Arsenic trioxide (
As2O3) has remarkable therapeutic efficacy against
leukemia. However, after
As2O3 biotransformation, the role of
arsenic metabolites in the clinical efficacy against
leukemia still needs to be elucidated. Therefore, to explore the contribution of trivalent methylated
arsenicals in the
therapeutic effects, we investigated and compared the effects of
arsenite (iAs(III)),
monomethylarsonous acid (
MMA(III)) and
dimethylarsinous acid (DMA(III)) on HL-60 cells. Methylated
arsenic species
MMA(III) and DMA(III) showed potentially reduced cell survival with IC50 values of 3 and 2 μM, respectively. We found that methylated metabolites caused apoptosis through oxidative stress and loss of mitochondrial membrane potential. Furthermore, we found that the
caspase-9 and -3 were markedly activated by exposure to methylated metabolites, with cleavage of
poly-ADP ribose polymerase (PARP). Conversely, cellular apoptosis, generation of ROS, activation of
caspase-3, -9 as well as PARP cleavage were significantly attenuated by pretreatment with an
antioxidant,
N-acetylcysteine (NAC). DNA damage was also markedly observed in HL-60 cells exposed to either
MMA(III) or DMA(III), while iAs(III) did not show any relevant effects in HL-60 cells. Likewise, phosphorylation of the
histone H2A variant (γ-H2AX), a
biomarker of DNA damage, significantly occurred in cellular nuclei following exposure to two methylated species, which was reduced in the presence of NAC, suggesting that the induction of DNA damage was predominantly caused by the two metabolites via oxidative stress. In conclusion, we suggest that
arsenic intermediate metabolites;
MMA(III) and DMA(III) might prove to be of clinical relevance in future as such approaches may help in the treatment of
leukemia and other types of
cancers.