Mechanisms of apoptosis induction by simultaneous inhibition of PI3K and FLT3-ITD in AML cells in the hypoxic bone marrow microenvironment.

Abstract

We investigated the antileukemia effects and molecular mechanisms of apoptosis induction by simultaneous blockade of PI3K and mutant FLT3 in AML cells grown under hypoxia in co-cultures with bone marrow stromal cells. Combined treatment with selective class I PI3K inhibitor GDC-0941 and sorafenib reversed the protective effects of bone marrow stromal cells on FLT3-mutant AML cells in hypoxia, which was associated with downregulation of Pim-1 and Mcl-1 expression levels. These findings suggest that combined inhibition of PI3K and FLT3-ITD may constitute a targeted approach to eradicating chemoresistant AML cells sequestered in hypoxic bone marrow niches.

• Authors: Linhua Jin, Yoko Tabe, Hongbo Lu, Gautam Borthakur, Takashi Miida, Hagop Kantarjian, Michael Andreeff, Marina Konopleva
• Journal: Cancer letters (Cancer Lett) Vol. 329 Issue 1 Pg. 45-58 (Feb 01 2013) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 23036488 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Ltd. All rights reserved.

Chemical References

• 2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine
• Antineoplastic Agents
• Enzyme Inhibitors
• Indazoles
• Myeloid Cell Leukemia Sequence 1 Protein
• Phenylurea Compounds
• Phosphoinositide-3 Kinase Inhibitors
• Proto-Oncogene Proteins c-bcl-2
• Sulfonamides
• Niacinamide
• Sorafenib
• FLT3 protein, human
• fms-Like Tyrosine Kinase 3
• PIM1 protein, human
• Proto-Oncogene Proteins c-akt
• Proto-Oncogene Proteins c-pim-1

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Bone Marrow (drug effects, metabolism)
• Cell Hypoxia (drug effects)
• Cellular Microenvironment (drug effects)
• Coculture Techniques
• Enzyme Inhibitors (pharmacology)
• Humans
• Indazoles (pharmacology)
• Leukemia, Myeloid, Acute (drug therapy, genetics, metabolism, pathology)
• Mutation
• Myeloid Cell Leukemia Sequence 1 Protein
• Niacinamide (analogs & derivatives, pharmacology)
• Phenylurea Compounds (pharmacology)
• Phosphoinositide-3 Kinase Inhibitors
• Proto-Oncogene Proteins c-akt (metabolism)
• Proto-Oncogene Proteins c-bcl-2 (genetics, metabolism)
• Proto-Oncogene Proteins c-pim-1 (genetics, metabolism)
• Sorafenib
• Stromal Cells (drug effects, metabolism)
• Sulfonamides (pharmacology)
• fms-Like Tyrosine Kinase 3 (antagonists & inhibitors, genetics, metabolism)