Induction of G(2)/M arrest and inhibition of c-myc and p53 transcription by WP631 in Jurkat T lymphocytes.
WP631, a new DNA-binding drug that bisintercalates into DNA with high affinity, seems to be highly cytotoxic against Jurkat T lymphocytes. The purpose of this study was to gain new insights into the mechanisms by which WP631 halts proliferation in this cell type. Treating Jurkat cells with nanomolar concentrations of WP631 produced G(2)/M arrest, inhibited the transcription of c-myc and p53 genes, and induced limited apoptosis during the duration of treatment. Suppression of c-myc and p53 expression, and time-dependent decline in c-Myc and p53 protein levels, was associated with growth arrest. A weak interdependence was also found between the potent antiproliferative activity and the apoptotic response; treatment with WP631 for 24-36hr produced arrest in G(2)/M and allowed for partial DNA repair. Longer treatments with WP631 allowed some repaired cells to re-enter the cell cycle, but produced aneuploidy or apoptosis in others.
Villamarín
Silvia
S
Departamento de Biología Molecular y Celular, Instituto de Biología Molecular de Barcelona, CSIC, Jordi Girona 18-26, 08034 Barcelona, Spain.
Ferrer-Miralles
Neus
N
Mansilla
Sylvia
S
Priebe
Waldemar
W
Portugal
José
J
D003630:Daunorubicin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D016195:G2 Phase / Q000187:drug effects*; D006801:Humans; D007364:Intercalating Agents / Q000494:pharmacology*; D019169:Jurkat Cells; D008938:Mitosis / Q000187:drug effects*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014158:Transcription, Genetic / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D007364:Intercalating Agents; D016271:Proto-Oncogene Proteins c-myc; D016159:Tumor Suppressor Protein p53; C104426:WP 631; D003630:Daunorubicin