title: Anti-inflammatory and immunomodulatory effects of bortezomib in various in vivo models.
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.
authors.affiliation: BioMed Valley Discoveries, Kansas City, MO 64111, USA. dtung@biomed-valley.com
authors.forename: David
authors.initials: D
authors.lastname: Tung
authors.forename: Peter H
authors.initials: PH
authors.lastname: Cheung
authors.forename: Pali
authors.initials: P
authors.lastname: Kaur
authors.forename: Oded
authors.initials: O
authors.lastname: Foreman
authors.forename: Anoop
authors.initials: A
authors.lastname: Kavirayani
authors.forename: Heather S
authors.initials: HS
authors.lastname: Hain
authors.forename: Saurabh
authors.initials: S
authors.lastname: Saha
mesh_terms: D000276:Adjuvants, Immunologic / Q000633:toxicity; D000634:Aminoquinolines / Q000633:toxicity; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D001897:Boronic Acids / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D000069286:Bortezomib; D004139:Dinitrofluorobenzene / Q000633:toxicity; D004195:Disease Models, Animal; D004339:Drug Compounding; D004353:Drug Evaluation, Preclinical; D004355:Drug Stability; D005260:Female; D006968:Hypersensitivity, Delayed / Q000139:chemically induced / Q000188:drug therapy; D000077271:Imiquimod; D007155:Immunologic Factors / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D007509:Irritants / Q000633:toxicity; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008813:Mice, Inbred ICR; D010538:Peritonitis / Q000139:chemically induced / Q000188:drug therapy; D011565:Psoriasis / Q000139:chemically induced / Q000188:drug therapy; D011719:Pyrazines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D011897:Random Allocation; D013696:Temperature; D013864:Thioglycolates / Q000633:toxicity
chemical_list: D000276:Adjuvants, Immunologic; D000634:Aminoquinolines; D000893:Anti-Inflammatory Agents; D001897:Boronic Acids; D007155:Immunologic Factors; D007509:Irritants; D011719:Pyrazines; D013864:Thioglycolates; D000069286:Bortezomib; D004139:Dinitrofluorobenzene; D000077271:Imiquimod