Hepoxilin Analogs, PBT-3 and PBT-4, Cause Apoptosis of Gleevec-resistant K562 Cells In Vitro

The use of Gleevec ® in the treatment of leukemia has been widely accepted, although resistance to Gleevec is commonly observed. Gleevec represents a new direction in the development of target-focused chemotherapeutic agents in cancer. Gleevec inhibits the tyrosine kinase activity of Bcr-Abl, which is responsible for leukemic cell survival. We have previously shown that PBT-3 (racemic anti-10(R/S)-hydroxy- 11,12-cyclopropyl-eicosa-5Z, 8Z,14Z-trienoic acid methyl ester) and PBT-4 (racemic syn-10(R/S)-hydroxy-11,12-cyclopropyl- eicosa-5Z 8Z,14Z-trienoic acid methyl ester), stable analogs of the hepoxilins, caused apoptosis of the human leukemic K562 cell line in vitro and in vivo. We also showed that PBTs inhibited the growth of tumours derived from the inoculation of immunodeficient mice with K562 cells and that the effect of PBTs was synergistic with that of Gleevec. We now show that the effect of PBT-3 and of PBT-4 is independent of that of Gleevec, demonstrating that Gleevec-resistant K562 cells retain their responsiveness to PBT treatment, resulting in apoptosis. These findings provide important information suggesting that the two compounds, PBT and Gleevec, can be used together in the treatment of leukemia. The PBTs may provide a new platform for the development of apoptotic drugs in cancer. Leukemia is a heterogeneous disease characterized by malignant proliferation of cells of the hematopoietic system. Leukemic cells contain a Bcr-Abl chimeric fusion protein,