Previously, we showed that arsenic trioxide potently inhibited the growth of myeloma cells and head and neck cancer cells. Here, we demonstrate that arsenic trioxide inhibited the proliferation of all the renal cell carcinoma cell lines (ACIIN, A498, Caki-2. Cos-7, and Renca) except only one cell line (Caki-1) with IC50 of about 2.5-10 muM, Arsenic trioxide induced a G, or a G-M phase arrest in these cells. When we examined the effects of this drug on A498 cells. arsenic trioxide (2.5 muM) decreased the levels of CDK2, CDK6, cyclin D1, cyclin E, and cyclin A proteins. Although p21 protein was not increased by arsenic trioxide. this drug markedly enhanced the binding of p21 with CDK2. In addition, the activities of CDK21- and CDK6-associated kinasc were reduced in association with hypophosphorylation of Rb protein. Arsenic trioxide (10 muM) also induced apoptosis in A498 cells. Apoptotic process of A498 cells was associated with the changes of Bcl-(XL), caspase-9, caspase-3, and caspase-7 proteins, as well us mitochondria transmembrane potential (Deltapsi(m)) loss. Taken together, these results demonstrate that arsenic trioxide inhibits the growth of renal cell carcinoma cells via cell cycle arrest or apoptosis. (C) 2002 Elsevier Science (USA). All rights reserved.