title: The impact of CDK inhibition in human malignancies associated with pronounced defects in apoptosis: advantages of multi-targeting small molecules.
abstract: Malignant cells in chronic lymphocytic leukemia (CLL) and related diseases are heterogeneous and consist primarily of long-lived resting cells in the periphery and a minor subset of dividing cells in proliferating centers. Both cell populations have different molecular signatures that play a major role in determining their sensitivity to therapy. Contemporary approaches to treating CLL are heavily reliant on cytotoxic chemotherapeutics. However, none of the current treatment regimens can be considered curative. Pharmacological CDK inhibitors have extended the repertoire of potential drugs for CLL. Multi-targeted CDK inhibitors affect CDKs involved in regulating both cell cycle progression and transcription. Their interference with transcriptional elongation represses anti-apoptotic proteins and, thus, promotes the induction of apoptosis. Importantly, there is evidence that treatment with CDK inhibitors can overcome resistance to therapy. The pharmacological CDK inhibitors have great potential for use in combination with other therapeutics and represent promising tools for the development of new curative treatments for CLL.
authors.affiliation: Cell Cycle Regulation Group, Division: Institute of Cancer Research, Dept of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria. jozefa.gadek-wesierski@meduniwien.ac.at
authors.forename: Józefa
authors.initials: J
authors.lastname: Węsierska-Gądek
authors.forename: Matthias P
authors.initials: MP
authors.lastname: Kramer
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D002986:Clinical Trials as Topic; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000502:physiology*; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000378:metabolism; D035683:MicroRNAs / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D051560:Proto-Oncogene Proteins c-bcl-6; D012097:Repressor Proteins / Q000502:physiology*; D054852:Small Molecule Libraries / Q000494:pharmacology* / Q000627:therapeutic use; D059016:Tumor Microenvironment
chemical_list: C084103:BCL6 protein, human; D004268:DNA-Binding Proteins; C486626:FOXP1 protein, human; D051858:Forkhead Transcription Factors; D035683:MicroRNAs; D047428:Protein Kinase Inhibitors; D051560:Proto-Oncogene Proteins c-bcl-6; D012097:Repressor Proteins; D054852:Small Molecule Libraries; D018844:Cyclin-Dependent Kinases