Novel dual-action prodrug triggers apoptosis in glioblastoma cells by releasing a glutathione quencher and lysine-specific histone demethylase 1A inhibitor

Martin Engel, Yi Sing Gee, Dale Cross, Alan Maccarone, Benjamin Heng, Amy Hulme, Grady Smith, Gilles J. Guillemin, Brett W. Stringer, Christopher J. T. Hyland, Lezanne Ooi

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Targeting epigenetic mechanisms has shown promise against several cancers but has so far been unsuccessful against glioblastoma (GBM). Altered histone 3 lysine 4 methylation and increased lysine-specific histone demethylase 1A (LSD1) expression in GBM tumours nonetheless suggest that epigenetic mechanisms are involved in GBM. We engineered a dual-action prodrug, which is activated by the high hydrogen peroxide levels associated with GBM cells. This quinone methide phenylaminecyclopropane prodrug releases the LSD1 inhibitor 2-phenylcyclopropylamine with the glutathione scavenger para-quinone methide to trigger apoptosis in GBM cells. Quinone methide phenylaminocyclopropane impaired GBM cell behaviours in two-dimensional and three-dimensional assays, and triggered cell apoptosis in several primary and immortal GBM cell cultures. These results support our double-hit hypothesis of potentially targeting LSD1 and quenching glutathione, in order to impair and kill GBM cells but not healthy astrocytes. Our data suggest this strategy is effective at selectively targeting GBM and potentially other types of cancers.

LanguageEnglish
Pages535-550
Number of pages16
JournalJournal of Neurochemistry
Volume149
Issue number4
Early online date28 Dec 2018
DOIs
Publication statusPublished - 1 May 2019

Fingerprint

Histone Demethylases
Prodrugs
Glioblastoma
Lysine
Glutathione
Apoptosis
Methylation
Cell culture
Histones
Hydrogen Peroxide
Epigenomics
Tumors
Quenching
Assays
Neoplasms
quinone methide
Astrocytes
Cell Culture Techniques

Bibliographical note

Copyright the Author(s) 2018. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

Keywords

  • apoptosis
  • glioblastoma
  • LSD1
  • methylation
  • oxidative stress

Cite this

Engel, Martin ; Gee, Yi Sing ; Cross, Dale ; Maccarone, Alan ; Heng, Benjamin ; Hulme, Amy ; Smith, Grady ; Guillemin, Gilles J. ; Stringer, Brett W. ; Hyland, Christopher J. T. ; Ooi, Lezanne. / Novel dual-action prodrug triggers apoptosis in glioblastoma cells by releasing a glutathione quencher and lysine-specific histone demethylase 1A inhibitor. In: Journal of Neurochemistry. 2019 ; Vol. 149, No. 4. pp. 535-550.
@article{b87c81779b114d0c8749ed5c4489ec4e,
title = "Novel dual-action prodrug triggers apoptosis in glioblastoma cells by releasing a glutathione quencher and lysine-specific histone demethylase 1A inhibitor",
abstract = "Targeting epigenetic mechanisms has shown promise against several cancers but has so far been unsuccessful against glioblastoma (GBM). Altered histone 3 lysine 4 methylation and increased lysine-specific histone demethylase 1A (LSD1) expression in GBM tumours nonetheless suggest that epigenetic mechanisms are involved in GBM. We engineered a dual-action prodrug, which is activated by the high hydrogen peroxide levels associated with GBM cells. This quinone methide phenylaminecyclopropane prodrug releases the LSD1 inhibitor 2-phenylcyclopropylamine with the glutathione scavenger para-quinone methide to trigger apoptosis in GBM cells. Quinone methide phenylaminocyclopropane impaired GBM cell behaviours in two-dimensional and three-dimensional assays, and triggered cell apoptosis in several primary and immortal GBM cell cultures. These results support our double-hit hypothesis of potentially targeting LSD1 and quenching glutathione, in order to impair and kill GBM cells but not healthy astrocytes. Our data suggest this strategy is effective at selectively targeting GBM and potentially other types of cancers.",
keywords = "apoptosis, glioblastoma, LSD1, methylation, oxidative stress",
author = "Martin Engel and Gee, {Yi Sing} and Dale Cross and Alan Maccarone and Benjamin Heng and Amy Hulme and Grady Smith and Guillemin, {Gilles J.} and Stringer, {Brett W.} and Hyland, {Christopher J. T.} and Lezanne Ooi",
note = "Copyright the Author(s) 2018. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.",
year = "2019",
month = "5",
day = "1",
doi = "10.1111/jnc.14655",
language = "English",
volume = "149",
pages = "535--550",
journal = "Journal of Neurochemistry",
issn = "0022-3042",
publisher = "Wiley-Blackwell, Wiley",
number = "4",

