Overproduction of BCR-ABL induces apoptosis in imatinib mesylate-resistant cell lines.
BACKGROUND
Imatinib mesylate, a BCR-ABL tyrosine kinase inhibitor, induces apoptosis in chronic myeloid leukemia cells. Resistance to imatinib is currently the most important concern of this treatment. One of the main mechanisms of this resistance is overexpression of BCR-ABL.


METHODS
In the current study, the authors investigated the correlation between BCR-ABL overexpression and apoptosis in BaF/BCR-ABL and LAMA84 cell lines resistant to imatinib suddenly deprived of the inhibitor, and compared with their sensitive counterpart.


RESULTS
Removal of imatinib from culture medium led to a decrease in Bcr-Abl protein expression by Day 5, which was sustained for > or = 3 weeks of imatinib deprivation. Apoptosis was observed after 3 days of imatinib deprivation in resistant lines accompanied by caspase activation, loss of membrane asymmetry (annexin V staining), and alteration of mitochondrial potential (dihexyloxacarbocyanine iodide [DiOC6]). Transient activation of the STAT5/Bcl-xL pathway and Akt kinase activity preceded these responses.


CONCLUSIONS
Thus, imatinib removal led to apoptosis of BCR-ABL-overexpressing leukemic cells, a phenomenon that could be exploited to sensitize imatinib-resistant cells to the cytotoxic effect of other drugs.
Desplat
Vanessa
V
Laboratoire Hematopoïése normale et pathologique FRE CNRS 2617, Université Victor Ségalen, Bordeaux Cedex, France.
Belloc
Francis
F
Lagarde
Valérie
V
Boyer
Catherine
C
Melo
Junia V
JV
Reiffers
Josy
J
Praloran
Vincent
V
Mahon
François-Xavier
FX
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics*; D001549:Benzamides; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D016044:Fusion Proteins, bcr-abl / Q000096:biosynthesis*; D016313:Genes, abl; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000473:pathology; D008928:Mitochondria; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl