The impact of multi-targeted cyclin-dependent kinase inhibition in breast cancer cells: clinical implications.
BACKGROUND
The progression of the mammalian cell cycle is driven by the transient activation of complexes consisting of cyclins and cyclin-dependent kinases (CDKs). Loss of control over the cell cycle results in accelerated cell division and malignant transformation and can be caused by the upregulation of cyclins, the aberrant activation of CDKs or the inactivation of cellular CDK inhibitors. For these reasons, cell cycle regulators are regarded as very promising therapeutic targets for the treatment of human malignancies.


METHODS
This review covers the structures and anti-breast cancer activity of selected pharmacological pan-specific CDK inhibitors. Multi-targeted CDK inhibitors affect CDKs involved in the regulation of both cell cycle progression and transcriptional control. The inhibition of CDK7/CDK9 has a serious impact on the activity of RNA polymerase II; when its carboxy-terminal domain is unphosphorylated, it is unable to recruit the cofactors required for transcriptional elongation, resulting in a global transcriptional block. Multi-targeted inhibition of CDKs represses anti-apoptotic proteins and thus promotes the induction of apoptosis. Moreover, the inhibition of CDK7 in estrogen receptor (ER)-positive breast cancer cells prevents activating phosphorylation of ER-α.


CONCLUSIONS
These diverse modes of action make multi-targeted CDK inhibitors promising drugs for the treatment of breast cancers.
Medical University of Vienna, Department of Medicine I, Institute of Cancer Research, Comprehensive Cancer Center, Cell Cycle Regulation Group, Borschkegasse 8a, 1090 Vienna, Austria. Jozefa.Gadek-Wesierski@meduniwien.ac.at
Józefa
J
Węsierska-Gądek
Matthias P
MP
Kramer
D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000378:metabolism*; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D058990:Molecular Targeted Therapy; D011960:Receptors, Estrogen / Q000378:metabolism
D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D011960:Receptors, Estrogen; D018844:Cyclin-Dependent Kinases