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Abstract Number: 2083

New Treatment Approach of Rheumatoid Arthritis Based On Inhibition of Cyclin Dependent Kinase-9

Annelie Hellvard1, Lutz Zeitlmann2, Ulrich Heiser3, André Niestroj3, Hans-Ulrich Demuth3, Jan Potempa4 and Piotr Mydel1, 1Broegelmann Research Laboratory, The Gade Institute, University of Bergen, Bergen, Norway, 2Ingenium Pharmaceuticals GmbH, Martinsried, Germany, 3Probiodrug AG, Halle/Saale, Germany, 4Microbiology Department, Jagiellonian University, Krakow, Poland

Meeting: 2012 ACR/ARHP Annual Meeting

Keywords: animal models and treatment, Apoptosis, rheumatoid arthritis

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Session Information

Title: Rheumatoid Arthritis: Animal Models

Session Type: Abstract Submissions (ACR)

Background/Purpose: Cyclin dependent kinase-9 (cdk-9) is transcription regulator of the carboxyterminal domain of RNA polymerase II. The usage of pan-cdk inhibitors such as flavopiridol has proven to be efficient in the treatment of cancer, targeting both cell cycle- and transcription-regulating cyclin dependent kinases. In this study we sought to investigate the effect of specific small molecular inhibitor of cell cycle independent cdk-9 development and progression of  collagen induced arthritis.

Methods: DBA/1 mice were immunized with 100ug bovine collagen type II at day 0 and day 21. During experiment mice were treated orally with highly specific cdk-9 inhibitors (compound 1 and compound 2), either 10mg/kg daily or 10mg/kg and 30mg/kg twice a week, respectively. Clinical scoring was performed every second day during experiment and was followed by histological evaluation at end of experiment. Protein expression of Mcl-1 and survivin in spleens was determined by western immunoblotting. Flow cytometric analysis of regulatory T cells in spleens from arthritic mice following daily treatment as well as 7day treatment of healthy NMRI mice was performed. 

Peripheral blood mononuclear cells were incubated with compound 1 and induction of apoptosis, as well as protein and RNA expression of Mcl-1 was investigated. Caspase-3 activity, LDH activity and Mcl-1 protein expression was assessed in human monocyte derived macrophages following incubation with compound 1.

Results: Mice treated with compound compound 1 or compound 2 showed striking delay in onset as well as significant reduction in severity of arthritis. This effect was shown, not only in daily treatment but also in bi-weekly regime. Western blot of spleens showed decreased level of Mcl-1 in a dose dependent manner, whereas survivin levels were significantly increased. Flow cytometric analysis of splenocytes in arthritic- and healthy mice treated with inhibitors showed an increase in frequency of regulatory T cells.

Cdk-9 inhibition in peripheral blood mononuclear cells resulted in loss of Mcl-1 expression both on protein and RNA level with a subsequent increase in apoptosis. Down-regulation of Mcl-1 was also observed in monocyte derived macrophages with an activation of caspase-3.

Conclusion: This study provides clear results that inhibition of cdk-9 is working in an immunomodulatory manner, independent of high survivin expression and may in the future serve as an alternative treatment, not only of cancer, but also of autoimmune- and inflammatory diseases.


Disclosure:

A. Hellvard,
None;

L. Zeitlmann,

Ingenium Pharmaceuticals GmbH,

3;

U. Heiser,

Probiodrug AG,

3;

A. Niestroj,

Probiodrug AG,

3;

H. U. Demuth,

Probiodrug AG,

3;

J. Potempa,
None;

P. Mydel,
None.

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