Successful Treatment of Animal Models of Rheumatoid Arthritis with Small-Molecule Cyclin-Dependent Kinase Inhibitors1

Intraarticular gene transfer of cyclin-dependent kinase (CDK) inhibitors to suppress synovial cell cycling has shown efficacy in treating animal models of rheumatoid arthritis. Endogenous CDK inhibitors also modulate immune function via a CDK-independent pathway. Accordingly, systemic administration of small molecules that inhibit CDK may or may not ameliorate arthritis. To address this issue, alvocidib (flavopiridol), known to be tolerated clinically for treating cancers, and a newly synthesized CDK4/6-selective inhibitor were tested for antiarthritic effects. In vitro, they inhibited proliferation of human and mouse synovial fibroblasts without inducing apoptosis. In vivo, treatment of collagen-induced arthritis mice with alvocidib suppressed synovial hyperplasia and joint destruction, whereas serum concentrations of anti-collagen type II (CII) Abs and proliferative responses to CII were maintained. Treatment was effective even when therapeutically administered. Treated mice developed arthritis after termination of treatment. Thus, immune responses to CII were unimpaired. The same treatment ameliorated arthritis induced by K/BxN serum transfer to lymphocyte-deficient mice. Similarly, the CDK4/6-selective inhibitor suppressed collagen-induced arthritis. Both small-molecule CDK inhibitors were effective in treating animal models of rheumatoid arthritis not by suppressing lymphocyte function. Thus, the two small-molecule CDK inhibitors ameliorated arthritis models in a distinctive way, compared with other immunosuppressive drugs.

[1]  E. Sausville,et al.  Early induction of apoptosis in hematopoietic cell lines after exposure to flavopiridol. , 1998, Blood.

[2]  N. Miyasaka,et al.  Gene Transfer of a Cell Cycle Modulator Exerts Anti-Inflammatory Effects in the Treatment of Arthritis 1 , 2003, The Journal of Immunology.

[3]  A. Kumar,et al.  New Therapies for Rheumatoid Arthritis. , 2003, Medical journal, Armed Forces India.

[4]  H. Hagiyama,et al.  Direct modulation of rheumatoid inflammatory mediator expression in retinoblastoma protein-dependent and -independent pathways by cyclin-dependent kinase 4/6. , 2006, Arthritis and rheumatism.

[5]  K. Hirokawa,et al.  Induction of the p16INK4a senescence gene as a new therapeutic strategy for the treatment of rheumatoid arthritis , 1999, Nature Medicine.

[6]  R. Holmdahl,et al.  The molecular pathogenesis of collagen-induced arthritis in mice—a model for rheumatoid arthritis , 2002, Ageing Research Reviews.

[7]  N. Miyasaka,et al.  Chemokines Regulate IL-6 and IL-8 Production by Fibroblast-Like Synoviocytes from Patients with Rheumatoid Arthritis1 , 2001, The Journal of Immunology.

[8]  Thomas S. Lin,et al.  Flavopiridol administered using a pharmacologically derived schedule is associated with marked clinical efficacy in refractory, genetically high-risk chronic lymphocytic leukemia. , 2007, Blood.

[9]  F. Sarkar,et al.  Induction of growth inhibition and apoptosis in prostate cancer cells by flavopiridol. , 2000, International journal of oncology.

[10]  S. Steinberg,et al.  Phase I trial of continuous infusion flavopiridol, a novel cyclin-dependent kinase inhibitor, in patients with refractory neoplasms. , 1998, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[11]  James M. Roberts,et al.  Inhibitors of mammalian G1 cyclin-dependent kinases. , 1995, Genes & development.

[12]  M. Ikeda,et al.  Suppression of arthritis by forced expression of cyclin-dependent kinase inhibitor p21(Cip1) gene into the joints. , 2001, International immunology.

[13]  H. Hirai,et al.  Identification of potent 5-pyrimidinyl-2-aminothiazole CDK4, 6 inhibitors with significant selectivity over CDK1, 2, 5, 7, and 9. , 2006, Bioorganic & medicinal chemistry letters.

[14]  N. Altorki,et al.  Flavopiridol mediates cell cycle arrest and apoptosis in esophageal cancer cells. , 1998, Clinical cancer research : an official journal of the American Association for Cancer Research.

