title: Inhibition of hedgehog signaling by GANT58 induces apoptosis and shows synergistic antitumor activity with AKT inhibitor in acute T cell leukemia cells.
abstract: The hedgehog (Hh) signaling pathways have a crucial role in cell proliferation and survival, and the de-regulation of these pathways can lead to tumorigenesis. Here we investigated the expression and function of these pathways in acute T lymphocytic leukemia cells (T-ALL). Profiling of Hh pathway members revealed common expression of key Hh signaling effectors in all T-ALL cells. We found that T-ALL cells were insensitive to specific Smoothened (SMO) inhibition following the use of low concentrations of the SMO antagonist cyclopamine. In contrast, treatment with the novel GLI antagonist GANT58 reduced expression of the target gene Patched 1 as well as GLI family zinc finger 1 (GLI1) and preferentially decreased the viability of T-ALL cells. We also found perifosine, a novel AKT inhibitor, down-regulated GLI1 protein by dephosphorylation of AKT and GSK3β dose-dependently and that pre-treatment with PD98059, a MEK/ERK pathway inhibitor, enhanced this down-regulation by 20%-30%. Then we questioned whether use of both GANT58 and AKT inhibitor together could confer a synergistic effect to decrease T-ALL cell viability. By applying the Chou-Talalay method, low concentration of GANT58 induced T-ALL cell death in a synergism fashion with perifosine or GSK690693 when used simultaneously. These findings indicate that the combined use of GANT58 and AKT inhibitor could help treat a broad range of malignant tumors in conjunction with existing cancer treatments.
authors.affiliation: Department of Pediatrics, Provincial Hospital Affiliated to Shandong University, Shandong University, Jinan, PR China. Electronic address: houxiaoming11111@hotmail.com.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Hou
authors.affiliation: Department of Pediatrics, Provincial Hospital Affiliated to Shandong University, Shandong University, Jinan, PR China.
authors.forename: Xing
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Neurosurgery, Qi Lu Hospital, Shandong University, Jinan, PR China.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Department of Pediatrics, Provincial Hospital Affiliated to Shandong University, Shandong University, Jinan, PR China.
authors.forename: Youfei
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Department of Pediatrics, Provincial Hospital Affiliated to Shandong University, Shandong University, Jinan, PR China.
authors.forename: Aihua
authors.initials: A
authors.lastname: Ma
authors.affiliation: Department of Pediatrics, Provincial Hospital Affiliated to Shandong University, Shandong University, Jinan, PR China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Pang
authors.affiliation: Department of Pediatrics, Provincial Hospital Affiliated to Shandong University, Shandong University, Jinan, PR China.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Song
authors.affiliation: Department of Pediatrics, Provincial Hospital Affiliated to Shandong University, Shandong University, Jinan, PR China.
authors.forename: Youpeng
authors.initials: Y
authors.lastname: Jin
authors.affiliation: Department of Pediatrics, Provincial Hospital Affiliated to Shandong University, Shandong University, Jinan, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Hao
authors.affiliation: Department of Pediatrics, Provincial Hospital Affiliated to Shandong University, Shandong University, Jinan, PR China.
authors.forename: Fengqin
authors.initials: F
authors.lastname: Liu
authors.affiliation: Department of Pediatrics, Provincial Hospital Affiliated to Shandong University, Shandong University, Jinan, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Pediatrics, Provincial Hospital Affiliated to Shandong University, Shandong University, Jinan, PR China. Electronic address: shandongwanghou@gmail.com.
authors.forename: Yulin
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D020935:MAP Kinase Signaling System; D010069:Oxadiazoles / Q000494:pharmacology*; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000494:pharmacology; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D011725:Pyridines / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology*; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism; D014704:Veratrum Alkaloids / Q000494:pharmacology; D000071676:Zinc Finger Protein GLI1
chemical_list: D000970:Antineoplastic Agents; C000593413:GANT58; C400551:GLI1 protein, human; C528328:GSK690693; D053823:Hedgehog Proteins; D010069:Oxadiazoles; D011725:Pyridines; D013876:Thiophenes; D014157:Transcription Factors; D014704:Veratrum Alkaloids; D000071676:Zinc Finger Protein GLI1; D010767:Phosphorylcholine; C105905:perifosine; D051057:Proto-Oncogene Proteins c-akt; C000541:cyclopamine
keywords: AKT inhibitor; Apoptosis; GANT58; GLI1; T-ALL