Visit our Expo - Redox and Inflammation signaling 2012

Session X : Cell death in cancer Poster X, 76
Modulation of p53 transcriptional activity by PRIMA-1 and Pifithrin-alpha : effects on
staurosporine-induced apoptosis of wild-type and mutated p53 epithelial cells.
Magali Nicolier, Jean-François Charlot, Jean-Luc Prétet and Christiane Mougin.
IFR133, EA 3181, Carcinogenèse épithéliale, UFR Médecine et Pharmacie, 19 rue
Ambroise Paré, 25000 Besançon, France. Email : magali.nicolier@univ-fcomte.fr
The p53, a specific DNA-binding transcription factor, triggers multiple biological
responses including cell cycle arrest and apoptosis. Inactivation of p53 functions by mutations
or by viral oncoproteins such as E6 from high risk papillomavirus (HPV) is a common event
in many human cancers. New chemotherapeutic approaches consist in the restoration of
apoptosis through refolding p53 mutants by PRIMA-1 (p53 reactivation and induction of
massive apoptosis). As a result, PRIMA-1 restores the transcriptional activity of mutated p53
(p53mt). Anti-cancer therapies also damage surrounding normal tissues which highly express
wild-type p53 (p53wt). That is why Pifithrin-alpha (p-fifty three inhibitor), a chemical
inhibitor of p53wt, has been proposed as an adjunct to protect normal cells from otherwise
lethal doses of chemo/radiotherapy.
Recently, we argued for a major role of p53 in staurosporine (ST)-induced apoptosis of
immortalized epithelial cells, according to p53 status (wt or mt) [Charlot et al., Apoptosis
2004]. Here, we investigated the effects of PRIMA-1 and Pifithrin-alpha on ST-induced
apoptosis of 5 different immortalized cell lines with variable p53 status (p53wt HeLa HPV
18+ and CaSki HPV 16+ cells ; p53mt C33-A cells; p53-/- SaOs-2 cells) [Charlot, Nicolier et
al., Apoptosis, in press]. As expected, PRIMA-1 has no effect on p53wt or p53-/- cells. On the
other hand, it increases p21 and Bax expression, mitochondrial membrane potential
dissipation and DNA fragmentation of p53mt cells. By contrast, Pifithrin-alpha does not
modify ST-induced apoptosis of p53mt and p53-/- cells but readily decreases the apoptosis of
cells harbouring a transcriptionnally active p53.
These data strength the evidence that PRIMA-1 could increase ST efficiency in tumors with
mutant p53. Moreover, Pifithrin-alpha could be used in combination with ST and PRIMA-1 to
prevent side effects of anti-tumor therapies on healthy tissues.
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