c-Myc inhibition negatively impacts lymphoma growth.
BACKGROUND
Proto-oncogene c-Myc dysregulation is commonly found in aggressive tumors. Dysregulation is central to lymphomagenesis in Burkitt lymphoma and other non-Hodgkin's lymphomas. This suggests targeting c-Myc as a treatment for myc-associated malignancies.


METHODS
Microarrays showed c-Myc dysregulation in a B-lymphoblastoid line, TIB-215. This was confirmed by real-time reverse transcriptase-polymerase chain reaction (RT-PCR) and extended to 3 additional Burkitt lymphoma lines. Growth effects of a c-Myc inhibitor, compound 10058-F4, were determined in these 4 lines using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide analyses and direct cell counts. Drug effects on c-Myc gene expression levels were measured using minor groove binding-TaqMan real-time reverse transcriptase-polymerase chain reaction. Drug specificity was analyzed in rat c-Myc knockout (-/-) and Myc-transfected cells.


RESULTS
c-Myc dysregulation was shown to be cell-cycle independent without rapid decay of c-Myc mRNA levels in all 4 lines. Using a c-Myc inhibitor, we found that growth inhibition was time- and dose-dependent. This inhibition caused unexpected downregulation (> or =65%) of c-Myc mRNAs.


CONCLUSIONS
The inhibition of c-Myc decreased growth in aggressive lymphoma cells. This mechanism included c-Myc mRNA downregulation and dissociation of c-Myc/Max protein heterodimer. These results support targeting c-Myc in tumors with high morbidity and mortality.
Gomez-Curet
Ilsa
I
Nemours Biomedical Research, Molecular Genetics, Cellular and Tissue Transplantation, Wilmington, DE 19803, USA.
Perkins
R Serene
RS
Bennett
Ryan
R
Feidler
Katherine L
KL
Dunn
Stephen P
SP
Krueger
Leslie J
LJ
D000818:Animals; D002051:Burkitt Lymphoma / Q000235:genetics* / Q000473:pathology; D015536:Down-Regulation; D005347:Fibroblasts; D020869:Gene Expression Profiling; D004854:Herpesvirus 4, Human; D020411:Oligonucleotide Array Sequence Analysis; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000473:pathology; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013778:Tetrazolium Salts; D013844:Thiazoles / Q000819:agonists; D014407:Tumor Cells, Cultured
C524814:5-(4-ethylbenzylidene)-2-thioxothiazolidin-4-one; C000715470:MAS1 protein, human; C489427:MYC protein, human; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D013778:Tetrazolium Salts; D013844:Thiazoles; C022616:thiazolyl blue