Abstract
Homoharringtonine (HHT) has been reported to be effective in a portion of patients with acute myeloid leukemia (AML) and chronic myeloid leukemia (CML). To investigate its mechanism of action, cell growth inhibition and cytotoxicity of HHT were investigated in three AML cell lines, HL-60, NB4, and U937, and in three CML cell lines, K562, KU812, and KCL22. AML cells were more sensitive than CML cells to HHT-induced cytotoxicity. Using HL-60 cells it was revealed that HHT decreased the levels of Mcl-1, XIAP, survivin, and BH3-only proteins as well as the mitochondria membrane potential. The levels of Bcl-2, Bax, and Bak proteins in HL-60 cells were not changed after HHT treatment. U937, K562, KU812 and KCL22 cells expressed Bcl-XL and were less responsive to HHT-induced apoptosis than HL-60 cells. Silencing Mcl-1 or Bxl-XL, but not XIAP or survivin, enhanced HHT-induced apoptosis in U937 cells. The levels of HHT-induced apoptosis in K562, KCL22, and KU812 cells were inversely correlated with the levels of Bcl-XL, but not Bcl-2 or Mcl-1. K562 cells expressing high levels of Bcl-XL but no Bcl-2 were less responsive to HHT-induced apoptosis than KCL22 cells which expressed lower levels of Bcl-XL and higher levels of Bcl-2 protein. In K562 cells, knock-down of Bcl-XL, but not of Mcl-1, enhanced HHT-induced apoptosis. Transfection of Bcl-XL into KCL22 cells attenuated HHT-induced apoptosis. These data suggest that Bcl-XL plays a more important role than Bcl-2 and Mcl-1 in protecting against HHT-induced apoptosis.
- Received August 30, 2010.
- Revision received March 17, 2011.
- Accepted March 17, 2011.
- The American Society for Pharmacology and Experimental Therapeutics