P-TEFb inhibitors interfere with activation of p53 by DNA-damaging agents.
Tumor suppressor p53 is stabilized in response to gamma-irradiation or treatment with DNA-damaging agents, and as a result p53 transcriptionally activates its targets leading to cell-cycle arrest or apoptosis. P-TEFb (positive transcription elongation factor b) inhibitors such as flavopiridol or 4-amino-6-hydrazino-7-b-d-ribofuranosyl-7H-pyrrolo[2,3-d]-pyrimidine-5-carboxamide (ARC) upregulate p53 protein levels, but inhibit the expression of its targets p21 and hdm2. DNA-damaging agents, doxorubicin and cisplatin are being used in combination with P-TEFb inhibitor flavopiridol in clinical trials for the treatment of some cancer patients. In this study, we found that P-TEFb inhibitors block the phosphorylation of p53 induced by doxorubicin. Furthermore, treatment of cells with P-TEFb inhibitors together with doxorubicin inhibits doxorubicin-induced binding of p53 to DNA and p53 transcriptional activity. These data suggest that P-TEFb inhibitors may antagonize the activation of p53 by DNA-damaging agents in tumors with wild-type p53.
Radhakrishnan
S K
SK
Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
Bhat
U G
UG
Halasi
M
M
Gartel
A L
AL
D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D004249:DNA Damage / Q000187:drug effects*; D004273:DNA, Neoplasm / Q000187:drug effects*; D005419:Flavonoids / Q000494:pharmacology; D016158:Genes, p53 / Q000187:drug effects*; D045325:HCT116 Cells; D006801:Humans; D009705:Nucleosides / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology; D042925:Positive Transcriptional Elongation Factor B / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*
C509961:4-amino-6-hydrazino-7-beta-D-ribofuranosyl-7H-pyrrolo(2,3-d)-pyrimidine-5-carboxamide; D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D005419:Flavonoids; D009705:Nucleosides; D010880:Piperidines; D011743:Pyrimidines; D016159:Tumor Suppressor Protein p53; C077990:alvocidib; D042925:Positive Transcriptional Elongation Factor B