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 G(1) phase, we tested its synergistic effect on cell death induced by dexamethasone (DEX), which also induces apoptosis by G(1) 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 CEM 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 G(1) cell cycle arrest involving downregulation of c-myc and upregulation of p27(Kip1). (C) 2004 Wiley-Liss, Inc.