In:
PLOS ONE, Public Library of Science (PLoS), Vol. 17, No. 11 ( 2022-11-22), p. e0277893-
Abstract:
Aberration of PI3K signaling pathway has been confirmed to be associated with several hematological malignancies including acute myeloid leukemia (AML). FD268, a pyridinesulfonamide derivative characterized by the conjugation of 7-azaindole group, is a newly identified PI3K inhibitor showing high potent enzyme activity at nanomole concentration. In this study, we demonstrated that FD268 dose-dependently inhibits survival of AML cells with the efficacy superior to that of PI-103 (pan-PI3K inhibitor) and CAL-101 (selective PI3Kδ inhibitor) in the tested HL-60, MOLM-16, Mv-4-11, EOL-1 and KG-1 cell lines. Further mechanistic studies focused on HL-60 revealed that FD268 significantly inhibits the PI3K/Akt/mTOR signaling pathway, promotes the activation of pro-apoptotic protein Bad and downregulates the expression of anti-apoptotic protein Mcl-1, thus suppressing the cell proliferation and inducing caspase-3-dependent apoptosis. The bioinformatics analysis of the transcriptome sequencing data also indicated a potential involvement of the PI3K/Akt/mTOR pathway. These studies indicated that FD268 possesses high potent activity toward AML cells via inhibition of PI3K/Akt/mTOR signaling pathway, which sheds some light on the pyridinesulfonamide scaffold for further optimization and investigation.
Type of Medium:
Online Resource
ISSN:
1932-6203
DOI:
10.1371/journal.pone.0277893
DOI:
10.1371/journal.pone.0277893.g001
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10.1371/journal.pone.0277893.g002
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10.1371/journal.pone.0277893.g003
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10.1371/journal.pone.0277893.g004
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10.1371/journal.pone.0277893.g005
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10.1371/journal.pone.0277893.g006
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10.1371/journal.pone.0277893.g007
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10.1371/journal.pone.0277893.g008
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10.1371/journal.pone.0277893.g009
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10.1371/journal.pone.0277893.s001
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10.1371/journal.pone.0277893.s011
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10.1371/journal.pone.0277893.s012
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10.1371/journal.pone.0277893.s013
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10.1371/journal.pone.0277893.r001
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10.1371/journal.pone.0277893.r002
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10.1371/journal.pone.0277893.r003
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10.1371/journal.pone.0277893.r004
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10.1371/journal.pone.0277893.r005
DOI:
10.1371/journal.pone.0277893.r006
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2022
detail.hit.zdb_id:
2267670-3
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