5-(4-ethylbenzylidene)-2-thioxothiazolidin-4-one and Precursor-Cell-Lymphoblastic-Leukemia-Lymphoma

The long‑term survival rate in paediatric acute lymphoblastic leukaemia (ALL) exceeds 80%; however, the outcome of adult ALL remains to be poor. Glucocorticoids (GCs) are the preferred drugs in the traditional treatment of ALL patients. In the anti‑leukaemia molecular mechanisms of GCs, c‑Myc inhibition serves a critical role. In the present study, a c‑Myc inhibitor that increased the sensitivity to GCs in NALM6 cells of the B‑cell‑ALL cell line and CEM cells of the T‑cell‑ALL cell line was investigated. The data demonstrated that 10058‑F4, a c‑Myc inhibitor, increased the growth inhibition, G0/G1 phase arrest and apoptosis of the NALM6 and CEM cells as induced by dexamethasone (DXM), a type of GC. Additionally, 10058‑F4 reinforced the decreased expressions of c‑Myc, cyclin‑dependent kinase (CDK)‑4 and CDK6 in the NALM6 and CEM cells treated with DXM. These findings indicated that DXM in combination with the c‑Myc inhibitor 10058‑F4 may be a novel, potent therapeutic strategy for the treatment of ALL.

Topics: Cell Line, Tumor; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Dexamethasone; Drug Synergism; Gene Expression Regulation, Leukemic; Humans; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Proto-Oncogene Proteins c-myc; Thiazoles

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.. 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.. 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.. 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.

Topics: Animals; Burkitt Lymphoma; Down-Regulation; Fibroblasts; Gene Expression Profiling; Herpesvirus 4, Human; Oligonucleotide Array Sequence Analysis; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Proto-Oncogene Mas; Proto-Oncogene Proteins c-myc; Rats; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tetrazolium Salts; Thiazoles; Tumor Cells, Cultured