title: Mcl-1 as a Therapeutic Target in Acute Myelogenous Leukemia (AML).
abstract: The B-cell lymphoma-2 (Bcl-2) family of proteins regulates the intrinsic, or mitochondrial pathway of apoptosis, the final common mechanism of cell death in response to a variety of physiologic and pharmacologic signals, and plays a central role in AML pathogenesis, prognosis and responsiveness to chemotherapy. Traditionally thought to be an important survival factor for multiple myeloma cells, the anti-apoptotic Bcl-2 family protein myeloid cell leukemia-1 (Mcl-1) has recently been shown in preclinical studies to be critical to the development and maintenance of AML, making it an attractive therapeutic target in this disease. Several characteristics, such as its very short half-life, distinguish Mcl-1 from other anti-apoptotic Bcl-2 family members. Additionally, Mcl-1 levels are regulated by a large number of pathways affecting its transcription, translation and degradation. A variety of approaches exploiting these features has been developed to inhibit directly or indirectly the anti-apoptotic function of Mcl-1. Many of these lend themselves well to combination therapies, leading to striking synergism, at least in preclinical models. In this brief review, we highlight some of the more promising strategies targeting Mcl-1 in AML, with a particular emphasis on rational combinations of novel agents.
authors: Massey Cancer Center, Virginia Commonwealth University, Richmond, VA ; Departments of Internal Medicine, Virginia Commonwealth University, Richmond, VA.
authors: Prithviraj
authors: P
authors: Bose
authors: Steven
authors: S
authors: Grant
keywords: AML; CDK inhibitors; Mcl-1; navitoclax; obatoclax; sorafenib
references: Cancer Res. 2007 Jan 15;67(2):782-91
references: 17234790
references: Blood. 2012 Jun 21;119(25):6089-98
references: 22446485
references: J Biol Chem. 2005 Oct 21;280(42):35217-27
references: 16109713
references: Cancer Cell. 2006 Nov;10(5):375-88
references: 17097560
references: J Clin Oncol. 2011 Aug 20;29(24):3293-300
references: 21768474
references: Leukemia. 2008 Apr;22(4):808-18
references: 18200035
references: J Clin Oncol. 2010 Apr 10;28(11):1856-62
references: 20212254
references: Leuk Lymphoma. 2013 Apr;54(4):760-6
references: 23061485
references: Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19512-7
references: 18040043
references: Clin Cancer Res. 2003 Jan;9(1):307-15
references: 12538483
references: Leuk Res. 2010 Jul;34(7):877-82
references: 19962759
references: Genes Dev. 2012 Jan 15;26(2):120-5
references: 22279045
references: Cancer Res. 2008 May 1;68(9):3413-20
references: 18451169
references: Leukemia. 2012 Apr;26(4):778-87
references: 22064351
references: Blood Cancer J. 2012 Mar;2(3):e60
references: 22829255