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

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.

Isolation and Functional Characterization of the Promoters of Miltiradiene Synthase Genes, TwTPS27a and TwTPS27b, and Interaction Analysis with the Transcription Factor TwTGA1 from Tripterygium wilfordii

“…The identification of hundreds of effective compounds isolated from the roots of T wilfordii [ 3 , 4 ], such as diterpenoids, triterpenoids, sesquiterpenoids, and alkaloids, has stimulated the study of their pharmacological properties. Triptolide, an important bioactive diterpenoid in T. wilfordii , has a variety of pharmacological activities, such as antitumor, anticancer, immunosuppressive, and anti-inflammatory activities [ 5 , 6 , 7 , 8 ]. In recent years, the biosynthetic pathway of triptolide has been widely studied.…”

Bcl-2 inhibition combined with PPARα activation synergistically targets leukemic stem cell-like cells in acute myeloid leukemia

“…A total of 1 × 10 4 KG-1α or Kasumi-1 cells were seeded in 96-well plates containing 100 μL medium and treated with designated drugs for 24 h. After treatment, the CCK-8 kit (MCE) was used to measure cell viability. CompuSyn software and the Chuou-Talalay medium effect analysis method were used to calculate the fraction affected (Fa) and the corresponding drug combination index (CI) of each treatment group and to draw the Fa-CI curve [ 51 ].…”

MYC2 Transcription Factors TwMYC2a and TwMYC2b Negatively Regulate Triptolide Biosynthesis in Tripterygium wilfordii Hairy Roots

“…The identification of hundreds of effective compounds isolated from the roots of T wilfordii , such as diterpenoids, triterpenoids, and sesquiterpenoids [ 3 , 4 ], has stimulated the study of their pharmacological properties. In T. wilfordii , much of the observed pharmacological activity can be attributed to the presence of triptolide, which has a variety of pharmacological activities, such as antitumor, anticancer, immunosuppressive, and anti-inflammatory activities [ 5 , 6 , 7 , 8 ]. Recently, numerous studies have focused on investigating the biosynthetic pathway of triptolide, leading to the isolation and functional characterization of many triptolide biosynthetic pathway genes, including not only the upstream pathway genes, such as TwHMGR1 [ 9 ], TwHMGS [ 10 , 11 ], TwDXR [ 12 , 13 ], TwDXS1/2 [ 12 , 14 ], TwHDR [ 15 ], TwIDI [ 16 , 17 ], and TwGGPPS1/4/8 [ 18 , 19 ], but also the downstream pathway genes, such as TwTPS7/7v2/9/9v2 [ 20 , 21 ], TwTPS27/27v2 [ 20 , 21 ], and TwCYP728B70 [ 22 ] (all of these functional pathway genes’ full names are shown in Table S1 ).…”