Adaphostin and bortezomib induce oxidative injury and apoptosis in imatinib mesylate-resistant hematopoietic cells expressing mutant forms of Bcr/Abl.
Effects of the tyrphostin adaphostin and bortezomib were examined in Bcr/Abl+ leukemia cell resistant to imatinib mesylate secondary to Bcr/Abl point mutations. Adaphostin was equally effective in inducing mitochondrial damage, caspase activation, JNK activation, and Raf-1, phospho-Stat3 and -Stat5 inactivation in mutant and wild-type cells, but differentially down-regulated phospho-Bcr/Abl. Adaphostin and bortezomib synergistically induced apoptosis in wild-type and mutant cells, including T315I mutants. Notably, adaphostin+/-bortezomib potently induced ROS and lethality in mutant cells, effects attenuated by the antioxidant NAC. These findings indicate that adaphostin+/-bortezomib circumvent imatinib resistance due to Bcr/Abl point mutations most likely through ROS generation.
Department of Medicine, Virginia Commonwealth University/Massey Cancer Center, Richmond, VA 23298, USA.
Girija
G
Dasmahapatra
Tri K
TK
Nguyen
Paul
P
Dent
Steven
S
Grant
D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D016044:Fusion Proteins, bcr-abl / Q000187:drug effects / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D006801:Humans; D006873:Hydroquinones / Q000494:pharmacology*; D000068877:Imatinib Mesylate; D007700:Kinetics; D009154:Mutation; D018384:Oxidative Stress / Q000187:drug effects*; D010879:Piperazines / Q000494:pharmacology*; D017354:Point Mutation; D011719:Pyrazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism
D000970:Antineoplastic Agents; D001549:Benzamides; D001897:Boronic Acids; D006873:Hydroquinones; C404397:NSC 680410; D010879:Piperazines; D011719:Pyrazines; D011743:Pyrimidines; D017382:Reactive Oxygen Species; D000069286:Bortezomib; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; D000218:Adamantane