PRIMA‐1 induces apoptosis in acute myeloid leukaemia cells with <i>p53</i> gene deletion

Nahi, Hareth; Merup, Mats; Lehmann, Sören; Bengtzén, Sofia; Möllgård, Lars; Selivanova, Galina; Wiman, Klas G.; Paul, Christer

doi:10.1111/j.1365-2141.2005.05851.x

Cited by 56 publications

(48 citation statements)

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“…The enzyme ATM phosphorylates p53, creating a stabilized molecule with enhanced transcriptional activity (Banin et al, 1998), (Lambert et al, 1998). Notably, samples with ATM deletion were more sensitive to RITA than TP53-deleted samples, a result in line with an earlier observation that RITA has a direct effect on p53 without a need for its phosphorylation (Issaeva et al, 2004).In a previous study, we showed that PRIMA-1 was more toxic to both AML and CLL cells with mutated TP53 compared with cells with wt p53 (Nahi et al, 2004(Nahi et al, , 2006. In the present study, this was confirmed in AML, with PRIMA-1 having a fivefold lower IC50 in samples with )17.…”

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confidence: 83%

Mutated and non‐mutated TP53 as targets in the treatment of leukaemia

et al. 2008

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SummaryTP53 is mutated in 10-20% of cases of chronic lymphocytic leukaemia (CLL) and 3-8% of cases of acute myeloid leukaemia (AML). Recently, two classes of compounds that restore the function of p53 in tumours have been described. PRIMA-1 (p53-dependent reactivation and induction of massive apoptosis) restores the wild-type conformation of mutant TP53, whereas RITA (reactivation of p53 and induction of tumour cell apoptosis) increases intracellular levels of p53. We evaluated the effects of RITA alone and in combination with PRIMA-1 or conventional cytostatics on leukaemic cells isolated from AML and CLL patients. AML samples with )17, which are more resistant to daunorubicin and cytarabine compared with samples without )17, were effectively killed by PRIMA-1. RITA, which stabilizes the function of wild-type p53, induced apoptosis in AML cells. In contrast to that seen with PRIMA-1, AML patient samples without )17 were significantly more sensitive to RITA. Similarly, RITA exerted dosedependent apoptosis and cytotoxicity in CLL cells, which was significantly more pronounced in samples without hemizygous TP53 deletion. Notably, a synergistic effect was observed in all CLL samples with RITA and fludarabine in combination. In both AML and CLL cells exposure to RITA resulted in induction of intracellular p53. We conclude that small molecules targeting p53 might be of clinical importance in the future for treating drug-resistant leukaemia.Keywords: PRIMA, RITA, )17, acute myeloid leukaemia, chronic lymphocytic leukaemia. (Xue et al, 2007). Thus, in vivo models provide firm support to the idea of p53 reactivation for treatment of cancer. Reinstating p53 appears to be feasible, since the p53 protein is usually expressed in tumours, although it is functionally inert.Different strategies of p53 rescue for the selective elimination of tumours can be envisioned, depending on the type of p53 inactivation. In tumours carrying wt TP53 its function can be inhibited by HDM2 (MDM2 in mice) (Momand et al, 1992). HDM2 forms a complex with p53 protein by binding to its amino terminus, leading to proteasomal degradation of p53 (Chene, 2003) (Banin et al, 1998). DNA damage decreases the activity of HDM2 and the interaction between HDM2 and p53, which eventually results in stabilization of p53 (Lakin & Jackson, 1999), (Vogelstein et al, 2000) via phosphorylation of both p53 and HDM2 by the protein kinase ATM (Kojima et al, 2005).Recently, two small molecules that can restore the tumour suppressor function of p53 in cancer cells have been described. They were identified after screening of the NCI diversity set chemical library. RITA (reactivation of p53 and induction of tumour cell apoptosis; 2AE5-bis (5-hydroxymethyl-2-thienyl) furan) (Bates & Vousden, 1999) was selected by using a pair of isogenic cell lines with different p53 status. RITA binds to the p53 N-terminal domain and induces its accumulation in tumour cells lines, increasing its half-life by preventing p53-HDM2 interaction. RITA exerts tumour suppression in tumours with ...

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confidence: 83%

Mutated and non‐mutated TP53 as targets in the treatment of leukaemia

et al. 2008

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“…Our further studies of PRIMA-1 and its structural analog PRIMA-1 MET (APR-246) showed that these compounds inhibit human xenograft tumor growth in SCID mice (Bykov et al, , 2005b and growth of mouse tumors in a syngeneic host (Zache et al, 2008b). They also show potent effect on primary human acute myeloid leukemia and chronic lymphoid leukemia cells (Nahi et al, 2004(Nahi et al, , 2006. Furthermore, we showed that PRIMA-1 MET (APR-246) is able to synergize with certain chemotherapeutic drugs, including adriamycin and cisplatin (Bykov et al, 2005b).…”

Section: Screening For Mutant P53-reactivating Compoundsmentioning

confidence: 86%

Pharmacological reactivation of mutant p53: from protein structure to the cancer patient

2010

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“…In this regard, interesting results about the substance PRIMA-1 (p53-dependent reactivation and induction of massive apoptosis) were published recently. 39 Furthermore, the latest results of research showed improvement in the in vitro drug chemosensitivity in p53-deleted cells after coincubation of RITA (reactivation of p53 and induction of tumor cell apoptosis) and PRIMA-1. 40 …”

Section: Discussionmentioning

confidence: 99%

The prognostic impact of 17p (p53) deletion in 2272 adults with acute myeloid leukemia

et al. 2009

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Loss of p53Fa tumor suppressor gene located on the short arm of chromosome 17 (band 17p13.1)Fwas detected in 105 out of 2272 (5%) adult acute myeloid leukemia (AML) patients who took part in the Study Alliance Leukemia AML96 and AML2003 multi center trials. There were 85 patients with 17p (p53) deletion with multiple aberrations and 20 patients with a 17p (p53) deletion as single aberration or with only one additional chromosomal abnormality. None of the p53-deleted patients displayed additional low-risk aberrations, like t(8;21) or inv(16). Significant positive association between p53 deletion and other high-risk factors was identified for del(5q) (Po0.001), À5 (Po0.001) and À7 (Po0.05). The molecular risk factors FLT3-ITD and NPM1 mutation showed an inverse correlation to the p53 deletion in complex aberrant patients (Po0.001). The multivariate analysis revealed p53 deletion without multiple aberrations as an independent negative prognostic factor for disease-free survival (Po0.001), relapse risk (P ¼ 0.028) and overall survival (Po0.001). Thus, the single p53 deletion should be considered as a high-risk aberration for future risk-adapted treatment strategies in AML.

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PRIMA‐1 induces apoptosis in acute myeloid leukaemia cells with p53 gene deletion

Cited by 56 publications

References 33 publications

Mutated and non‐mutated TP53 as targets in the treatment of leukaemia

Mutated and non‐mutated TP53 as targets in the treatment of leukaemia

Pharmacological reactivation of mutant p53: from protein structure to the cancer patient

The prognostic impact of 17p (p53) deletion in 2272 adults with acute myeloid leukemia

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