The Bcr-Abl kinase inhibitor INNO-406 induces autophagy and different modes of cell death execution in Bcr-Abl-positive leukemias.
Bcr-Abl tyrosine kinase (TK) inhibitors are promising therapeutic agents for Bcr-Abl-positive (Bcr-Abl(+)) leukemias. Although they are known to promote caspase-mediated apoptosis, it remains unclear whether caspase-independent cell death-inducing mechanisms are also triggered. Here we demonstrated that INNO-406, a second-generation Bcr-Abl TK inhibitor, induces programmed cell death (PCD) in chronic myelogenous leukemia (CML) cell lines through both caspase-mediated and caspase-independent pathways. The latter pathways include caspase-independent apoptosis (CIA) and necrosis-like cell death (CIND), and the cell lines varied regarding which mechanism was elicited upon INNO-406 treatment. We also observed that the propensity toward CIA or CIND in cells was strongly associated with cellular dependency on apoptosome-mediated caspase activity. Cells that undergo CIND have a high apoptosome activity potential whereas cells that undergo CIA tend to have a lower potential. Moreover, we found that INNO-406 promotes autophagy. When autophagy was inhibited with chloroquine or gene knockdown of beclin1 by shRNA, INNO-406-induced cell death was enhanced, which indicates that the autophagic response of the tumor cells is protective. These findings suggest new insights into the biology and therapy of Bcr-Abl(+) leukemias.
Kamitsuji
Y
Y
Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Kuroda
J
J
Kimura
S
S
Toyokuni
S
S
Watanabe
K
K
Ashihara
E
E
Tanaka
H
H
Yui
Y
Y
Watanabe
M
M
Matsubara
H
H
Mizushima
Y
Y
Hiraumi
Y
Y
Kawata
E
E
Yoshikawa
T
T
Maekawa
T
T
Nakahata
T
T
Adachi
S
S
D000818:Animals; D053478:Apoptosomes / Q000187:drug effects / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002738:Chloroquine / Q000494:pharmacology; D019610:Cytoprotection / Q000187:drug effects; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000201:enzymology* / Q000473:pathology*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D053478:Apoptosomes; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D002738:Chloroquine; D016044:Fusion Proteins, bcr-abl; D020169:Caspases; C506918:bafetinib