Proteasome Inhibitors Show Promise for Treatment of Bone Cancer

Proteasome inhibitors have been approved for treatment of some types of lymphomas and multiple myeloma, and a recent study has found that they may also be effective for the treatment of osteosarcomas, which are primary bone tumors of osteoblastic origin that mostly affect adolescent patients. Osteosarcoma is an aggressive cancer that starts in bone, spreads quickly, and responds poorly to current chemotherapies.

Investigators at the University of Rochester Medical Center (NY, USA) studied the effects of the proteasome inhibitor bortezomib on an animal model of osteosarcoma as well as on bone cancer cells growing in culture. Bortezomib contains a boron atom that binds to the catalytic site of the 26S proteasome with high affinity and specificity. In normal cells, the proteasome regulates protein expression and function by degradation of ubiquitinylated proteins and cleanses the cell of abnormal or misfolded proteins. In cancer cells proteasome inhibition seems to promote apoptosis by preventing degradation of proapoptotic factors.

Results published in the November 5, 2009, online edition of the International Journal of Cancer revealed that bortezomib, increased the activity of Runx2 and Bax in osteosarcoma cells. The Runx2 protein complex is a key osteoblastic differentiation factor that transcriptionally regulates expression of the major proapoptotic factor, Bax.

In vitro, bortezomib suppressed growth and induced apoptosis in osteosarcoma cells but not in nonmalignant osteoblasts. Experiments involving tumor xenografts in nude mice demonstrated significant tumor regression in bortezomib-treated animals. Immunohistochemical studies revealed that bortezomib inhibited cell proliferation and induced apoptosis in osteosarcoma xenografts.

"Our most clinically relevant finding is that a drug already proven safe and effective in treating the most common cancers of the blood may be equally effective in suppressing bone cancer," said senior author Dr. Roman Eliseev, assistant professor of musculoskeletal research at the University of Rochester. "Bortezomib caused osteosarcoma cells to self destruct, and prevented their spread. While further studies are needed, our findings suggest that this drug may represent a new treatment option for a devastating disease and an effective complement to current chemotherapies."

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University of Rochester Medical Center