[15]  W. Arend,et al.  Physiology of cytokine pathways in rheumatoid arthritis. , 2001, Arthritis and rheumatism.

[16]  S H Kim,et al.  Structural basis for specificity and potency of a flavonoid inhibitor of human CDK2, a cell cycle kinase. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[17]  A. Senderowicz Small-molecule cyclin-dependent kinase modulators , 2003, Oncogene.

[18]  美紀 野々村 Suppression of arthritis by forced expression of cyclin-dependent kinase inhibitor p21Cip1 gene into the joints , 2002 .

[19]  James M. Roberts,et al.  CDK inhibitors: positive and negative regulators of G1-phase progression. , 1999, Genes & development.

[20]  B. Bresnihan Pathogenesis of joint damage in rheumatoid arthritis. , 1999, The Journal of rheumatology.

[21]  V. Kouskoff,et al.  Organ-Specific Disease Provoked by Systemic Autoimmunity , 1996, Cell.

[22]  G. Firestein,et al.  Mitogen activated protein kinase inhibitors: where are we now and where are we going? , 2006, Annals of the rheumatic diseases.

[23]  K. Rajewsky,et al.  From systemic T cell self-reactivity to organ-specific autoimmune disease via immunoglobulins. , 1999, Immunity.

[24]  H. Nakajima,et al.  FR180204, a novel and selective inhibitor of extracellular signal-regulated kinase, ameliorates collagen-induced arthritis in mice , 2006, Naunyn-Schmiedeberg's Archives of Pharmacology.

[25]  E. Sausville,et al.  Flavopiridol induces G1 arrest with inhibition of cyclin-dependent kinase (CDK) 2 and CDK4 in human breast carcinoma cells. , 1996, Cancer research.

[26]  M. Liang,et al.  The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. , 1988, Arthritis and rheumatism.

[27]  Yiwei Li,et al.  Induction of apoptosis and inhibition of c-erbB-2 in breast cancer cells by flavopiridol. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[28]  J. Kriegsmann,et al.  Susceptibility to collagen-induced arthritis is modulated by TGFβ responsiveness of T cells , 2004, Arthritis research & therapy.

[29]  H. Sedlacek Mechanisms of action of flavopiridol. , 2001, Critical reviews in oncology/hematology.

[30]  M. Weitzman,et al.  Gene therapy: twenty-first century medicine. , 2005, Annual review of biochemistry.

[31]  S. Kaufmann,et al.  Antineoplastic Agents: the Importance of Sequence of Administration' , 2022 .

[32]  那須 公雄 Adenoviral transfer of cyclin-dependent kinase inhibitor genes suppresses collagen-induced arthritis in mice , 2003 .

[33]  M. Salmon,et al.  Treating very early rheumatoid arthritis. , 2006, Best practice & research. Clinical rheumatology.

[34]  Jiahuai Han,et al.  Retinoblastoma suppression of matrix metalloproteinase 1, but not interleukin-6, through a p38-dependent pathway in rheumatoid arthritis synovial fibroblasts. , 2004, Arthritis and rheumatism.

[35]  E. Sausville,et al.  Flavopiridol induces apoptosis of normal lymphoid cells, causes immunosuppression, and has potent antitumor activity In vivo against human leukemia and lymphoma xenografts. , 1998, Blood.

[36]  E. Sausville,et al.  Flavopiridol, a novel cyclin-dependent kinase inhibitor, suppresses the growth of head and neck squamous cell carcinomas by inducing apoptosis. , 1998, The Journal of clinical investigation.

[37]  G. Haines,et al.  IL-6 and Matrix Metalloproteinase-1 Are Regulated by the Cyclin-Dependent Kinase Inhibitor p21 in Synovial Fibroblasts , 2002 .

[38]  Christopher Haslett,et al.  Cyclin-dependent kinase inhibitors enhance the resolution of inflammation by promoting inflammatory cell apoptosis , 2006, Nature Medicine.

[39]  D E Griswold,et al.  Pharmacological profile of SB 203580, a selective inhibitor of cytokine suppressive binding protein/p38 kinase, in animal models of arthritis, bone resorption, endotoxin shock and immune function. , 1996, The Journal of pharmacology and experimental therapeutics.

[40]  D. Gauguier,et al.  Genetic Influences on the End-Stage Effector Phase of Arthritis , 2001, The Journal of experimental medicine.