Blockage of cyclin cdk's, PKC and phosphoinositol 3-kinase pathways leads to augmentation of apoptosis in drug-resistant leukemia cells: evidence for interactive effects of flavopiridol, LY 294002, roscovitine,wortmannin and UCN-01.
A mouse leukemia L1210 cell line (Y8), selected for resistance to deoxyadenosine, has a markedly altered phenotypic expression that includes loss of sensitivity to dATP as an allosteric inhibitor of ribonucleotide reductase, increased expression of c-myc, c-fos and WAF1/p21, but decreased expression of p53. In addition, the Y8 cells have a Very strong apoptotic response to a variety of agents under conditions in which the parental wild-type cells do not apoptose. In these studies, we show that flavopiridol (a cdk inhibitor) causes the Y8 cells to undergo apoptosis via a caspase-3 activation process. The apoptotic response to flavopiridol is markedly enhanced by LY294002. Data also show that the apoptotic response of the Y8 cells to roscovitine (a cdk inhibitor) is enhanced by UCN-01 (a PKC inhibitor). These data show that simultaneous blockage of specific pathways leads to increased apoptosis in the Y8 cells with essentially no effects on the parental wild-type L1210 cells.
Cory
Ann H
AH
Department of Biochemistry and Molecular Biology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA.
Somerville
Lilla
L
Cory
Joseph G
JG
D000730:Androstadienes / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002867:Chromones / Q000008:administration & dosage / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D005419:Flavonoids / Q000008:administration & dosage / Q000494:pharmacology; D007939:Leukemia L1210 / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D009025:Morpholines / Q000008:administration & dosage / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011687:Purines / Q000008:administration & dosage / Q000494:pharmacology; D000077546:Roscovitine; D019311:Staurosporine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D000077191:Wortmannin
D000730:Androstadienes; D002867:Chromones; D004791:Enzyme Inhibitors; D005419:Flavonoids; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010880:Piperidines; D011687:Purines; D000077546:Roscovitine; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C077990:alvocidib; C054852:7-hydroxystaurosporine; D011493:Protein Kinase C; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D019311:Staurosporine; D000077191:Wortmannin