Valproic acid exerts anti-tumor as well as anti-angiogenic effects on myeloma.

Multiple myeloma is still an incurable disease, most commonly occurring in the elderly. The myeloma-induced bone marrow microenvironment protects myeloma cells from drug-induced apoptosis. Therefore, the development of novel and tolerable therapeutic alternatives to overcome the drug resistance is an important clinical issue. Valproic acid (VPA), a safe and widely used anti-epileptic agent, is revisited as a class I- and IIa-specific histone deacetylase inhibitor. In the present study, we evaluated the effect as well as a mechanism of actions of VPA on myeloma cell growth and survival, with special reference to the myeloma-induced bone marrow microenvironment. VPA at therapeutic concentrations for epilepsy induced cell death in primary CD138-positive myeloma cells as well as myeloma cell lines, but not in CD138-negative bone marrow cells. VPA suppressed osteoclastogenesis as well as osteoclast-mediated myeloma cell growth. VPA also inhibited vascular tubule formation enhanced by co-cultures of myeloma cells and osteoclasts in concert with thalidomide. In addition, VPA induced both caspase-dependent and -independent cell death in myeloma cells, and potentiated the anti-myeloma effects of melphalan and dexamethasone. Collectively, VPA is suggested to exert multi-factorial anti-myeloma actions, and may serve as a safe adjuvant to be included in conventional chemotherapies against myeloma.

Therapy with bortezomib plus dexamethasone induces osteoblast activation in responsive patients with multiple myeloma.

Bortezomib is a novel proteasome inhibitor that has shown marked antitumor effects in patients with multiple myeloma (MM). We evaluated the feasibility and efficacy of bortezomib plus dexamethasone (BD) therapy and assessed bone metabolism in relapsed or refractory MM. Fourteen patients received 1.3 mg/m2 bortezomib on days 1, 4, 8, and 11 along with 20 mg/dose of dexamethasone on days 1, 2, 4, 5, 8, 9, 11, and 12 in a 21-day cycle. After 1 to 3 cycles of BD therapy, 9 patients (64%) achieved an objective response (5 very good partial responses and 4 partial responses). Notably, a rapid increase in the serum concentration of alkaline phosphatase (ALP) was observed in 6 of the treatment-responsive patients. Moreover, serum levels of bone-formation markers (bone-specific ALP and osteocalcin) significantly increased in 5 and 2 responsive patients, respectively. Radiographic examination showed improvement in bone lesions, suggesting that BD therapy induces osteoblast activation in responders. Adverse events included thrombocytopenia of grades 1 to 3, peripheral neuropathy of grades 1 to 2, and grade 3 ileus and were transient and manageable. Although severe lung injury has been reported among Japanese patients treated with bortezomib, no pulmonary complications were observed during BD therapy. Our results suggest that BD therapy is a safe and promising therapeutic approach for Japanese patients with MM.

Malignant B-lymphoid cells with bone lesions express receptor activator of nuclear factor-kappaB ligand and vascular endothelial growth factor to enhance osteoclastogenesis.

PURPOSE: Receptor activator of nuclear factor-kappaB ligand (RANKL) is a key mediator of osteoclastogenesis. Because certain types of tumor cells aberrantly express RANKL, and because bone destruction also develops in B-cell lymphomas of bone origin, we investigated RANKL expression and the mechanisms of osteoclastogenesis in B-lymphoid neoplasms. EXPERIMENTAL DESIGN AND RESULTS: Immunohistochemistry of bone specimens resected from patients with primary B-cell lymphoma of bone with bone destruction revealed that lymphoma cells express RANKL as well as vascular endothelial cell growth factor (VEGF). The tumor cells isolated from the bone specimens enhanced osteoclastogenesis in vitro. In contrast, B-cell lymphoma infiltrating to the bone marrow without bone destruction did not express RANKL. Both RANKL and VEGF were expressed by a portion of B-lymphoid cell lines, including Daudi and IM-9. These RANKL-expressing tumor cells enhanced osteoclastogenesis from RAW264.7 cells and human monocyte-derived preosteoclasts in the absence of stromal cells/osteoblasts in a RANKL-dependent manner. Furthermore, conditioned media from Daudi cells enhanced transmigration of preosteoclasts that was inhibited by anti-VEGF antibody, suggesting that tumor cell-derived VEGF mediates recruitment of osteoclast precursors. Moreover, cocultures of B-lymphoid cell lines with osteoclasts enhanced the growth of B-lymphoid cells. CONCLUSIONS: Some malignant B cells aberrantly express functional RANKL as well as VEGF to enhance osteoclastogenesis. The coexpression of RANKL and VEGF may also contribute to the close cellular interactions with osteoclastic cells, thereby forming a vicious cycle between osteoclastic bone destruction and tumor expansion in bone.