[109] cs1, a new surface target on multiple myeloma (mm) cells, protects myeloma cells from apoptosis via regulation of erk1/2, akt and stat3 signaling cascades

[3523] Bortezomib Protects Osteoblasts from Glucocorticoid-Induced Damage, and Enhances
Glucocorticoid-Induced Toxicity Against Osteoclasts and Myeloma Cells. Session Type: Poster
Session, Board #742-III

Kent Soe, Thomas L. Andersen, Katarzyna Kupisiewicz, Torben Plesner, Jean-Marie Delaisse Clinical
Cell Biology and Hematology, Vejle Hospital, IRS/CSFU, Southern Denmark University, Vejle,

Introduction: Multiple myeloma is characterized by the accumulation of malignant plasma cells in the bone
marrow, and leads most often to bone destruction by osteoclasts and prevention of bone repair by
osteoblasts. Bortezomib and glucocorticoids are both powerful anti-myeloma drugs that are used for killing
malignant plasma cells in the patients. Furthermore bortezomib has direct anti-osteoclastic and pro-
osteoblastic properties that may contribute to bone protection in multiple myeloma, while glucocorticoids
have more ambiguous effects on these bone cells and are clearly anti-osteoblastic. Recent clinical trials
based on the combination of bortezomib and glucocorticoids drew the attention on the very promising anti -
myeloma efficiency of this combination. However, the bone cell response of this combination has not been
tested. In order to address this question, we performed an in vitro study, and importantly adapted our in vitro
model to mimic the pharmacokinetics of bortezomib and glucocorticoid in the patients. Methods: Myeloma
cell lines, primary human osteoclasts and osteoblast-like cells (MC3T3) were pulse-treated or not with
clinically relevant doses of bortezomib (12.5, 25 or 50 nM) for 3 hours. Subsequently, the cells were
exposed during a 3-day culture to 1.6 M prednisolone which approximately corresponds to a dose of 50 mg
prednisolone in a patient. The impact of the treatment on the cells was determined by survival, activity and
gene expression. Results: Bortezomib as a single treatment was very efficient in killing sensitive m yeloma
cells (OPM2) whereas the more resistant cells (U266) were more efficiently killed in combination with
prednisolone. The release of TRAP from primary human osteoclasts, a marker of osteoclastic activation,
was strongly inhibited by bortezomib treatment alone, but only in combination with prednisolone did it result
in killing of osteoclasts. Survival of osteoblast like cells was uninfluenced by treatment with bortezomib
alone. In contrast, as shown previously, prednisolone strongly reduced osteoblast s urvival. Most importantly
however, a 3 hr pre-treatment with bortezomib protected the osteoblasts against the detrimental effects of
glucocorticoids. Ongoing investigations by Q-PCR indicate that important markers of osteoblast maturation
remain high if the osteoblasts were pre-treated with bortezomib prior to prednisolone exposure. Conclusion:
Our study demonstrates in conditions relevant to treatment of myeloma patients, that combining bortezomib
and glucocorticoids has a direct synergistic effect against myeloma cells and osteoclasts, and that
bortezomib protects directly osteoblasts from the negative impact of glucocorticoids. Thus, the combination
of bortezomib and glucocorticoids is not only a powerful treatment of multiple myeloma itself, but also shows
promise for treating myeloma bone disease.
Abstract #3523 appears in Blood, Volume 110, issue 11, November 16, 2007
Keywords: Bone Disease|Velcade|Prednisolone
Disclosure: Consultancy: Torben Plesner is member of an international advisory board for Janssen-Cilag.
Membership Information: Torben Plesner is member of an international advisory board for Janssen-Cilag.
Monday, December 10, 2007 5:00 PM
Session Info: Poster Session: Myeloma: Biology and Pathophysiology, excluding Therapy III (5:00 p.m.-
7:00 p.m.)

Source: http://www.cancereducation.com/CancerSysPagesNB/abstracts/mmrf/90/abdm18.pdf


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