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- Title
Arsenic disulfide synergizes with the phosphoinositide 3-kinase inhibitor PI-103 to eradicate acute myeloid leukemia stem cells by inducing differentiation.
- Authors
Hong, Zhenya; Xiao, Min; Yang, Yang; Han, Zhiqiang; Cao, Yang; Li, Chunrui; Wu, Ying; Gong, Quan; Zhou, Xiaoxi; Xu, Danmei; Meng, Li; Ma, Ding; Zhou, Jianfeng
- 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 As2S2 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 As2S2. 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 As2S2/PI-103 treatment synergized strongly to kill non-APL leukemia cells and promote their differentiation in vitro. Furthermore, the combined As2S2/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 As2S2. Targeting the PI3K/AKT/mTOR pathway in combination with As2S2 could be exploited as a novel strategy to enhance the differentiation and killing of non-APL LSCs.
- Subjects
ARSENIC sulfide; PHOSPHOINOSITIDES; ENZYME inhibitors; MYELOID leukemia; CELL differentiation; PHOSPHORYLATION; LABORATORY mice
- Publication
Carcinogenesis, 2011, Vol 32, Issue 10, p1550
- ISSN
0143-3334
- Publication type
Article
- DOI
10.1093/carcin/bgr176