Modulation of p53 transcriptional activity by PRIMA-1 and Pifithrin-alpha on staurosporine-induced apoptosis of wild-type and mutated p53 epithelial cells.
We recently argued for a major role of p53 in staurosporine(ST)-induced apoptosis of immortalized epithelial cells, depending on their p53 status. Here, we studied the effects of PRIMA-1 (p53 reactivation and induction of massive apoptosis) and Pifithrin-alpha (p fifty-three inhibitor) in combination with ST to reinforce our previous results by respectively restoring or inhibiting the p53 transcriptional activity in different cell lines.PRIMA-1 does modify neither expression of apoptosis-related proteins nor the percentage of wild-type p53 HeLa and CaSki cells with [symbol: see text]delta psi m and DNA cleavage, whilst it increases by 45% Bax expression and apoptosis of mutated p53 C33A cells. Pifithrin-alpha, does modify neither Bax expression nor apoptosis level of C33A cells, but readily inhibits both [symbol: see text]delta psi m and DNA fragmentation of p53wt cells with decreasing Bax expression. These data support the evidence that PRIMA-1 could be a good candidate, as an anti-cancer drug targeting mutant p53, in order to increase ST efficiency. Moreover, Pifithrin-alpha could be used in combination with ST and PRIMA-1 to prevent side effects of anti-tumor therapies in cells expressing mutant P53.
Université de Franche-Comté, UFR Médecine et Pharmacie, EA 3181, IFR 133. 19 rue Ambroise Paré, 25000 Besançon, France.
J F
JF
Charlot
M
M
Nicolier
J L
JL
Prétet
C
C
Mougin
D017209:Apoptosis / Q000187:drug effects*; D052160:Benzothiazoles; D018929:Cell Culture Techniques; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002472:Cell Transformation, Viral; D004273:DNA, Neoplasm / Q000032:analysis / Q000378:metabolism; D004338:Drug Combinations; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects*; D005260:Female; D006367:HeLa Cells; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D008565:Membrane Proteins / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000494:pharmacology*; D027383:Papillomaviridae / Q000502:physiology; D019311:Staurosporine / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology*; D014050:Toluene / Q000031:analogs & derivatives* / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D052160:Benzothiazoles; D004273:DNA, Neoplasm; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C446290:PRIMA1 protein, human; D013844:Thiazoles; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D014050:Toluene; C121565:pifithrin; D019311:Staurosporine