Combinations of Novel Histone Deacetylase and Bcr-Abl Inhibitors in the Therapy of Imatinib Mesylate-Sensitive and -Refractory Bcr-Abl Expressing Leukemia
Final rept. 1 Mar 2005-28 Nov 2008
MEDICAL COLL OF GEORGIA AUGUSTA
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Overall, our findings demonstrate that the novel Bcr-Abl kinase inhibitors nilotinib or the dual Bcr-AblSrc kinase inhibitor dasatinib synergistically interact with pan-HDAC inhibitors vorinostat or panobinostat to deplete Bcr-Abl and inhibit its downstream signaling through STAT5 and AKT. This is associated with growth arrest and apoptosis of CML cells. Significantly, our findings also demonstrate that treatment with the pan-HDAC inhibitor vorinostat or panobinostat depletes the levels of unmutated and mutant forms of Bcr-Abl, as well as induces growth arrest and apoptosis of CML cells with unmutated and mutant forms of Bcr-Abl. Additionally, our findings indicate that combined treatment with vorinostat or panobinostat with nilotinib, dasatinib or MK-0457 exerts synergistic anti-Bcr-Abl activity against imatinib-sensitive and resistant CML cells. Collectively, these findings support the rationale to test the in vivo efficacy of the combination of vorinostat or panobinostat with nilotinib, dasatinib or MK-0457 against imatinib-sensitive and imatinib-resistant CML.
- Medicine and Medical Research