Acadesine kills chronic myelogenous leukemia (CML) cells through PKC-dependent induction of autophagic cell death.

Acadesine kills chronic myelogenous leukemia (CML) cells through PKC-dependent induction of autophagic cell death.

CML is an hematopoietic stem cell disease characterized by the t(9;22) (q34;q11) translocation encoding the oncoprotein p210BCR-ABL. The effect of acadesine (AICAR, 5-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside) a compound with known antileukemic effect on B cell chronic lymphoblastic leuke...

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Autores principales: Guillaume Robert, Issam Ben Sahra, Alexandre Puissant, Pascal Colosetti, Nathalie Belhacene, Pierre Gounon, Paul Hofman, Fréderic Bost, Jill-Patrice Cassuto, Patrick Auberger
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Publicado: Public Library of Science (PLoS) 2009
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Acceso en línea:https://doaj.org/article/fdb62ae3eb444b589d2b79bad894e00c
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spelling oai:doaj.org-article:fdb62ae3eb444b589d2b79bad894e00c2021-11-25T06:28:02ZAcadesine kills chronic myelogenous leukemia (CML) cells through PKC-dependent induction of autophagic cell death.1932-620310.1371/journal.pone.0007889https://doaj.org/article/fdb62ae3eb444b589d2b79bad894e00c2009-11-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19924252/?tool=EBIhttps://doaj.org/toc/1932-6203CML is an hematopoietic stem cell disease characterized by the t(9;22) (q34;q11) translocation encoding the oncoprotein p210BCR-ABL. The effect of acadesine (AICAR, 5-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside) a compound with known antileukemic effect on B cell chronic lymphoblastic leukemia (B-CLL) was investigated in different CML cell lines. Acadesine triggered loss of cell metabolism in K562, LAMA-84 and JURL-MK1 and was also effective in killing imatinib-resistant K562 cells and Ba/F3 cells carrying the T315I-BCR-ABL mutation. The anti-leukemic effect of acadesine did not involve apoptosis but required rather induction of autophagic cell death. AMPK knock-down by Sh-RNA failed to prevent the effect of acadesine, indicating an AMPK-independent mechanism. The effect of acadesine was abrogated by GF109203X and Ro-32-0432, both inhibitor of classical and new PKCs and accordingly, acadesine triggered relocation and activation of several PKC isoforms in K562 cells. In addition, this compound exhibited a potent anti-leukemic effect in clonogenic assays of CML cells in methyl cellulose and in a xenograft model of K562 cells in nude mice. In conclusion, our work identifies an original and unexpected mechanism by which acadesine triggers autophagic cell death through PKC activation. Therefore, in addition to its promising effects in B-CLL, acadesine might also be beneficial for Imatinib-resistant CML patients.Guillaume RobertIssam Ben SahraAlexandre PuissantPascal ColosettiNathalie BelhacenePierre GounonPaul HofmanFréderic BostJill-Patrice CassutoPatrick AubergerPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 4, Iss 11, p e7889 (2009)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Guillaume Robert
Issam Ben Sahra
Alexandre Puissant
Pascal Colosetti
Nathalie Belhacene
Pierre Gounon
Paul Hofman
Fréderic Bost
Jill-Patrice Cassuto
Patrick Auberger
Acadesine kills chronic myelogenous leukemia (CML) cells through PKC-dependent induction of autophagic cell death.
description CML is an hematopoietic stem cell disease characterized by the t(9;22) (q34;q11) translocation encoding the oncoprotein p210BCR-ABL. The effect of acadesine (AICAR, 5-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside) a compound with known antileukemic effect on B cell chronic lymphoblastic leukemia (B-CLL) was investigated in different CML cell lines. Acadesine triggered loss of cell metabolism in K562, LAMA-84 and JURL-MK1 and was also effective in killing imatinib-resistant K562 cells and Ba/F3 cells carrying the T315I-BCR-ABL mutation. The anti-leukemic effect of acadesine did not involve apoptosis but required rather induction of autophagic cell death. AMPK knock-down by Sh-RNA failed to prevent the effect of acadesine, indicating an AMPK-independent mechanism. The effect of acadesine was abrogated by GF109203X and Ro-32-0432, both inhibitor of classical and new PKCs and accordingly, acadesine triggered relocation and activation of several PKC isoforms in K562 cells. In addition, this compound exhibited a potent anti-leukemic effect in clonogenic assays of CML cells in methyl cellulose and in a xenograft model of K562 cells in nude mice. In conclusion, our work identifies an original and unexpected mechanism by which acadesine triggers autophagic cell death through PKC activation. Therefore, in addition to its promising effects in B-CLL, acadesine might also be beneficial for Imatinib-resistant CML patients.
format article
author Guillaume Robert
Issam Ben Sahra
Alexandre Puissant
Pascal Colosetti
Nathalie Belhacene
Pierre Gounon
Paul Hofman
Fréderic Bost
Jill-Patrice Cassuto
Patrick Auberger
author_facet Guillaume Robert
Issam Ben Sahra
Alexandre Puissant
Pascal Colosetti
Nathalie Belhacene
Pierre Gounon
Paul Hofman
Fréderic Bost
Jill-Patrice Cassuto
Patrick Auberger
author_sort Guillaume Robert
title Acadesine kills chronic myelogenous leukemia (CML) cells through PKC-dependent induction of autophagic cell death.
title_short Acadesine kills chronic myelogenous leukemia (CML) cells through PKC-dependent induction of autophagic cell death.
title_full Acadesine kills chronic myelogenous leukemia (CML) cells through PKC-dependent induction of autophagic cell death.
title_fullStr Acadesine kills chronic myelogenous leukemia (CML) cells through PKC-dependent induction of autophagic cell death.
title_full_unstemmed Acadesine kills chronic myelogenous leukemia (CML) cells through PKC-dependent induction of autophagic cell death.
title_sort acadesine kills chronic myelogenous leukemia (cml) cells through pkc-dependent induction of autophagic cell death.
publisher Public Library of Science (PLoS)
publishDate 2009
url https://doaj.org/article/fdb62ae3eb444b589d2b79bad894e00c
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