Arginine deprivation achieved by means of recombinant
arginine-degrading
enzymes is currently being developed as a novel anticancer
enzymotherapy. In this study, we showed that
arginine deprivation in vitro profoundly and selectively sensitized human
cancer cells of different organ origin to low doses of
canavanine, an
arginine analogue of plant origin. In sensitive
cancer cells
arginine starvation led to the activation of
caspase-9,
caspase-3 and
caspase-7, cleavage of reparation
enzyme, polyADP ribosyl polymerase, and DNA fragmentation, which are the typical hallmarks of intrinsic apoptosis realized by the mitochondrial pathway. Co-administration of
canavanine significantly accelerated and enhanced apoptotic manifestations induced by
arginine deprivation. The augmentation of
canavanine toxicity for
cancer cells was observed when either a formulated
arginine-free medium or complete medium supplemented with bovine
arginase preparation was used.
Cycloheximide efficiently rescued malignant cells from
canavanine-induced cytotoxicity under
arginine deprivation, suggesting that it results mainly from
canavanine incorporation into newly synthesized
proteins.
Cancer cells sensitive or resistant to
arginine deprivation alone were not capable of restoring their proliferation after 24 h of combined treatment, whereas pseudonormal cells retained such ability. Our data suggest that the incorporation of
canavanine into anticancer treatment schemes based on artificially created
arginine starvation could be a novel strategy in
tumor enzymochemotherapy.