Novel Cdk inhibitors restore TGF-beta sensitivity in Cdk4 overexpressing epithelial cells

Transforming growth factor-beta (TGF-beta) is a potent mitogen that effects a wide variety of cells by blocking cell growth. TGF-beta acts by interact ing with components of cell cycle machinery to cause G1 arrest and in mink lung epithelial cells (Mv1Lu) it does so by inhibiting Cdk4 synthesis. Over expression of Cdk4 in these cells (B7) renders them resistant to the effect s of TGF-beta. Here we report that two novel Cdk inhibitors (pyridopyrimidi nes) that not only inhibit Cdk4 and Cdk2 in an in vitro kinase assay but al so, in the absence of TGF-beta, block growth of Mv1Lu cells in G1 more effi ciently than their B7 (overexpressing Cdk4) counterparts. Interestingly, th ese inhibitors restored sensitivity of B7 cells towards TGF-beta. This may have implications for the treatment of tumors that have lost TGF-beta respo nsiveness due to deregulated cellular growth in vivo. These Cdk inhibitors could therefore be used in conjunction with TGF-beta to understand the mech anism of growth arrest in normal versus tumour cells, (C) 2000 Academic Pre ss.