The c-Jun-N-terminal-Kinase inhibitor SP600125 enhances the butyrate derivative D1-induced apoptosis via caspase 8 activation in Kasumi 1 t(8;21) acute myeloid leukaemia cells.
We recently showed that the histone deacetylase inhibitor D1 induced apoptosis in the t(8;21) Kasumi 1 acute myeloid leukaemia (AML) cell line and activated caspase 9. The present study characterised the effects of the combined administration of D1 with PD98059, SB203580 or SP600125, specific inhibitors of mitogen-activated protein kinase, extracellular signal-regulated kinases 1 and 2 (ERK1/2), p38 or Jun N-terminal kinase (JNK), respectively. Among these inhibitors, SP600125 was the only one to markedly induce apoptosis and decrease cell proliferation. These experiments showed that SP600125 activated caspase 8 and confirmed that D1 activated the intrinsic pathway of apoptosis, as caspase 8 was not affected while Bcl-2 was down-regulated following D1 administration. The combination of the two drugs enhanced caspase-8 activation and induced apoptosis in an additive fashion. JNK was constitutively activated in the Kasumi 1, NB4, HL60 and THP-1 human AML cell lines, as well as in primary blasts from a t(8;21) AML patient. In all these cells, the pro-apoptotic effect of the two drugs alone was increased when they were combined. On this basis, the combined administration of D1 with SP600125 seems to be very promising as a potential anti-leukaemic tool in AML.
Rovida
Elisabetta
E
Department of Experimental Pathology and Oncology, Università degli Studi di Firenze, Firenze, Italy.
Gozzini
Antonella
A
Barbetti
Valentina
V
Giuntoli
Serena
S
Santini
Valeria
V
Dello Sbarba
Persio
P
D000873:Anthracenes / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western / Q000379:methods; D002087:Butyrates / Q000627:therapeutic use*; D053181:Caspase 8 / Q000032:analysis / Q000378:metabolism; D045744:Cell Line, Tumor; D002891:Chromosomes, Human, Pair 21; D002898:Chromosomes, Human, Pair 8; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D005419:Flavonoids / Q000627:therapeutic use; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D008358:Mannose / Q000031:analogs & derivatives* / Q000627:therapeutic use; D011725:Pyridines / Q000627:therapeutic use; D014178:Translocation, Genetic; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
D000873:Anthracenes; D002087:Butyrates; D005419:Flavonoids; D056572:Histone Deacetylase Inhibitors; D007093:Imidazoles; C517551:O-n-butanoyl-2,3-O-isopropylidenemannofuranoside; D011725:Pyridines; C432165:pyrazolanthrone; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D053181:Caspase 8; C093642:SB 203580; D008358:Mannose; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one