Canavanine augments proapoptotic effects of arginine deprivation in cultured human cancer cells.
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.
Vynnytska
Bozhena O
BO
Institute of Cell Biology, National Academy of Sciences of Ukraine, Lviv, Ukraine.
Mayevska
Oksana M
OM
Kurlishchuk
Yuliya V
YV
Bobak
Yaroslav P
YP
Stasyk
Oleh V
OV
D017209:Apoptosis / Q000187:drug effects*; D001120:Arginine / Q000031:analogs & derivatives / Q000172:deficiency* / Q000378:metabolism; D002172:Canavanine / Q000493:pharmacokinetics / Q000494:pharmacology*; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D057809:HEK293 Cells; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D011485:Protein Binding
D002172:Canavanine; D001120:Arginine