title: Arsenic trioxide and all-trans-retinoic acid selectively exert synergistic cytotoxicity against FLT3-ITD AML cells via co-inhibition of FLT3 signaling pathways.
abstract: FLT3-ITD mutations occur in approximately 30% of acute myeloid leukemia (AML) and are associated with a poor outcome. Currently available FLT3 inhibitors have in vitro but limited clinical activity in FLT3-ITD AML. Reports have shown that an arsenic trioxide (ATO)/all-trans-retinoic acid (ATRA) combination improves prognosis in acute promyelocytic leukemia, especially with FLT3-ITD, and ATO or ATRA alone enhances apoptosis in FLT3-ITD AML cells treated with FLT3 inhibitors, providing a rationale to investigate the role of ATO/ATRA in FLT3-ITD AML. Here, we demonstrate that an ATO/ATRA combination selectively exerts synergistic cytotoxicity against FLT3-ITD AML cell lines (MV4;11/MOLM-13). The signaling pathways affected by ATO/ATRA include FLT3/STAT5/MYC, FLT3/STAT5/E2F1, FLT3/ERK/ATF5 and FLT3/AKT/ATF5.ATF5 may function as an oncogene in FLT3-ITD AML. Our findings provide experimental evidence that supports further exploration of ATO/ATRA in FLT3-ITD AML in vivo and warrants a clinical evaluation of regimens comprising an ATO/ATRA combination.
authors.affiliation: a Department of Pediatrics , The First Affiliated Hospital of Sun Yat-sen University , Guangzhou , China.
authors.forename: Li-Na
authors.initials: LN
authors.lastname: Wang
authors.affiliation: a Department of Pediatrics , The First Affiliated Hospital of Sun Yat-sen University , Guangzhou , China.
authors.forename: Yan-Lai
authors.initials: YL
authors.lastname: Tang
authors.affiliation: a Department of Pediatrics , The First Affiliated Hospital of Sun Yat-sen University , Guangzhou , China.
authors.forename: Yin-Chuan
authors.initials: YC
authors.lastname: Zhang
authors.affiliation: a Department of Pediatrics , The First Affiliated Hospital of Sun Yat-sen University , Guangzhou , China.
authors.forename: Zu-Han
authors.initials: ZH
authors.lastname: Zhang
authors.affiliation: a Department of Pediatrics , The First Affiliated Hospital of Sun Yat-sen University , Guangzhou , China.
authors.forename: Xiao-Jian
authors.initials: XJ
authors.lastname: Liu
authors.affiliation: a Department of Pediatrics , The First Affiliated Hospital of Sun Yat-sen University , Guangzhou , China.
authors.forename: Zhi-Yong
authors.initials: ZY
authors.lastname: Ke
authors.affiliation: a Department of Pediatrics , The First Affiliated Hospital of Sun Yat-sen University , Guangzhou , China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Li
authors.affiliation: a Department of Pediatrics , The First Affiliated Hospital of Sun Yat-sen University , Guangzhou , China.
authors.forename: Hui-Zhen
authors.initials: HZ
authors.lastname: Tan
authors.affiliation: a Department of Pediatrics , The First Affiliated Hospital of Sun Yat-sen University , Guangzhou , China.
authors.forename: Li-Bin
authors.initials: LB
authors.lastname: Huang
authors.affiliation: a Department of Pediatrics , The First Affiliated Hospital of Sun Yat-sen University , Guangzhou , China.
authors.forename: Xue-Qun
authors.initials: XQ
authors.lastname: Luo
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide / Q000494:pharmacology; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy; D015398:Signal Transduction / Q000187:drug effects; D014212:Tretinoin / Q000494:pharmacology; D051941:fms-Like Tyrosine Kinase 3 / Q000187:drug effects
chemical_list: D014212:Tretinoin; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; D000077237:Arsenic Trioxide
keywords: ATF5; Acute myeloid leukemia; FLT3-ITD; all-trans-retinoic acid; arsenictrioxide