HIV protease inhibitors (HIV-PI) are oral drugs for HIV treatment. HIV-PI have antitumor activity via induction of ER-stress, inhibition of phospho-AKT (p-AKT) and the proteasome, suggesting antimyeloma activity. We characterize the effects of all approved HIV-PI on myeloma cells. HIV-PI were compared regarding cytotoxicity, proteasome activity, ER-stress induction and AKT phosphorylation using...

We investigated the effects of bortezomib (PS-341) and immunomodulatory thalidomide analogs (immunomodulatory compounds; CC-4047, CC-6032, and CC-5013, or lenalidomide) on osteoblast and osteoclast differentiation in vitro using human mesenchymal stem cells (hMSC) to commit to osteoprogenitor cells and peripheral blood mononuclear cells (PBMCs) isolated from healthy donors, respectively. First,...

It was shown that the proteasome inhibitor, bortezomib, administered immediately following allogeneic bone marrow transplantation resulted in marked inhibition of acute graft-versus-host disease (aGVHD), with retention of graft-versus-tumor effects. However, continuous bortezomib administration resulted in significant acceleration of graft-versus-host disease-dependent morbidity. We carried out...

Bortezomib is a proteasome inhibitor with remarkable clinical antitumor activity in multiple myeloma (MM) and is under evaluation in clinical trials in various types of cancer including breast cancer. Although the initial rationale for its use in cancer treatment was the inhibition of NF-κB activity by blocking proteasomal degradation of IκBα, direct evidence indicating inhibition of constituti...

Purpose: Proteasome inhibition disrupts protein homeostasis and induces apoptosis. Up to 50% of patients with relapsed mantle cell lymphoma (MCL) respond to bortezomib. We used gene expression profilingtoinvestigatetheconnectionbetweenproteasomeinhibition,cellularresponse,andclinicalefficacy. Experimental Design: We assessed transcriptional changes in primary tumor cells from five patients duri...

PURPOSE Novel therapeutic agents have significantly improved the survival of patients with multiple myeloma. Nonetheless, the prognosis of patients with multiple myeloma who become refractory to the novel agents lenalidomide and bortezomib is very poor, indicating the urgent need for new therapeutic options for these patients. The human CD38 monoclonal antibody daratumumab is being evaluated as...

Bortezomib has been introduced recently in the therapy of multiple myeloma (MM), a disease that is frequently associated with progressive renal failure. Because bortezomib-based therapy has been reported to lead to a rapid recovery of kidney function in patients with MM, we decided to study its direct effects in proximal tubular epithelial cells (PTCs) compared with glomerular mesangial cells (...

OBJECTIVE The proteasome inhibitor bortezomib has potent anti-myeloma and bone-protective activity. Recently, bortezomib was shown to directly inhibit osteoclastogenesis. The aim of this study was to analyze the influence and therapeutic effect of bortezomib in a mouse model of inflammatory arthritis. METHODS Heterozygous human tumor necrosis factor α (hTNFα)-transgenic mice and their wild-ty...

Bortezomib is a first-generation proteasome inhibitor used in the treatment of multiple myeloma (MM). A few reports have linked bortezomib exposure with the development of thrombotic microangiopathy (TMA). We describe a case of biopsy-proven renal thrombotic microangiopathy associated with the use of bortezomib in a 51-year-old man with IgG lambda MM. To our knowledge, this is the first biopsy-...

BACKGROUND Bortezomib is a proteasome inhibitor currently studied in clinical trials of childhood cancers. So far, no side effects on bone growth have been reported in treated children. However, bortezomib was recently found to induce apoptosis in growth plate chondrocytes and impair linear bone growth in treated mice. We hypothesize that [Gly(14)]-humanin (HNG), a 24-amino acid synthetic antia...