Cargando…

Effects of the Autophagy-Inhibiting Agent Chloroquine on Acute Myeloid Leukemia Cells; Characterization of Patient Heterogeneity

Autophagy is a highly conserved cellular degradation process that prevents cell damage and promotes cell survival, and clinical efforts have exploited autophagy inhibition as a therapeutic strategy in cancer. Chloroquine is a well-known antimalarial agent that inhibits late-stage autophagy. We evalu...

Descripción completa

Detalles Bibliográficos
Autores principales: Grønningsæter, Ida Sofie, Reikvam, Håkon, Aasebø, Elise, Bartaula-Brevik, Sushma, Hernandez-Valladares, Maria, Selheim, Frode, Berven, Frode S., Tvedt, Tor Henrik, Bruserud, Øystein, Hatfield, Kimberley Joanne
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8399694/
https://www.ncbi.nlm.nih.gov/pubmed/34442423
http://dx.doi.org/10.3390/jpm11080779
_version_ 1783745139357777920
author Grønningsæter, Ida Sofie
Reikvam, Håkon
Aasebø, Elise
Bartaula-Brevik, Sushma
Hernandez-Valladares, Maria
Selheim, Frode
Berven, Frode S.
Tvedt, Tor Henrik
Bruserud, Øystein
Hatfield, Kimberley Joanne
author_facet Grønningsæter, Ida Sofie
Reikvam, Håkon
Aasebø, Elise
Bartaula-Brevik, Sushma
Hernandez-Valladares, Maria
Selheim, Frode
Berven, Frode S.
Tvedt, Tor Henrik
Bruserud, Øystein
Hatfield, Kimberley Joanne
author_sort Grønningsæter, Ida Sofie
collection PubMed
description Autophagy is a highly conserved cellular degradation process that prevents cell damage and promotes cell survival, and clinical efforts have exploited autophagy inhibition as a therapeutic strategy in cancer. Chloroquine is a well-known antimalarial agent that inhibits late-stage autophagy. We evaluated the effects of chloroquine on cell viability and proliferation of acute myeloid leukemia acute myeloid leukemia (AML) cells derived from 81 AML patients. Our results show that chloroquine decreased AML cell viability and proliferation for the majority of patients. Furthermore, a subgroup of AML patients showed a greater susceptibility to chloroquine, and using hierarchical cluster analysis, we identified 99 genes upregulated in this patient subgroup, including several genes related to leukemogenesis. The combination of chloroquine with low-dose cytarabine had an additive inhibitory effect on AML cell proliferation. Finally, a minority of patients showed increased extracellular constitutive mediator release in the presence of chloroquine, which was associated with strong antiproliferative effects of chloroquine as well as cytarabine. We conclude that chloroquine has antileukemic activity and should be further explored as a therapeutic drug against AML in combination with other cytotoxic or metabolic drugs; however, due to the patient heterogeneity, chloroquine therapy will probably be effective only for selected patients.
format Online
Article
Text
id pubmed-8399694
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-83996942021-08-29 Effects of the Autophagy-Inhibiting Agent Chloroquine on Acute Myeloid Leukemia Cells; Characterization of Patient Heterogeneity Grønningsæter, Ida Sofie Reikvam, Håkon Aasebø, Elise Bartaula-Brevik, Sushma Hernandez-Valladares, Maria Selheim, Frode Berven, Frode S. Tvedt, Tor Henrik Bruserud, Øystein Hatfield, Kimberley Joanne J Pers Med Article Autophagy is a highly conserved cellular degradation process that prevents cell damage and promotes cell survival, and clinical efforts have exploited autophagy inhibition as a therapeutic strategy in cancer. Chloroquine is a well-known antimalarial agent that inhibits late-stage autophagy. We evaluated the effects of chloroquine on cell viability and proliferation of acute myeloid leukemia acute myeloid leukemia (AML) cells derived from 81 AML patients. Our results show that