Small‐molecule MDM2 inhibitor LQFM030‐induced apoptosis in p53‐null K562 chronic myeloid leukemia cells

Our group designed and synthesized the N‐phenyl‐piperazine LQFM030 [1‐(4‐((1‐(4‐chlorophenyl)‐1H–pyrazol‐4‐yl)methyl) piperazin‐1‐yl) ethanone], a small molecule derived from molecular simplification of the Nutlin‐1, an inhibitor of the human homologue of murine double minute 2 (MDM2) protein that i...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Fundamental & clinical pharmacology 2020-08, Vol.34 (4), p.444-457
Hauptverfasser: Oliveira Ribeiro, Higor, Cortez, Alane Pereira, Ávila, Renato Ivan, Silva, Artur Christian Garcia, Carvalho, Flávio Silva, Menegatti, Ricardo, Lião, Luciano Morais, Valadares, Marize Campos
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
Beschreibung
Zusammenfassung:Our group designed and synthesized the N‐phenyl‐piperazine LQFM030 [1‐(4‐((1‐(4‐chlorophenyl)‐1H–pyrazol‐4‐yl)methyl) piperazin‐1‐yl) ethanone], a small molecule derived from molecular simplification of the Nutlin‐1, an inhibitor of the human homologue of murine double minute 2 (MDM2) protein that is expressed in several types of cancer. To better investigate the effects of LQFM030 regarding the p53 mutation status, this study investigated the antiproliferative activity of LQFM030 against the p53‐null K562 leukemia cells as well as the cell death pathways involved. In addition, the effects of LQFM030 on the levels of the p53/MDM2 complex were also carried out using 3T3 cells as a p53 wild‐type model. Our data suggest that LQFM030 triggered apoptosis in K562 cells via different mechanisms including cell cycle arrest, caspase activation, reduction of mitochondrial activity, decrease in MDM2 expression, and transcriptional modulation of MDMX, p73, MYC, and NF‐ĸB. Additionally, it promoted effects in p53/MDM2 binding in p53 wild‐type 3T3 cells. Therefore, LQFM030 has antiproliferative effects in cancer cells by a p53 mutation status‐independent manner with different signaling pathways. These findings open new perspectives to the treatment of leukemic cells considering the resistance development associated with cancer treatment with conventional cytotoxic drugs.
ISSN:0767-3981
1472-8206
DOI:10.1111/fcp.12540