DT-13 induced apoptosis and promoted differentiation of acute myeloid leukemia cells by activating AMPK-KLF2 pathway.
Pharmacol Res
; 158: 104864, 2020 08.
Article
en En
| MEDLINE
| ID: mdl-32416217
Acute myeloid leukemia (AML) is a malignant disease originating from hematopoietic stem cells (HSC). Chemotherapy and/or HSC transplantation is unsatisfactory due to serious side effects, multidrug resistance, and high relapse rate. Thus, alternative strategies are urgently needed to develop more effective therapies. Liriope muscari baily saponins C (DT-13) is a novel compound isolated from Liriope muscari (Decne.) Baily, and exhibited a potent cytotoxicity against several solid tumors. However, the anti-AML activity of DT-13 and the potential mechanisms are still unknown. This study is the first to demonstrate that DT-13 had preferential cytotoxicity against AML cells, and remarkably inhibited proliferation and colony forming ability. Moreover, DT-13 induced the death receptor pathway-dependent apoptosis of HL-60 and Kasumi-1 cells by up-regulating Fas, FasL, DR5 and TRAIL as well as promoted the cleavage of caspase 8, caspase 3 and PARP. Meanwhile, DT-13 induced the differentiation with morphological change related to myeloid differentiation, elevated NBT and α-NAE positive cell rates, differentiation markers CD11b and CD14 as well as level of transcription factors C/EBPα and C/EBPß. RNA-sequencing analysis revealed that KLF2 may be one of the potential targets regulated by DT-13. Further studies indicated that KLF2 played a critical role in DT-13-induced apoptosis and differentiation. Moreover, activation of AMPK-FOXO was proved to be the upstream of KLF2 pathway that contributed to the induction of apoptosis and differentiation by DT-13. Additionally, restoration of KLF2 by DT-13 was highly correlated with the AMPK-related histone acetylation mechanisms. Finally, DT-13 exhibited an obvious anti-AML effect in NOD/SCID mice with the engraftment of HL-60 cells. Our study suggests that DT-13 may serve as a novel agent for AML by AMPL-KLF2-mediated apoptosis and differentiation.
Palabras clave
AMPK; Acute myeloid leukemia; Apoptosis; Chloroquine phosphate (PubChem CID: 64927); Compound C (PubChem CID: 11524144); DT-13; DT-13 (PubChem CID: 101514160); Differentiation; Dimethyl sulfoxide (PubChem CID: 679); KLF2; Nitro blue tetrazolium (PubChem CID: 9281); Sulforhodamine B (PubChem CID: 65191)
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Saponinas
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Leucemia Mieloide Aguda
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Transducción de Señal
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Diferenciación Celular
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Apoptosis
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Factores de Transcripción de Tipo Kruppel
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Proteínas Quinasas Activadas por AMP
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Antineoplásicos Fitogénicos
Límite:
Animals
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Humans
Idioma:
En
Revista:
Pharmacol Res
Asunto de la revista:
FARMACOLOGIA
Año:
2020
Tipo del documento:
Article
País de afiliación:
China
Pais de publicación:
Países Bajos