Back to Search
Start Over
Arsenic disulfide synergizes with the phosphoinositide 3-kinase inhibitor PI-103 to eradicate acute myeloid leukemia stem cells by inducing differentiation
- Source :
- Carcinogenesis. 32(10)
- Publication Year :
- 2011
-
Abstract
- Although dramatic clinical success has been achieved in acute promyelocytic leukemia (APL), the success of differentiating agents has not been reproduced in non-APL leukemia. A key barrier to the clinical success of arsenic is that it is not potent enough to achieve a clinical benefit at physiologically tolerable concentrations by targeting the leukemia cell differentiation pathway alone. We explored a novel combination approach to enhance the eradication of leukemia stem cells (LSCs) by arsenic in non-APL leukemia. In the present study, phosphatidylinositol 3-kinase /AKT/mammalian target of rapamycin (mTOR) phosphorylation was strengthened after As(2)S(2) exposure in leukemia cell lines and stem/progenitor cells, but not in cord blood mononuclear cells (CBMCs). propidium iodide-103, the dual PI3K/mTOR inhibitor, effectively inhibited the transient activation of the PI3K/AKT/mTOR pathway by As(2)S(2). The synergistic killing and differentiation induction effects on non-APL leukemia cells were examined both in vitro and in vivo. Eradication of non-APL LSCs was determined using the nonobese diabetic/severe combined immunodeficiency mouse model. We found that a combined As(2)S(2)/PI-103 treatment synergized strongly to kill non-APL leukemia cells and promote their differentiation in vitro. Furthermore, the combined As(2)S(2)/PI-103 treatment effectively reduced leukemia cell repopulation and eradicated non-APL LSCs partially via induction of differentiation while sparing normal hematopoietic stem cells. Taken together, these findings suggest that induction of the PI3K/AKT/mTOR pathway could provide a protective response to offset the antitumor efficacy of As(2)S(2). Targeting the PI3K/AKT/mTOR pathway in combination with As(2)S(2) could be exploited as a novel strategy to enhance the differentiation and killing of non-APL LSCs.
- Subjects :
- Acute promyelocytic leukemia
Cancer Research
Pyridines
Cellular differentiation
Blotting, Western
Phosphoinositide 3-kinase inhibitor
Apoptosis
Mice, SCID
Sulfides
Arsenicals
Mice
Phosphatidylinositol 3-Kinases
Mice, Inbred NOD
Cell Line, Tumor
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
medicine
Animals
Humans
Furans
Protein kinase B
PI3K/AKT/mTOR pathway
Phosphoinositide-3 Kinase Inhibitors
Chemistry
TOR Serine-Threonine Kinases
Myeloid leukemia
Cell Differentiation
Drug Synergism
General Medicine
medicine.disease
Leukemia
Leukemia, Myeloid, Acute
Pyrimidines
Immunology
Cancer research
Neoplastic Stem Cells
Stem cell
Proto-Oncogene Proteins c-akt
Subjects
Details
- ISSN :
- 14602180
- Volume :
- 32
- Issue :
- 10
- Database :
- OpenAIRE
- Journal :
- Carcinogenesis
- Accession number :
- edsair.doi.dedup.....1da7677b55c9b392f31f801da39b7349