Abstract:
Acute myeloid leukemia (AML) is the most common acute leukemia in adults. It has
the lowest survival rate in children, and only 5.4% of elders survive. For the past 40
years, chemotherapy remains the common treatment for AML with minimal lifestyle
improvements largely due to better risk classifications and enhancements in supportive
care. Hence, novel approaches for targeting AML cells are needed. A common mutation in cancer is amino acid auxotrophy, particularly arginine, which
is needed for the production of many metabolites and also involved in
immunoregulation and protein modification.
We have previously shown that AML cells were auxotrophic for arginine and highly
sensitive to arginine deprivation induced by a PEGylated human recombinant
Arginase I cobalt [HuArgI (Co)-PEG5000], hence demonstrating that arginine
deprivation may constitute an attractive strategy for the selective targeting of AML cells. In this study, we aim to further investigate the mechanisms of HuArgI (Co)-PEG5000
induced cytotoxicity in AML cells. We have demonstrated that arginine depletion is
cytotoxic in a time-dependent manner. We have also demonstrated that autophagy is
significantly activated following arginine deprivation starting at 12 hours and
continuing up to 72 hours following arginine deprivation. Inhibition of autophagy using Chloroquine, rescued AML cells from arginine deprivation-induced cytotoxicity
indicating that the observed cell death following arginine deprivation is due to the
prolonged over-activation of autophagy (death by autophagy). Finally, combining
HuArgI(Co)-PEG5000-induced arginine deprivation with Anthrax lethal toxinmediated
inhibition of the MAPK pathway has revealed a synergistic cytotoxic effect
on selective AML cell lines that are usually sensitive to MAPK inhibition.
