Proapoptotic effects of novel pentabromobenzylisothioureas in human leukemia cell lines

Abstract

A series of new pentabromobenzylisothioureas [ZKK-1-ZKK-5; (ZKKs)] carrying additional substituents on nitrogen atoms has been synthesized. The ZKKs were found to induce apoptosis in HL-60 (human promyleocytic leukemia) and K-562 (human chronic erythromyeloblastoid leukemia) cell lines in a concentration-dependent manner at low micromolar concentrations. ZKK-3 [(N,N'- dimethyl-S-2,3,4,5,6-pentabromobenzyl)isothiouronium bromide] showed the highest proapoptotic activity in HL-60 cells, whereas ZKK-2 [N-methyl-S-(2,3,4,5,6- pentabromobenzyl)isothiouronium bromide] was most effective in this respect in K-562 cells. During the ZKKsinduced apoptosis, an 85 kDa fragment of cleaved PARP (caspase-3 and caspase-7 substrate) was detected in both cell lines tested. The studied compounds also decreased mitochondrial transmembrane potential in both these cell lines and caused the cells to accumulate in G 1 and at the G 1/S border of the cell cycle in a concentration-dependent manner. These results show promise for their study as new compounds in the treatment of leukemia, after an appropriate preclinical toxicity profile. © Springer Science+Business Media, LLC 2011.