enzyme Inhibitors; D016898:Interferon-alpha; D009363:Neoplasm Proteins; D014635:Valproic Acid