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 interacting with components of cell cycle machinery to cause G1 arrest and in mink lung epithelial cells (Mv1Lu) it does so by inhibiting Cdk4 synthesis. Overexpression of Cdk4 in these cells (B7) renders them resistant to the effects of TGF-beta. Here we report that two novel Cdk inhibitors (pyridopyrimidines) that not only inhibit Cdk4 and Cdk2 in an in vitro kinase assay but also, in the absence of TGF-beta, block growth of Mv1Lu cells in G1 more efficiently than their B7 (overexpressing Cdk4) counterparts. Interestingly, these inhibitors restored sensitivity of B7 cells towards TGF-beta. This may have implications for the treatment of tumors that have lost TGF-beta responsiveness due to deregulated cellular growth in vivo. These Cdk inhibitors could therefore be used in conjunction with TGF-beta to understand the mechanism of growth arrest in normal versus tumour cells.
Soni
R
R
Oncology Research, Novartis Pharma AG, Basel, Switzerland.
Fretz
H
H
Muller
L
L
Schoepfer
J
J
Chaudhuri
B
B
D000818:Animals; D042846:CDC2-CDC28 Kinases; D020134:Catalytic Domain; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D019925:Cyclin A / Q000378:metabolism; D019938:Cyclin D1 / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004247:DNA / Q000032:analysis / Q000096:biosynthesis; D004361:Drug Tolerance; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D005434:Flow Cytometry; D020128:Inhibitory Concentration 50; D008907:Mink; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D011728:Pyridones / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology; D013379:Substrate Specificity; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D019925:Cyclin A; D004791:Enzyme Inhibitors; D011518:Proto-Oncogene Proteins; D011728:Pyridones; D011743:Pyrimidines; D016212:Transforming Growth Factor beta; D019938:Cyclin D1; D004247:DNA; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases