Title

Anti-inflammatory and immunomodulatory effects of bortezomib in various in vivo models.

Document Type

Article

Publication Date

1-2011

Keywords

Adjuvants, Immunologic, Aminoquinolines, Animals, Anti-Inflammatory Agents, Boronic Acids, Dinitrofluorobenzene, Disease Models, Animal, Drug Compounding, Drug Evaluation, Preclinical, Drug Stability, Female, Hypersensitivity, Delayed, Immunologic Factors, Irritants, Male, Mice, Mice, Inbred BALB C, Mice, Inbred ICR, Peritonitis, Psoriasis, Pyrazines, Random Allocation, Temperature, Thioglycolates

JAX Location

Reprint Collection

JAX Source

Pharmacology 2011; 88(1-2):100-13.

PMID

21865767

Volume

88

Issue

1-2

First Page

100

Last Page

113

ISSN

1423-0313

Abstract

Bortezomib (Velcade®) is a proteasome inhibitor that has been approved for the treatment of multiple myeloma and mantle cell lymphoma. It has been shown to inhibit the expression of cell adhesion molecules, co-stimulatory molecules, and NFκB activation, to deplete alloreactive T lymphocytes, and to decrease Th1 cytokine production. The anti-inflammatory effects of bortezomib were further investigated in this current set of studies. Systemic treatment with bortezomib was efficacious in the thioglycolate-induced MCP-1 production model, and the dinitrofluorobenzene-induced delayed-type hypersensitivity model. Psoriasis is an autoimmune disease that affects about 2% of the world population. Many treatments have been reported with varying degrees of efficacy. A topical bortezomib formulation was developed to minimize systemic exposure. Its tolerability was investigated in a topical imiquimod (IMQ)-induced psoriasis model. Daily application of IMQ on mouse skin induced inflamed scaly skin lesions resembling plaque-type psoriasis. Fatality was observed in the 1-mg/ml dose group. At 0.1 and 0.01 mg/ml, bortezomib potentiated IMQ-induced erythema, scaling, skin thickening, and caused necrotic lesions. Lower doses had no effect on the clinical observations. Histologically, bortezomib dose-dependently increased parakeratosis, hyperkeratosis, acanthosis, and inflammatory cell infiltration. This study demonstrated that topical bortezomib is not suitable for the treatment of psoriasis.

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