Combining triptolide with ABT-199 is effective against acute myeloid leukemia through reciprocal regulation of Bcl-2 family proteins and activation of the intrinsic apoptotic pathway.
Cell Death Dis
; 11(7): 555, 2020 07 22.
Article
em En
| MEDLINE
| ID: mdl-32699295
ABSTRACT
Bcl-2 inhibitors display an effective activity in acute myeloid leukemia (AML), but its clinical efficacy as a monotherapy was limited in part owing to failure to target other antiapoptotic Bcl-2 family proteins, such as Mcl-1. In this context, the combination strategy may be a promising approach to overcome this barrier. Here, we report the preclinical efficacy of a novel strategy combining ABT-199 with triptolide (TPL), a natural product extracted from a traditional Chinese medicine, in AML. Combination treatment exhibited markedly increased cytotoxicity in leukemic cells irrespective of p53 status while largely sparing normal cells of the hematopoietic lineage. Moreover, co-administration of ABT-199 with TPL dramatically suppressed leukemia progression as well as prolonged animal survival in a xenograft AML model. The potentiated effect of ABT-199 and TPL against AML was associated with activation of the mitochondrum-related intrinsic apoptotic pathway through a mechanism reciprocally modulating Bcl-2 family proteins. In this case, TPL not only downregulated Mcl-1 but also upregulated proapoptotic BH3-only proteins, thereby overcoming the resistance toward ABT-199. Conversely, ABT-199 abrogated Bcl-2-mediated cytoprotection against TPL. Together, these findings suggest that the regimen combining TPL and ABT-199 might be active against AML by inducing robust apoptosis through reciprocal regulation of anti- and proapoptotic Bcl-2 family proteins, therefore providing a strong rationale for the clinical investigation of this combination regimen for the treatment of AML.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fenantrenos
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Sulfonamidas
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Leucemia Mieloide Aguda
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Apoptose
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Compostos Bicíclicos Heterocíclicos com Pontes
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Proteínas Proto-Oncogênicas c-bcl-2
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Diterpenos
Tipo de estudo:
Prognostic_studies
Limite:
Adolescent
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Adult
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Aged
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Animals
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Child
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
Cell Death Dis
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
China