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

2020; Wiley; Volume: 34; Issue: 4 Linguagem: Inglês

10.1111/fcp.12540

1472-8206

Higor de Oliveira Ribeiro, Alane Pereira Cortez, Renato Ivan de Ávila, Artur Christian Garcia da Silva, Flávio Silva de Carvalho, Ricardo Menegatti, Luciano M. Lião, Marize Campos Valadares,

Cell death mechanisms and regulation

Abstract 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.