The hepoxilin analog PBT-3 induces apoptosis in BCR-ABL-positive K562 leukemia cells.
BACKGROUND
Leukemia is a heterogeneous disease characterized by malignant proliferation of cells of the hematopoietic system. The use of chemotherapeutic agents is still the mainstay of anti-leukemia therapy. Despite this, significant morbidity and mortality still occurs. We describe herein novel apoptotic effects of PBT-3, one of a family of stable analogs of the Hepoxilins, natural products derived from arachidonic acid.


METHODS
Inhibition of [3H]-thymidine incorporation, nuclear fragmentation, DNA laddering, FACS analysis as well as Annexin V binding were assessed.


RESULTS
PBT-3 dose-dependently causes apoptosis of the CML cell line, K562, in vitro. PBT-3 acts by increasing cytochrome c release into the cytoplasm and by activation of caspase-3 degradation. The effects of PBT-3 compare favorably with those of STI571 (Gleevec), while thromboxane agonists and antagonists are without effect.


CONCLUSIONS
These results suggest that PBT analogs may provide a new platform for the development of apoptotic drugs in leukemia.
Qiao
Na
N
Research Institute and Division of Haematopathology, Hospital for Sick Children, 555 University Avenue, Toronto, M5G 1X8, Canada.
Lam
Janice
J
Reynaud
Denis
D
Abdelhaleem
Mohamed
M
Pace-Asciak
Cecil R
CR
D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism; D006801:Humans; D020014:K562 Cells; D017482:Receptors, Thromboxane / Q000378:metabolism
C453725:PBT-3 compound; D017482:Receptors, Thromboxane; D045304:Cytochromes c; D016044:Fusion Proteins, bcr-abl; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D015126:8,11,14-Eicosatrienoic Acid