}

Novel dual-action prodrug triggers apoptosis in glioblastoma cells by releasing a glutathione quencher and lysine-specific histone demethylase 1A inhibitor. / Engel, Martin; Gee, Yi Sing; Cross, Dale; Maccarone, Alan; Heng, Benjamin; Hulme, Amy; Smith, Grady; Guillemin, Gilles J.; Stringer, Brett W.; Hyland, Christopher J. T.; Ooi, Lezanne.

In: Journal of Neurochemistry, Vol. 149, No. 4, 01.05.2019, p. 535-550.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Novel dual-action prodrug triggers apoptosis in glioblastoma cells by releasing a glutathione quencher and lysine-specific histone demethylase 1A inhibitor

AU - Engel,Martin

AU - Gee,Yi Sing

AU - Cross,Dale

AU - Maccarone,Alan

AU - Heng,Benjamin

AU - Hulme,Amy

AU - Smith,Grady

AU - Guillemin,Gilles J.

AU - Stringer,Brett W.

AU - Hyland,Christopher J. T.

AU - Ooi,Lezanne

N1 - Copyright the Author(s) 2018. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

PY - 2019/5/1

Y1 - 2019/5/1

N2 - Targeting epigenetic mechanisms has shown promise against several cancers but has so far been unsuccessful against glioblastoma (GBM). Altered histone 3 lysine 4 methylation and increased lysine-specific histone demethylase 1A (LSD1) expression in GBM tumours nonetheless suggest that epigenetic mechanisms are involved in GBM. We engineered a dual-action prodrug, which is activated by the high hydrogen peroxide levels associated with GBM cells. This quinone methide phenylaminecyclopropane prodrug releases the LSD1 inhibitor 2-phenylcyclopropylamine with the glutathione scavenger para-quinone methide to trigger apoptosis in GBM cells. Quinone methide phenylaminocyclopropane impaired GBM cell behaviours in two-dimensional and three-dimensional assays, and triggered cell apoptosis in several primary and immortal GBM cell cultures. These results support our double-hit hypothesis of potentially targeting LSD1 and quenching glutathione, in order to impair and kill GBM cells but not healthy astrocytes. Our data suggest this strategy is effective at selectively targeting GBM and potentially other types of cancers.

AB - Targeting epigenetic mechanisms has shown promise against several cancers but has so far been unsuccessful against glioblastoma (GBM). Altered histone 3 lysine 4 methylation and increased lysine-specific histone demethylase 1A (LSD1) expression in GBM tumours nonetheless suggest that epigenetic mechanisms are involved in GBM. We engineered a dual-action prodrug, which is activated by the high hydrogen peroxide levels associated with GBM cells. This quinone methide phenylaminecyclopropane prodrug releases the LSD1 inhibitor 2-phenylcyclopropylamine with the glutathione scavenger para-quinone methide to trigger apoptosis in GBM cells. Quinone methide phenylaminocyclopropane impaired GBM cell behaviours in two-dimensional and three-dimensional assays, and triggered cell apoptosis in several primary and immortal GBM cell cultures. These results support our double-hit hypothesis of potentially targeting LSD1 and quenching glutathione, in order to impair and kill GBM cells but not healthy astrocytes. Our data suggest this strategy is effective at selectively targeting GBM and potentially other types of cancers.

KW - apoptosis

KW - glioblastoma

KW - LSD1

KW - methylation

KW - oxidative stress

UR - http://www.scopus.com/inward/record.url?scp=85061008185&partnerID=8YFLogxK

U2 - 10.1111/jnc.14655

DO - 10.1111/jnc.14655

M3 - Article

VL - 149

SP - 535

EP - 550

JO - Journal of Neurochemistry

T2 - Journal of Neurochemistry

JF - Journal of Neurochemistry

SN - 0022-3042

IS - 4

ER -