The hepoxilin analog PBT-3 induces apoptosis in BCR-ABL-positive K562 leukemia cells

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.

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

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.

These results suggest that PBT analogs may provide a new platform for the development of apoptotic drugs in leukemia.