Kevetrin induces apoptosis in TP53 wildtype and mutant acute myeloid leukemia cells.
Oncol Rep
; 44(4): 1561-1573, 2020 10.
Article
em En
| MEDLINE
| ID: mdl-32945487
ABSTRACT
Tumor protein p53 is a key regulator of several cellular pathways, including DNA repair, cell cycle and angiogenesis. Kevetrin exhibits p53dependent as well asindependent activity in solid tumors, while its effects on leukemic cells remain unknown. The aim of the present study was to analyze the response of acute myeloid leukemia (AML) cell lines (TP53 wildtype OCIAML3 and MOLM13; and TP53mutant KASUMI1 and NOMO1) to kevetrin at a concentration range of 85340 µM. The cellular and molecular effects of the treatment were analyzed in terms of cell growth, viability [Annexin Vpropidium iodide (PI) staining] and cell cycle alterations (PI staining). Gene expression profiling, western blotting and immunofluorescence were performed to elucidate the pathways underlying kevetrin activity. Pulsed exposure exerted no effect on the wildtype cells, but was effective on mutant cells. After continuous treatment, significant cell growth arrest and apoptosis were observed in all cell lines, with TP53mutant models displaying a higher sensitivity and p53 induction. Kevetrin also displayed efficacy against TP53 wildtype and mutant primary AML, with a preferential cytotoxic activity against blast cells. Gene expression profiling revealed a common core transcriptional program altered by drug exposure and the downregulation of glycolysis, DNA repair and unfolded protein response signatures. These findings suggest that kevetrin may be a promising therapeutic option for patients with both wildtype and TP53mutant AML.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Leucemia Mieloide Aguda
/
Proteína Supressora de Tumor p53
/
Proliferação de Células
/
Antineoplásicos
Tipo de estudo:
Prognostic_studies
Limite:
Aged
/
Aged80
/
Female
/
Humans
/
Male
Idioma:
En
Revista:
Oncol Rep
Ano de publicação:
2020
Tipo de documento:
Article