Antitumor Effects of PRIMA-1 and PRIMA-1Met (APR246) in Hematological Malignancies: Still a Mutant P53-Dependent Affair?

Abstract

Because of its role in the regulation of the cell cycle, DNA damage response, apoptosis, DNA repair, cell migration, autophagy, and cell metabolism, the TP53 tumor suppressor gene is a key player for cellular homeostasis. TP53 gene is mutated in more than 50% of human cancers, although its overall dysfunction may be even more frequent. TP53 mutations are detected in a lower percentage of hematological malignancies compared to solid tumors, but their frequency generally increases with disease progression, generating adverse effects such as resistance to chemotherapy. Due to the crucial role of P53 in therapy response, several molecules have been developed to re-establish the wild-type P53 function to mutant P53. PRIMA-1 and its methylated form PRIMA-1Met (also named APR246) are capable of restoring the wild-type conformation to mutant P53 and inducing apoptosis in cancer cells; however, they also possess mutant P53-independent properties. This review presents the activities of PRIMA-1 and PRIMA-1Met/APR246 and describes their potential use in hematological malignancies.

• Authors: Paola Menichini, Paola Monti, Andrea Speciale, Giovanna Cutrona, Serena Matis, Franco Fais, Elisa Taiana, Antonino Neri, Riccardo Bomben, Massimo Gentile, Valter Gattei, Manlio Ferrarini, Fortunato Morabito, Gilberto Fronza
• Journal: Cells (Cells) Vol. 10 Issue 1 (01 07 2021) ISSN: 2073-4409 [Electronic] Switzerland
• PMID: 33430525 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)

Chemical References

• Antineoplastic Agents
• Aza Compounds
• Bridged Bicyclo Compounds, Heterocyclic
• Tumor Suppressor Protein p53
• 2,2-bis(hydroxymethyl)-1-azabicyclo(2,2,2,)octan-3-one

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Aza Compounds (pharmacology)
• Bridged Bicyclo Compounds, Heterocyclic (pharmacology)
• Clinical Trials as Topic
• Hematologic Neoplasms (genetics)
• Humans
• Methylation
• Mutation (genetics)
• Tumor Suppressor Protein p53 (genetics)