Combinatorial targeting of telomerase and DNA-PK induces synergistic apoptotic effects against Pre-B acute lymphoblastic leukemia cells.
Mol Biol Rep
; 51(1): 163, 2024 Jan 22.
Article
em En
| MEDLINE
| ID: mdl-38252348
ABSTRACT
BACKGROUND:
Due to the high demand for novel approaches for leukemia-targeted therapy, this study investigates the impact of DNA-PK inhibitor NU7441 on the sensitivity of pre-B ALL cells to the telomerase inhibitor MST-312.METHODS:
The study involved NALM-6 cells treated with MST-312 and NU7441, assessing their viability and metabolic activity using trypan blue and MTT assays. The study also evaluated apoptosis, gene expression changes, and DNA damage using flow cytometry, qRT-PCR, and micronucleus assays. The binding energy of MST-312 in the active site of telomerase was calculated using molecular docking.RESULTS:
The study's findings revealed a synergistic decline in both cell viability and metabolic activity in NALM-6 cells when exposed to the combined treatment of MST-312 and NU7441, and this decrease occurred without any adverse effects on healthy PBMC cells. Furthermore, the combination treatment exhibited a significantly higher induction of apoptosis than treatment with MST-312 alone, as observed through flow cytometry assay. qRT-PCR analysis revealed that this enhanced apoptosis was associated with a notable downregulation of Bcl-2 expression and an upregulation of Bax gene expression. Moreover, the combination therapy decreased expression levels of hTERT and c-Myc genes. The micronucleus assay indicated that the combination treatment increased DNA damage in NALM-6 cells. Also, a good conformation between MST-312 and the active site of telomerase was revealed by docking data.CONCLUSIONS:
The study suggests that simultaneous inhibition of telomerase and DNA-PK in pre-B ALL presents a novel targeted therapy approach.Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Benzamidas
/
Leucemia-Linfoma Linfoblástico de Células Precursoras B
/
Telomerase
Limite:
Humans
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article