The pro-apoptotic effect of non-specific CDK inhibitors is mediated through inhibition of CDK9, which increases apoptosis by reducing the expression of pro-inflammatory proteins such as Mcl-1 and XIAP 8, 11, 12. Treatment with the non-specific CDK inhibitor, roscovitine, induces neutrophil apoptosis by down-regulating Mcl-1 and activating caspases 10. CDK inhibitors have been used to treat inflammatory diseases in an attempt to address the over-proliferation of immune cells and fibroblasts. However, recent studies show that the most potent treatments (i.e., those that target CDK9) induce high levels of apoptosis in cancer cell lines 8, 9. Initially, CDK inhibitors were thought to regulate proliferative diseases by inhibiting cell cycle-regulating CDKs, thereby inducing cytostasis. Small-molecule compounds such as flavopiridol and roscovitine inhibit a number of different CDKs (CDK1, 2, 4, 6, 7 and 9 and CDK2, 5, 7 and 9, respectively) 6, 7 and various inhibitors are undergoing phase II clinical trials for the treatment of cancer. CDKs are enzymes that, together with their cyclin subunits, regulate cell cycle progression (CDK1, 2, 4 and 6) and transcription (CDK7 and 9). Recently, small-molecule inhibitors of cyclin-dependent kinases (CDKs) has been tested for their ability to induce apoptosis. Synovial fluid, synovial fibroblasts and macrophages from RA patients express high levels of anti-apoptotic Bcl-2 family proteins 4, 5 and synovial fluid from RA patients protects neutrophils from apoptosis in vitro due (at least in part) to the presence of accumulated pro-inflammatory mediators and anti-apoptotic stimuli within the fluid 1. This apparent dysregulation of apoptosis may enable autoreactive cells to survive and/or fail to control the number of activated effector cells, thereby promoting the development of autoimmune conditions 3. Despite the high influx of inflammatory cells into RA joints and synovial hyperplasia, only low levels of apoptosis are observed 1, 2. The hallmark of RA is inflammation of the joints due to autoimmune reactions, which over time cause irreversible damage to both cartilage and bone. Taken together, these results show that transient inhibition of CDK9 induces apoptosis in leukocyte subsets and modulates the immune response.
CDK9 specific inhibitors may be a potential alternative treatment not only of cancer, but also for autoimmune- and inflammatory diseases.
Inhibiting CDK9 activity in peripheral blood mononuclear cells resulted in the loss of Mcl-1 expression at both the protein and RNA levels, along with a subsequent increase in apoptosis. Mice showed a significant delay in disease onset and a reduction in disease severity following treatment with CDK9 inhibitors. The effects of CDK9 inhibition on RNA levels and protein expression, apoptosis induction, caspase activation and lymphocyte phenotype were further analysed. DBA/1 mice were immunised with bovine collagen type II and treated orally with specific CDK9 inhibitors. Here we examined the effects of specific oral small-molecule inhibitors of the transcription regulating cyclin-dependent kinase 9 on the development and progression of collagen-induced arthritis. The induction of apoptosis has long been proposed as a target for proliferative autoimmune diseases and has further been shown to act as a successful treatment of experimental models of arthritis, such as collagen-induced arthritis. Rheumatoid arthritis is characterised by synovial inflammation and proliferation of fibroblast-like synoviocytes.
0 kommentar(er)
