Cell death triggered by synthetic flavonoids in human leukemia cells is amplified by the inhibition of extracellular signal-regulated kinase signaling

Abstract A new class of methyl esters of flavonoids, with different substituents on the B ring were synthesized and evaluated for their antiproliferative activity against the human leukemia cell line HL-60. The presence of either a methyl group ( 1f ) or a chlorine atom ( 1o ) at position 2′ of the B ring played an important role in affecting antiproliferative activity. The cytotoxic effects of these compounds were accompanied by the concentration- and time-dependent appearance of DNA- and nuclear-fragmentation, increase in the percentage of sub-G 1 cells, and processing of multiple caspases and poly(ADP-ribose)polymerase cleavage. Pretreatment of cells with the specific mitogen-activated extracellular kinases (MEK) 1/2 inhibitor PD98059, together with 1f and 1o , resulted in an important enhancement of cell death, which might have clinical implications for the use of both compounds in combination with MEK 1/2 inhibitors as potential therapeutic agents.