Cancer Drug Shows Promise as Treatment for Rheumatoid Arthritis in Rodent Model

The chemotherapeutic drug bortezomib, a protease inhibitor approved for use in treating multiple myeloma, was shown in a preclinical trial to protect rats from adjuvant-induced arthritis (AIA), which resembles human rheumatoid arthritis (RA).

Investigators at George Papanicolaou Hospital (Thessaloniki, Greece) induced AIA in rats by injection with Freund's complete adjuvant. Bortezomib was administered either before or after injection of Freund's complete adjuvant, and severity of arthritis was assessed clinically and histologically.

Splenocyte and fibroblast-like synoviocyte (FLS) proliferation and apoptosis were measured by radioactivity incorporation and flow cytometry, respectively. The invasiveness of FLS from rats with AIA was tested in a Transwell system. The pattern of cytokine secretion was evaluated by cytometric bead array in splenocyte supernatants. Immunohistochemistry was performed for markers of inflammation and angiogenesis in joints. Hematologic and biochemical parameters were tested in peripheral blood (PB). Representative animals were examined by computed tomography (CT) scanning before and after bortezomib administration. The expression of Toll-like receptor 2 (TLR-2), TLR-3, and TLR-4 in PB and FLS was measured by real-time polymerase chain reaction, and alterations in specific cell populations in PB and spleen were determined by flow cytometry.

Results published in the October 29, 2010, online edition of the journal Arthritis & Rheumatism revealed that in vitro, bortezomib exhibited significant inhibitory and proapoptotic activity in splenocytes and FLS from rats with AIA, altered the inflammatory cytokine pattern, and reduced the invasiveness of FLS from rats with AIA.

In vivo, bortezomib significantly ameliorated disease severity. Remission was associated with improved histology and decreased expression of CD3, CD79a, CD11b, cyclooxygenase I, and factor VIII in target tissues as well as down-regulation of TLR expression in PB and cultured FLS. CT scanning demonstrated a bone healing effect after treatment.

"Our research showed that bortezomib is a useful treatment in targeting critical cell populations involved in the development of inflammation and autoimmunity in RA,” said first author Dr. Evangelia Yannaki, a researcher at George Papanicolaou Hospital. "We believe that bortezomib should be further explored in a clinical setting, as it represents an attractive intervention for inflammatory conditions and a highly promising agent in the treatment of RA."

"The definitive role of biologic agents in treating this difficult-to-cure population has yet to be defined in prospective trials comparing the available therapeutic options,” said Dr. Yannaki. "Given the lack of options for poor responders and the increased risk of infections and malignancies with available biologic agents for RA, there is a great need for novel therapies that are safe and effective.”

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