It appears that MB cells are more resistant to PEITC and taxol than MCF cells, and higher concentra tions of taxol did not further enhance the effect on growth inhibition. major clinical sellekchem limitations are neurotoxicity and cellular resistance after prolonged treatment. PEITC is a novel epigenetic agent with a dual effect of histone deacetylation and DNA methylation. This study found that the two agents have a profound synergistic inhibitory effect on the growth of two different breast cancer cell lines, MCF and MDA MB 231. The IC50 of PEITC and taxol decrease dramatically when the two chemicals are used in combination. These results suggest that it is highly possible to significantly reduce side effects of taxol while maintaining or enhancing clinical efficacy by combining the two drugs.

We hypothesize that by combining PEITC and taxol, it is possible to significantly reduce toxicity in vivo by reducing the dosage of taxol needed while maintaining clinical efficacy for breast cancer and other solid tumors. This hypothesis appears to be supported by this in vitro study, and can be tested further in mouse model carrying breast cancer xenografts. Novel agents targeting different molecular pathways are being actively studied for targeted cancer therapy. A recent study has shown that the HDAC inhibitor vorinostat can up regulate estrogen receptors and make breast cancer cells more sensitive to tamoxifen. A preliminary report from a recent clinical study seems to corroborate this laboratory finding, where patients with hormone refractory breast cancer showed responses to tamoxifen again after vorinostat treatment.

Since PEITC is a HDAC inhibitor as well as a tubulin targeting agent, it would be worthwhile to test the combination of PEITC and tamoxifen for therapy of hormone refractory breast cancer. Similar to previous reports, we also observed that very high concentrations of taxol did not further increase growth inhibition and apoptosis. This may be due to the fact that higher concentrations of taxol have the oppos ite effect on cell growth as reported earlier. The exact mechanism remains unclear. In conclusion, this is the first study to show that the combination of the epigenetic agent PEITC with the chemotherapeutic agent taxol exhibits a synergistic ef fect on growth inhibition, cell cycle arrest, and apoptosis in breast cancer cells.

This novel strategy deserves further study in vivo. Background Chronic myeloid leukemia is a hematopoietic dis order characterized by unregulated proliferation of predom inantly myeloid cells in the bone marrow. BCR ABL fusion proteins resulting from the chromosomal transloca tion t cause CML. BCR ABL activity leads to uncontrolled cell prolifera tion, reduced apoptosis, AV-951 and malignant expansion of hematopoietic stem cell populations.