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 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.
Robert
Guillaume
G
INSERM UMR 895, Team 2: Cell Death Differentiation and Cancer, Nice, France.
Ben Sahra
Issam
I
Puissant
Alexandre
A
Colosetti
Pascal
P
Belhacene
Nathalie
N
Gounon
Pierre
P
Hofman
Paul
P
Bost
Fréderic
F
Cassuto
Jill-Patrice
JP
Auberger
Patrick
P
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006801:Humans; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D011493:Protein Kinase C / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D012263:Ribonucleosides / Q000494:pharmacology*; D014178:Translocation, Genetic
D034741:RNA, Small Interfering; D012263:Ribonucleosides; D000620:Aminoimidazole Carboxamide; C011651:acadesine; D011493:Protein Kinase C; D055372:AMP-Activated Protein Kinases