ABSTRACT
Here we report that targeting casein kinase 1-α1 (CSNK1α1) is a potential novel treatment strategy in multiple myeloma (MM) therapy distinct from proteasome inhibition. CSNK1α1 is expressed in all the tested MM cell lines and patient MM cells, and is not altered during bortezomib-triggered cytotoxicity. Inhibition of CSNK1α1 kinase activity in MM cells with targeted therapy D4476 or small hairpin RNAs triggers cell G0/G1-phase arrest, prolonged G2/M phase and apoptosis. D4476 also induced cytotoxicity in bortezomib-resistant MM cells and enhanced bortezomib-triggered cytotoxicity. CSNK1α1 signaling pathways include CDKN1B, P53 and FADD; gene signatures involved included interferon-α, tumor necrosis factor-α and LIN9. In addition, reduction of Csnk1α1 prevents cMYC/KRAS12V transformation of BaF3 cells independent of interleukin-3. Impartially, reducing Csnk1α1 prevented development of cMYC/KRAS12V-induced plasmacytomas in mice, suggesting that CSNK1α1 may be involved in MM initiation and progression. Our data suggest that targeting CSNK1α1, alone or combined with bortezomib, is a potential novel therapeutic strategy in MM. Moreover, inhibition of CSNK1α1 may prevent the progression of monoclonal gammopathy of undetermined significance to MM.
Subject(s)
Casein Kinase Ialpha/physiology , Multiple Myeloma/metabolism , Plasma Cells/cytology , Animals , Apoptosis , Boronic Acids/chemistry , Bortezomib , Cell Cycle , Cell Line, Tumor , Cell Survival , Disease Progression , Gene Expression Profiling , Humans , Interleukin-3/metabolism , Lentivirus/genetics , Mice , Monoclonal Gammopathy of Undetermined Significance/prevention & control , Multiple Myeloma/therapy , Plasmacytoma/therapy , Proteasome Endopeptidase Complex/metabolism , Pyrazines/chemistry , Signal TransductionABSTRACT
No disponible
Subject(s)
Humans , Male , Female , Xanthomatosis/complications , Xanthomatosis/diagnosis , Monoclonal Gammopathy of Undetermined Significance/complications , Monoclonal Gammopathy of Undetermined Significance/epidemiology , Monoclonal Gammopathy of Undetermined Significance/prevention & control , Xanthomatosis/physiopathology , Xanthomatosis/therapy , Xanthomatosis , Monoclonal Gammopathy of Undetermined Significance/physiopathology , Monoclonal Gammopathy of Undetermined SignificanceABSTRACT
Over the last decades there has been an increasing interest in a possible role of curcumin on cancer. Although curcumin is considered safe for healthy people, conclusive evidence on the safety and efficacy of curcumin for patients with monoclonal gammopathies is, so far, lacking. The present paper reviews the literature on molecular, cellular and clinical effects of curcumin in an attempt to identify, reasons for optimism but also for concern. The results of this critical evaluation can be useful for both patient- selection and monitoring in the context of clinical trials. Curcumin might be helpful for some but certainly not for all patients with monoclonal gammopathies. It is important to avoid unnecessary detrimental side effects in some in order to safeguard curcumin for those that could benefit. Parameters for patient monitoring, that can be used as early warning signs and as indicators of a favorable development have therefore been suggested.
Subject(s)
Curcumin/therapeutic use , Paraproteinemias/drug therapy , Bone Marrow/drug effects , Curcumin/pharmacology , Humans , Immune System/drug effects , Inflammation/complications , Inflammation/drug therapy , Monoclonal Gammopathy of Undetermined Significance/etiology , Monoclonal Gammopathy of Undetermined Significance/prevention & controlABSTRACT
Monoclonal gammopathy of undetermined significance (MGUS) is a common premalignant plasma cell proliferative disorder with a lifelong risk of progression to multiple myeloma. Because myeloma is an incurable malignancy, strategies to delay or prevent progression in high-risk patients are of considerable importance.
