Abstract
p53 protects cells from genetic assaults by triggering cell-cycle arrest and apoptosis. Inactivation of p53 pathway is found in the vast majority of human cancers often due to somatic missense mutations in TP53 or to an excessive degradation of the protein. Accordingly, reactivation of p53 appears as a quite promising pharmacological approach and, effectively, several attempts have been made in that sense. The most widely investigated compounds for this purpose are PRIMA-1 (p53 reactivation and induction of massive apoptosis )and PRIMA-1Met (APR-246), that are at an advanced stage of development, with several clinical trials in progress. Based on publications referenced in PubMed since 2002, here we review the reported effects of these compounds on cancer cells, with a specific focus on their ability of p53 reactivation, an overview of their unexpected anti-cancer effects, and a presentation of the investigated drug combinations.
Highlights
Laboratory of Oncology and Experimental Surgery, Institut Jules Bordet, Université Libre de Bruxelles, Clinical Laboratory, Department of Biopathology, Henri Becquerel Centre, 76038 Rouen, France
This screening has led to the identification of the molecule 2,2-bis(hydroxymethyl)-1-azabicyclo[2,2,2]octan-3-one, named PRIMA-1 for “p53 reactivation and induction of massive apoptosis”
The aim of this review, based on the publications referenced in PubMed since 2002 and using the key words PRIMA-1 or APR-246, is (1) to question, 15 years after their discovery, the initial published properties of PRIMA-1 and APR-246, (2) to present the new hypothetical mechanisms of action of these molecules, and (3) to list and comment the therapeutic associations already tested and ongoing, in order to prepare the future clinical combination of p53 restoration and targeted therapies
Summary
Anne Perdrix 1,2,3,† , Ahmad Najem 1,† , Sven Saussez 4 , Ahmad Awada 1,5 , Fabrice Journe 1,4 , Ghanem Ghanem 1 and Mohammad Krayem 1, *. Clinical Laboratory, Department of Biopathology, Henri Becquerel Centre, 76038 Rouen, France. Equipe de Recherche en Oncologie (IRON), Inserm U1245, Rouen University Hospital, 76000 Rouen, France. The most widely investigated compounds for this purpose are PRIMA-1 (p53 reactivation and induction of massive apoptosis )and PRIMA-1Met (APR-246), that are at an advanced stage of development, with several clinical trials in progress. Based on publications referenced in PubMed since 2002, here we review the reported effects of these compounds on cancer cells, with a specific focus on their ability of p53 reactivation, an overview of their unexpected anti-cancer effects, and a presentation of the investigated drug combinations
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