Abstract
Several lines of evidence have demonstrated that deregulated activation of NF-κB plays a pivotal role in the initiation and progression of a variety of cancers including multiple myeloma (MM). Therefore, novel molecules that can effectively suppress deregulated NF-κB upregulation can potentially reduce MM growth. In this study, the effect of celastrol (CSL) on patient derived CD138+ MM cell proliferation, apoptosis, cell invasion, and migration was investigated. In addition, we studied whether CSL can potentiate the apoptotic effect of bortezomib, a proteasome inhibitor in MM cells and in a xenograft mouse model. We found that CSL significantly reduced cell proliferation and enhanced apoptosis when used in combination with bortezomib and upregulated caspase-3 in these cells. CSL also inhibited invasion and migration of MM cells through the suppression of constitutive NF-κB activation and expression of downstream gene products such as CXCR4 and MMP-9. Moreover, CSL when administered either alone or in combination with bortezomib inhibited MM tumor growth and decreased serum IL-6 and TNF-α levels. Overall, our results suggest that CSL can abrogate MM growth both in vitro and in vivo and may serve as a useful pharmacological agent for the treatment of myeloma and other hematological malignancies.
Highlights
Multiple myeloma (MM) is a plasma cell proliferative disorder with distinct genomic instability, reflected by its heterogeneous clinical course
We primarily investigated whether CSL can potentiate the apoptotic effect of bortezomib in MM cells and a xenograft mouse model
We investigated whether treatment with CSL can induce apoptosis in CD138+ cells using flow cytometric analysis
Summary
Multiple myeloma (MM) is a plasma cell proliferative disorder with distinct genomic instability, reflected by its heterogeneous clinical course. Advent of novel targeted therapies has expanded the armamentarium of MM therapy thereby resulting in increased longevity (Palumbo and Cavallo, 2012). Bortezomib, a small molecule inhibitor of proteasome is an important addition to the chemotherapy of myeloma (Cavo, 2006; Moreau et al, 2012; Suzuki, 2013). Combination strategies have been exploited in cancer chemotherapy for long to gain the advantage of improved efficacy with fewer side effects (Tu et al, 1998; Roodman, 2002; Ackler et al, 2010; Galmarini et al, 2012; Palumbo and Cavallo, 2012)
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