chloroquine decreased AML cell viability and proliferation for the majority of patients. Furthermore, a subgroup of AML patients showed a greater susceptibility to chloroquine, and using hierarchical cluster analysis, we identified 99 genes upregulated in this patient subgroup, including several genes related to leukemogenesis. The combination of chloroquine with low-dose cytarabine had an additive inhibitory effect on AML cell proliferation. Finally, a minority of patients showed increased extracellular constitutive mediator release in the presence of chloroquine, which was associated with strong antiproliferative effects of chloroquine as well as cytarabine. We conclude that chloroquine has antileukemic activity and should be further explored as a therapeutic drug against AML in combination with other cytotoxic or metabolic drugs; however, due to the patient heterogeneity, chloroquine therapy will probably be effective only for selected patients. MDPI 2021-08-10 /pmc/articles/PMC8399694/ /pubmed/34442423 http://dx.doi.org/10.3390/jpm11080779 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Grønningsæter, Ida Sofie
Reikvam, Håkon
Aasebø, Elise
Bartaula-Brevik, Sushma
Hernandez-Valladares, Maria
Selheim, Frode
Berven, Frode S.
Tvedt, Tor Henrik
Bruserud, Øystein
Hatfield, Kimberley Joanne
Effects of the Autophagy-Inhibiting Agent Chloroquine on Acute Myeloid Leukemia Cells; Characterization of Patient Heterogeneity
title Effects of the Autophagy-Inhibiting Agent Chloroquine on Acute Myeloid Leukemia Cells; Characterization of Patient Heterogeneity
title_full Effects of the Autophagy-Inhibiting Agent Chloroquine on Acute Myeloid Leukemia Cells; Characterization of Patient Heterogeneity
title_fullStr Effects of the Autophagy-Inhibiting Agent Chloroquine on Acute Myeloid Leukemia Cells; Characterization of Patient Heterogeneity
title_full_unstemmed Effects of the Autophagy-Inhibiting Agent Chloroquine on Acute Myeloid Leukemia Cells; Characterization of Patient Heterogeneity
title_short Effects of the Autophagy-Inhibiting Agent Chloroquine on Acute Myeloid Leukemia Cells; Characterization of Patient Heterogeneity
title_sort effects of the autophagy-inhibiting agent chloroquine on acute myeloid leukemia cells; characterization of patient heterogeneity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8399694/
https://www.ncbi.nlm.nih.gov/pubmed/34442423
http://dx.doi.org/10.3390/jpm11080779
work_keys_str_mv AT grønningsæteridasofie effectsoftheautophagyinhibitingagentchloroquineonacutemyeloidleukemiacellscharacterizationofpatientheterogeneity
AT reikvamhakon effectsoftheautophagyinhibitingagentchloroquineonacutemyeloidleukemiacellscharacterizationofpatientheterogeneity
AT aasebøelise effectsoftheautophagyinhibitingagentchloroquineonacutemyeloidleukemiacellscharacterizationofpatientheterogeneity
AT bartaulabreviksushma effectsoftheautophagyinhibitingagentchloroquineonacutemyeloidleukemiacellscharacterizationofpatientheterogeneity
AT hernandezvalladaresmaria effectsoftheautophagyinhibitingagentchloroquineonacutemyeloidleukemiacellscharacterizationofpatientheterogeneity
AT selheimfrode effectsoftheautophagyinhibitingagentchloroquineonacutemyeloidleukemiacellscharacterizationofpatientheterogeneity
AT bervenfrodes effectsoftheautophagyinhibitingagentchloroquineonacutemyeloidleukemiacellscharacterizationofpatientheterogeneity
AT tvedttorhenrik effectsoftheautophagyinhibitingagentchloroquineonacutemyeloidleukemiacellscharacterizationofpatientheterogeneity
AT bruserudøystein effectsoftheautophagyinhibitingagentchloroquineonacutemyeloidleukemiacellscharacterizationofpatientheterogeneity
AT hatfieldkimberleyjoanne effectsoftheautophagyinhibitingagentchloroquineonacutemyeloidleukemiacellscharacterizationofpatientheterogeneity