title: Arsenic disulfide synergizes with the phosphoinositide 3-kinase inhibitor PI-103 to eradicate acute myeloid leukemia stem cells by inducing differentiation.
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.
authors.affiliation: Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China.
authors.forename: Zhenya
authors.initials: Z
authors.lastname: Hong
authors.forename: Min
authors.initials: M
authors.lastname: Xiao
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Han
authors.forename: Yang
authors.initials: Y
authors.lastname: Cao
authors.forename: Chunrui
authors.initials: C
authors.lastname: Li
authors.forename: Ying
authors.initials: Y
authors.lastname: Wu
authors.forename: Quan
authors.initials: Q
authors.lastname: Gong
authors.forename: Xiaoxi
authors.initials: X
authors.lastname: Zhou
authors.forename: Danmei
authors.initials: D
authors.lastname: Xu
authors.forename: Li
authors.initials: L
authors.lastname: Meng
authors.forename: Ding
authors.initials: D
authors.lastname: Ma
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Zhou
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001152:Arsenicals / Q000494:pharmacology*; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor / Q000637:transplantation; D004357:Drug Synergism; D005663:Furans / Q000494:pharmacology*; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D013440:Sulfides / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D001152:Arsenicals; D005663:Furans; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011725:Pyridines; D011743:Pyrimidines; D013440:Sulfides; D058570:TOR Serine-Threonine Kinases; C522973:PI103; C058317:arsenic disulfide