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 & Disease
Yuan-Fei ShiBing Xu

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 ...Continue Reading

References

Feb 22, 2012·British Journal of Clinical Pharmacology·Rui HanUlrich Mrowietz
May 12, 2012·Cancer Discovery·Sarat Chandarlapaty
Jan 30, 2016·Nature Reviews. Cancer·Alex R D DelbridgeDavid L Vaux
Apr 23, 2016·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Xiaojia NiuYubin Ge
Feb 18, 2017·Nature Reviews. Drug Discovery·Avi AshkenaziAndrew J Souers
Apr 20, 2017·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Frank ReichenbachFrank Edlich
May 28, 2017·Advances in Biological Regulation·Maria Rosaria RicciardiAgostino Tafuri
Jun 1, 2017·Anti-cancer Drugs·Ahmed Hamed SalemSuresh K Agarwal
Dec 22, 2017·Expert Review of Hematology·Meera Yogarajah, Richard M Stone
Mar 22, 2018·Cancer Research·Mohamed RahmaniSteven Grant
May 29, 2018·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Zhen-Yan HouMiao Yan
Jul 10, 2018·Current Hematologic Malignancy Reports·Prashant Sharma, Daniel A Pollyea
Jul 25, 2018·Blood·Marina Konopleva, Anthony Letai
Jan 10, 2019·Journal of Cellular Physiology·Le Xuan Truong NguyenVinod Pullarkat
Jan 19, 2019·Nature Reviews. Molecular Cell Biology·Rumani SinghKristopher Sarosiek

❮ Previous
Next ❯

Datasets Mentioned

BETA
ABT-199

Methods Mentioned

BETA
density gradient centrifugation
flow cytometry
Protein Assay
electrophoresis
xenograft

Software Mentioned

CompuSyn
SPSS
Calcusyn
NovoExpress

Related Concepts

Related Feeds

AML: Role of LSD1 by CRISPR (Keystone)

Find the latest rersearrch on the ability of CRISPR-Cas9 mutagenesis to profile the interactions between lysine-specific histone demethylase 1 (LSD1) and chemical inhibitors in the context of acute myeloid leukemia (AML) here.

Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis

Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a clinically and genetically heterogeneous disease with approximately 20,000 cases per year in the United States. AML also accounts for 15-20% of all childhood acute leukemias, while it is responsible for more than half of the leukemic deaths in these patients. Here is the latest research on this disease.