Anti-leukemia effects of omipalisib in acute myeloid leukemia: inhibition of PI3K/AKT/mTOR signaling and suppression of mitochondrial biogenesis
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Anti-leukemia effects of omipalisib in acute myeloid leukemia : inhibition of PI3K/AKT/mTOR signaling and suppression of mitochondrial biogenesis. / Tseng, Chi Yang; Fu, Yu-Hsuan; Ou, Da Liang; Lu, Jeng-Wei; Hou, Hsin An; Lin, Liang In.
In: Cancer Gene Therapy, Vol. 30, 2023, p. 1691-1701.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Anti-leukemia effects of omipalisib in acute myeloid leukemia
T2 - inhibition of PI3K/AKT/mTOR signaling and suppression of mitochondrial biogenesis
AU - Tseng, Chi Yang
AU - Fu, Yu-Hsuan
AU - Ou, Da Liang
AU - Lu, Jeng-Wei
AU - Hou, Hsin An
AU - Lin, Liang In
N1 - Publisher Copyright: © 2023, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2023
Y1 - 2023
N2 - Omipalisib (GSK2126458), a potent dual PI3K/mTOR inhibitor, is reported to exhibit anti-tumor effect in several kinds of cancers. More than 50% of acute myeloid leukemia (AML) patients display a hyperactivation of PI3K/AKT/mTOR signaling. We investigated the anti-proliferative effect of omipalisib in AML cell lines with varied genetic backgrounds. The OCI-AML3 and THP-1 cell lines had a significant response to omipalisib, with IC50 values of 17.45 nM and 8.93 nM, respectively. We integrated transcriptomic profile and metabolomic analyses, and followed by gene set enrichment analysis (GSEA) and metabolite enrichment analysis. Our findings showed that in addition to inhibiting PI3K/AKT/mTOR signaling and inducing cell cycle arrest at the G0/G1 phase, omipalisib also suppressed mitochondrial respiration and biogenesis. Furthermore, omipalisib downregulated several genes associated with serine, glycine, threonine, and glutathione metabolism, and decreased their protein and glutathione levels. In vivo experiments revealed that omipalisib significantly inhibited tumor growth and prolonged mouse survival without weight loss. Gedatolisib and dactolisib, another two PI3K/mTOR inhibitors, exerted similar effects without affecting mitochondria biogenesis. These results highlight the multifaceted anti-leukemic effect of omipalisib, revealing its potential as a novel therapeutic agent in AML treatment.
AB - Omipalisib (GSK2126458), a potent dual PI3K/mTOR inhibitor, is reported to exhibit anti-tumor effect in several kinds of cancers. More than 50% of acute myeloid leukemia (AML) patients display a hyperactivation of PI3K/AKT/mTOR signaling. We investigated the anti-proliferative effect of omipalisib in AML cell lines with varied genetic backgrounds. The OCI-AML3 and THP-1 cell lines had a significant response to omipalisib, with IC50 values of 17.45 nM and 8.93 nM, respectively. We integrated transcriptomic profile and metabolomic analyses, and followed by gene set enrichment analysis (GSEA) and metabolite enrichment analysis. Our findings showed that in addition to inhibiting PI3K/AKT/mTOR signaling and inducing cell cycle arrest at the G0/G1 phase, omipalisib also suppressed mitochondrial respiration and biogenesis. Furthermore, omipalisib downregulated several genes associated with serine, glycine, threonine, and glutathione metabolism, and decreased their protein and glutathione levels. In vivo experiments revealed that omipalisib significantly inhibited tumor growth and prolonged mouse survival without weight loss. Gedatolisib and dactolisib, another two PI3K/mTOR inhibitors, exerted similar effects without affecting mitochondria biogenesis. These results highlight the multifaceted anti-leukemic effect of omipalisib, revealing its potential as a novel therapeutic agent in AML treatment.
U2 - 10.1038/s41417-023-00675-2
DO - 10.1038/s41417-023-00675-2
M3 - Journal article
C2 - 37821641
AN - SCOPUS:85173676841
VL - 30
SP - 1691
EP - 1701
JO - Cancer Gene Therapy
JF - Cancer Gene Therapy
SN - 0929-1903
ER -
ID: 371688582