PMID- 24824212
OWN - NLM
STAT- MEDLINE
DCOM- 20150416
LR  - 20231120
IS  - 1531-2267 (Electronic)
IS  - 1094-8341 (Print)
IS  - 1094-8341 (Linking)
VI  - 46
IP  - 13
DP  - 2014 Jul 1
TI  - Rational combination of dual PI3K/mTOR blockade and Bcl-2/-xL inhibition in AML.
PG  - 448-56
LID - 10.1152/physiolgenomics.00173.2013 [doi]
AB  - Acute myeloid leukemia (AML) continues to represent an area of critical unmet 
      need with respect to new and effective targeted therapies. The Bcl-2 family of 
      pro- and antiapoptotic proteins stands at the crossroads of cellular survival and 
      death, and the expression of and interactions between these proteins determine 
      tumor cell fate. Malignant cells, which are often primed for apoptosis, are 
      particularly vulnerable to the simultaneous disruption of cooperative survival 
      signaling pathways. Indeed, the single agent activity of agents such as mammalian 
      target of rapamycin (mTOR) and mitogen-activated protein kinase kinase (MEK) 
      inhibitors in AML has been modest. Much work in recent years has focused on 
      strategies to enhance the therapeutic potential of the bona fide BH3-mimetic, 
      ABT-737, which inhibits B-cell lymphoma 2 (Bcl-2) and Bcl-xL. Most of these 
      strategies target Mcl-1, an antiapoptotic protein not inhibited by ABT-737. The 
      phosphatidylinositol-3-kinase (PI3K)/Akt/mTOR and Ras/Raf/MEK/ERK signaling 
      pathways are central to the growth, proliferation, and survival of AML cells, and 
      there is much interest currently in pharmacologically interrupting these 
      pathways. Dual inhibitors of PI3K and mTOR overcome some intrinsic disadvantages 
      of rapamycin and its derivatives, which selectively inhibit mTOR. In this review, 
      we discuss why combining dual PI3K/mTOR blockade with inhibition of Bcl-2 and 
      Bcl-xL, by virtue of allowing coordinate inhibition of three mutually synergistic 
      pathways in AML cells, may be a particularly attractive therapeutic strategy in 
      AML, the success of which may be predicted for by basal Akt activation.
CI  - Copyright (c) 2014 the American Physiological Society.
FAU - Vachhani, Pankit
AU  - Vachhani P
AD  - Department of Internal Medicine, Virginia Commonwealth University, Richmond, 
      Virginia;
FAU - Bose, Prithviraj
AU  - Bose P
AD  - Department of Internal Medicine, Virginia Commonwealth University, Richmond, 
      Virginia; Virginia Commonwealth University Massey Cancer Center, Richmond, 
      Virginia.
FAU - Rahmani, Mohamed
AU  - Rahmani M
AD  - Department of Internal Medicine, Virginia Commonwealth University, Richmond, 
      Virginia; Virginia Commonwealth University Massey Cancer Center, Richmond, 
      Virginia.
FAU - Grant, Steven
AU  - Grant S
AD  - Department of Internal Medicine, Virginia Commonwealth University, Richmond, 
      Virginia; Department of Microbiology and Immunology, Virginia Commonwealth 
      University, Richmond, Virginia; Department of Biochemistry and Molecular Biology, 
      Virginia Commonwealth University, Richmond, Virginia; Department of Human and 
      Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia; 
      Institute of Molecular Medicine, Virginia Commonwealth University; and Virginia 
      Commonwealth University Massey Cancer Center, Richmond, Virginia stgrant@vcu.edu.
LA  - eng
GR  - P50 CA-142509-04/CA/NCI NIH HHS/United States
GR  - R01 CA-100866-09/CA/NCI NIH HHS/United States
GR  - R01 CA-167708-01A1/CA/NCI NIH HHS/United States
GR  - P50 CA-130805-05/CA/NCI NIH HHS/United States
GR  - P30 CA016059/CA/NCI NIH HHS/United States
GR  - R21 CA-137823-02/CA/NCI NIH HHS/United States
GR  - R01 CA-093738-09/CA/NCI NIH HHS/United States
GR  - R01 CA167708/CA/NCI NIH HHS/United States
GR  - P30 CA-16059-31/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Review
DEP - 20140513
PL  - United States
TA  - Physiol Genomics
JT  - Physiological genomics
JID - 9815683
RN  - 0 (ABT-737)
RN  - 0 (BCL2L1 protein, human)
RN  - 0 (Biphenyl Compounds)
RN  - 0 (Nitrophenols)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Piperazines)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Proto-Oncogene Proteins c-bcl-2)
RN  - 0 (Sulfonamides)
RN  - 0 (bcl-X Protein)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Antineoplastic Combined Chemotherapy Protocols/*therapeutic use
MH  - Biphenyl Compounds/*administration & dosage
MH  - Humans
MH  - Leukemia, Myeloid, Acute/*drug therapy
MH  - Nitrophenols/*administration & dosage
MH  - Phosphoinositide-3 Kinase Inhibitors
MH  - Piperazines/administration & dosage
MH  - Protein Kinase Inhibitors/*administration & dosage
MH  - Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors/physiology
MH  - Signal Transduction
MH  - Sirolimus/*administration & dosage
MH  - Sulfonamides/*administration & dosage
MH  - TOR Serine-Threonine Kinases/antagonists & inhibitors
MH  - bcl-X Protein/antagonists & inhibitors/physiology
PMC - PMC4080281
OTO - NOTNLM
OT  - AML
OT  - Bcl-2
OT  - Bcl-xL
OT  - PI3K
OT  - mTOR
EDAT- 2014/05/16 06:00
MHDA- 2015/04/17 06:00
PMCR- 2015/07/01
CRDT- 2014/05/15 06:00
PHST- 2014/05/15 06:00 [entrez]
PHST- 2014/05/16 06:00 [pubmed]
PHST- 2015/04/17 06:00 [medline]
PHST- 2015/07/01 00:00 [pmc-release]
AID - physiolgenomics.00173.2013 [pii]
AID - PG-00173-2013 [pii]
AID - 10.1152/physiolgenomics.00173.2013 [doi]
PST - ppublish
SO  - Physiol Genomics. 2014 Jul 1;46(13):448-56. doi: 
      10.1152/physiolgenomics.00173.2013. Epub 2014 May 13.