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
Mar 25, 2006·Blood·Bing Z CarterMichael Andreeff
Jan 25, 2012·Natural Product Reports·Zhao-Li ZhouZe-Hong Miao
Feb 22, 2012·British Journal of Clinical Pharmacology·Rui HanUlrich Mrowietz
May 12, 2012·Cancer Discovery·Sarat Chandarlapaty
Oct 17, 2012·Cancer Discovery·Livio Trusolino, Andrea Bertotti
Aug 13, 2013·Pharmacogenomics·Feili ChenBing Xu
Jun 6, 2015·Blood·Rongqing PanPeter P Ruvolo
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
Nov 27, 2016·Oncotarget·Haijun ZhaoBing Xu
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 13, 2017·Cancer Cell·Rongqing PanMichael Andreeff
Dec 22, 2017·Signal Transduction and Targeted Therapy·Daniel A LuedtkeYubin Ge
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
Nov 14, 2018·Nature Medicine·Daniel A PollyeaCraig T Jordan
Jan 10, 2019·Journal of Cellular Physiology·Le Xuan Truong NguyenVinod Pullarkat
Jan 19, 2019·Nature Reviews. Molecular Cell Biology·Rumani SinghKristopher Sarosiek