The phosphatidylethanolamine biosynthesis pathway provides a new target for cancer chemotherapy.
Adult
Aged
Animals
Carcinoma, Hepatocellular
/ drug therapy
Cell Survival
/ drug effects
Drug Therapy, Combination
/ methods
Female
Gene Knockout Techniques
Glycolysis
/ drug effects
Hep G2 Cells
Humans
Induced Pluripotent Stem Cells
/ drug effects
Leukemia, Myeloid, Acute
/ blood
Liver
/ embryology
Liver Neoplasms
/ drug therapy
Male
Meclizine
/ administration & dosage
Mice
Middle Aged
Organogenesis
/ drug effects
Organoids
/ drug effects
Phosphatidylethanolamines
/ antagonists & inhibitors
Pyridines
/ administration & dosage
Quinolines
/ administration & dosage
RNA Nucleotidyltransferases
/ deficiency
Retrospective Studies
Treatment Outcome
Xenograft Model Antitumor Assays
AML
Cancer
Chemotherapy
HCC
Hepatic organoid
Pluripotent stem cells
Tumor
Journal
Journal of hepatology
ISSN: 1600-0641
Titre abrégé: J Hepatol
Pays: Netherlands
ID NLM: 8503886
Informations de publication
Date de publication:
04 2020
04 2020
Historique:
received:
16
08
2019
revised:
01
11
2019
accepted:
01
11
2019
pubmed:
25
11
2019
medline:
7
10
2021
entrez:
25
11
2019
Statut:
ppublish
Résumé
Since human induced pluripotent stem cells (iPSCs) develop into hepatic organoids through stages that resemble human embryonic liver development, they can be used to study developmental processes and disease pathology. Therefore, we examined the early stages of hepatic organoid formation to identify key pathways affecting early liver development. Single-cell RNA-sequencing and metabolomic analysis was performed on developing organoid cultures at the iPSC, hepatoblast (day 9) and mature organoid stage. The importance of the phosphatidylethanolamine biosynthesis pathway to early liver development was examined in developing organoid cultures using iPSC with a CRISPR-mediated gene knockout and an over the counter medication (meclizine) that inhibits the rate-limiting enzyme in this pathway. Meclizine's effect on the growth of a human hepatocarcinoma cell line in a xenotransplantation model and on the growth of acute myeloid leukemia cells in vitro was also examined. Transcriptomic and metabolomic analysis of organoid development indicated that the phosphatidylethanolamine biosynthesis pathway is essential for early liver development. Unexpectedly, early hepatoblasts were selectively sensitive to the cytotoxic effect of meclizine. We demonstrate that meclizine could be repurposed for use in a new synergistic combination therapy for primary liver cancer: a glycolysis inhibitor reprograms cancer cell metabolism to make it susceptible to the cytotoxic effect of meclizine. This combination inhibited the growth of a human liver carcinoma cell line in vitro and in a xenotransplantation model, without causing significant side effects. This drug combination was also highly active against acute myeloid leukemia cells. Our data indicate that phosphatidylethanolamine biosynthesis is a targetable pathway for cancer; meclizine may have clinical efficacy as a repurposed anti-cancer drug when used as part of a new combination therapy. The early stages of human liver development were modeled using human hepatic organoids. We identified a pathway that was essential for early liver development. Based upon this finding, a novel combination drug therapy was identified that could be used to treat primary liver cancer and possibly other types of cancer.
Sections du résumé
BACKGROUND & AIMS
Since human induced pluripotent stem cells (iPSCs) develop into hepatic organoids through stages that resemble human embryonic liver development, they can be used to study developmental processes and disease pathology. Therefore, we examined the early stages of hepatic organoid formation to identify key pathways affecting early liver development.
METHODS
Single-cell RNA-sequencing and metabolomic analysis was performed on developing organoid cultures at the iPSC, hepatoblast (day 9) and mature organoid stage. The importance of the phosphatidylethanolamine biosynthesis pathway to early liver development was examined in developing organoid cultures using iPSC with a CRISPR-mediated gene knockout and an over the counter medication (meclizine) that inhibits the rate-limiting enzyme in this pathway. Meclizine's effect on the growth of a human hepatocarcinoma cell line in a xenotransplantation model and on the growth of acute myeloid leukemia cells in vitro was also examined.
RESULTS
Transcriptomic and metabolomic analysis of organoid development indicated that the phosphatidylethanolamine biosynthesis pathway is essential for early liver development. Unexpectedly, early hepatoblasts were selectively sensitive to the cytotoxic effect of meclizine. We demonstrate that meclizine could be repurposed for use in a new synergistic combination therapy for primary liver cancer: a glycolysis inhibitor reprograms cancer cell metabolism to make it susceptible to the cytotoxic effect of meclizine. This combination inhibited the growth of a human liver carcinoma cell line in vitro and in a xenotransplantation model, without causing significant side effects. This drug combination was also highly active against acute myeloid leukemia cells.
CONCLUSION
Our data indicate that phosphatidylethanolamine biosynthesis is a targetable pathway for cancer; meclizine may have clinical efficacy as a repurposed anti-cancer drug when used as part of a new combination therapy.
LAY SUMMARY
The early stages of human liver development were modeled using human hepatic organoids. We identified a pathway that was essential for early liver development. Based upon this finding, a novel combination drug therapy was identified that could be used to treat primary liver cancer and possibly other types of cancer.
Identifiants
pubmed: 31760071
pii: S0168-8278(19)30676-2
doi: 10.1016/j.jhep.2019.11.007
pmc: PMC7085447
mid: NIHMS1545591
pii:
doi:
Substances chimiques
PFK158
0
Phosphatidylethanolamines
0
Pyridines
0
Quinolines
0
Meclizine
3L5TQ84570
RNA Nucleotidyltransferases
EC 2.7.7.-
Ethanolamine-phosphate cytidylyltransferase
EC 2.7.7.14
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
746-760Subventions
Organisme : NCI NIH HHS
ID : K99 CA207731
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK102182
Pays : United States
Informations de copyright
Copyright © 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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