Pegylated Recombinant Human Arginase, Rharg-Peg_5,000MW, Targets Cell Cycle Machinery in Multiple Myeloma Cells.

Arginase has been shown to inhibit growth of human hepatocellular carcinoma by depletion of arginine. We have studied the effects of the pegylated human recombinant arginase (BCT-100, rhArg-peg_5,000MW) on RPMI8226 cells, a multiple myeloma cell line. This study showed that three day exposure of the myeloma cells to pegylated rhArg at a concentration of 0.08 IU/ml and 0.48 IU/ml resulted in growth suppression of 10% and 70% respectively, as compared to untreated control. Cell cycle analysis revealed significant decreases in the proportion of cells in both S- and G2M-phase and a concomitant increase of cells in G1-phase in a time- and concentration- dependent manner. We further studied the mechanisms of cell cycle arrest induced by the pegylated rhArg. The pegylated rhArg inhibited both cyclin-dependent kinases CDK2 and CDK4, enhanced the expression of the CDK inhibitor p21, and reduced the expression of cyclinD1, D2, and E. The level of phosphorylated Rb protein was also found to be significantly decreased. The regulators of cell cycle have thus been revealed as targets of pegylated rhArg for myeloma growth arrest. The pegylated rhArg may serve as a novel antitumor agent for multiple myeloma.