Arginine deiminase enhances dexamethasone-induced cytotoxicity in human T-lymphoblastic leukemia CCRF-CEM cells

Since arginine deiminase (ADI; EC 3.5.3.6) inhibits cell proliferation by arresting cells in the G₁ phase, we tested its synergistic effect on cell death induced by dexamethasone (DEX), which also induces apoptosis by G₁ cell cycle arrest. ADI inhibited cell proliferation and induced apoptosis in human leukemic CEM cells in a dose-dependent manner. Simultaneous treatment with ADI and DEX showed synergistic effects on DNA fragmentation and LDH release. In addition, ADI exerted its anti-proliferative activity against DEX-resistant CEH cells. ADI suppressed expression of c-myc, a potential key regulator of cell proliferation and apoptosis, and increased expression of p27^Kip1 cyclin-dependent kinase inhibitor. These results suggest that ADI efficiently increases the anti-cancer effect of DEX on human leukemic CEM cells through G₁ cell cycle arrest involving downregulation of c-myc and upregulation of p27^Kip1.