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

Abstract

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 ...

RITA Inhibits Multiple Myeloma Cell Growth through Induction of p53-Mediated Caspase-Dependent Apoptosis and Synergistically Enhances Nutlin-Induced Cytotoxic Responses

“…Increased levels of p53 in response to RITA correlated with the induction of apoptosis reported earlier (31). Activation of the p53 apoptotic pathway in MM cells was further documented by the upregulation of NOXA and GADD45A, which was confirmed and verified by microarray and qRT-PCR.…”

“…RITA has been shown to have efficacy in various solid tumors such as colon, breast, cervical, and lung carcinoma, osteosarcoma, and renal cell carcinoma (20,(26)(27)(28)(29)(30). There has been only one report describing antileukemic activity of RITA in acute myelogenous leukemia and chronic lymphocytic leukemia, which was limited to the study of the expression of p53 only (31). The role of RITA in MM has not been addressed, and little is known about the downstream effectors of the p53/MDM2 pathway in response to RITA in hematologic malignancies.…”

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

“…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 …”

The p53 pathway in hematopoiesis: lessons from mouse models, implications for humans

“…[33][34][35] Surprisingly, in contrast to solid tumors, hematologic malignancies present a rather low incidence of genetic alterations in TP53 (10%-20%). 37,38 TP53 mutations/deletions have been reported in chronic lymphocytic leukemia (CLL), marginal zone lymphoma, follicular lymphoma, and diffuse large B-cell lymphoma. 39 Nonetheless, aberrations in TP53 correlate with an inferior clinical outcome in hematologic cancers.…”