Cell cycle arrest mediated by a pyridopyrimidine is not abrogated by over-expression of Bcl-2 and cyclin D1.
Inhibition of cyclin dependent kinases (Cdks) is of pivotal importance in tumor cell biology as these kinases are the drivers of cell proliferation. This inhibition can be achieved either by naturally occurring biological proteins or by small molecule compounds. They cause cell cycle arrest and/or apoptosis depending upon the specificity and efficacy of the inhibitor in question. We have reported earlier that specific pyridopyrimidines (novel Cdk inhibitors) cause cell cycle arrest in mink lung epithelial cells and the arrest is abrogated by over-expression of Cdk4. In contrast, we show here that one of these inhibitors effectively maintains cell cycle arrest in a leukemic or a breast cancer cell line even after the respective cells over-express an oncogene, either Bcl-2 or cyclin D1. However, in the leukemic cells, Bcl-2 over-expression suppresses apoptosis induced by the pyridopyrimidine. Thus, novel Cdk inhibitors can prove to be useful chemical genetics tools for understanding the underlying mechanisms of growth arrest and/or apoptosis in normal versus tumor cells. This could also lead to the development of improved inhibitors of cell proliferation.
Soni
R
R
Leicester School of Pharmacy, Hawthorn Building, De Montfort University, The Gateway, Leicester, LE1 9BH, UK.
Chaudhuri
B
B
D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects* / Q000502:physiology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D019938:Cyclin D1 / Q000378:metabolism*; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D009363:Neoplasm Proteins / Q000378:metabolism; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000502:physiology
D004791:Enzyme Inhibitors; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011743:Pyrimidines; D019938:Cyclin D1; D018844:Cyclin-Dependent Kinases