Abstract
BackgroundMultiple myeloma (MM) is a disease of cell cycle dysregulation while cell cycle modulation can be a target for MM therapy. In this study we investigated the effects and mechanisms of action of a sesquiterpene lactone 6-O-angeloylplenolin (6-OAP) on MM cells.Methodology/Principal FindingsMM cells were exposed to 6-OAP and cell cycle distribution were analyzed. The role for cyclin B1 to play in 6-OAP-caused mitotic arrest was tested by specific siRNA analyses in U266 cells. MM.1S cells co-incubated with interleukin-6 (IL-6), insulin-like growth factor-I (IGF-I), or bone marrow stromal cells (BMSCs) were treated with 6-OAP. The effects of 6-OAP plus other drugs on MM.1S cells were evaluated. The in vivo therapeutic efficacy and pharmacokinetic features of 6-OAP were tested in nude mice bearing U266 cells and Sprague-Dawley rats, respectively. We found that 6-OAP suppressed the proliferation of dexamethasone-sensitive and dexamethasone-resistant cell lines and primary CD138+ MM cells. 6-OAP caused mitotic arrest, accompanied by activation of spindle assembly checkpoint and blockage of ubiquitiniation and subsequent proteasomal degradation of cyclin B1. Combined use of 6-OAP and bortezomib induced potentiated cytotoxicity with inactivation of ERK1/2 and activation of JNK1/2 and Casp-8/-3. 6-OAP overcame the protective effects of IL-6 and IGF-I on MM cells through inhibition of Jak2/Stat3 and Akt, respectively. 6-OAP inhibited BMSCs-facilitated MM cell expansion and TNF-α-induced NF-κB signal. Moreover, 6-OAP exhibited potent anti-MM activity in nude mice and favorable pharmacokinetics in rats.Conclusions/SignificanceThese results indicate that 6-OAP is a new cell cycle inhibitor which shows therapeutic potentials for MM.
Highlights
Multiple myeloma (MM) is a malignant proliferation of bone marrow (BM) plasma cells that produce monoclonal immunoglobulin [1]
By using the trypan blue exclusion assay, we found that at 5 to 7.5 mM 6-OAP markedly inhibited cell growth of U266, RPMI 8226, MM.1S, and MM.1R cells (Figure 1C). 6-OAP suppressed cell growth of CD138+ primary cells harvested from 7 MM patients (Figure 1D), but did not drastically affect the growth of normal Peripheral blood mononuclear cells (PBMCs) from 5 healthy volunteers (Figure 1E), suggestive of a relative selectivity against MM cells
6-OAP induces mitotic arrest in MM cells We carefully examined the morphological change of the cells, and found that after treatment with 6-OAP at 7.5 mM for 24 to 48 h, the commonly round-shaped U266 cells transformed into ellipse-shaped or spindle-shaped ones (Figure 2A)
Summary
Multiple myeloma (MM) is a malignant proliferation of bone marrow (BM) plasma cells that produce monoclonal immunoglobulin [1]. The use of high-dose chemotherapy followed by autologous stem cell transplantation as well as novel agents including thalidomide, bortezomib (BOR), and lenalidomide has increased remission rates and progression-free survival [4,5,6,7]. Studies demonstrate that BM microenvironment, including BM stromal cells (BMSC) [8], paracrine signaling loops involving cytokines interleukin-6 (IL-6) and insulin-like growth factor-I (IGF-I) [9], plays pivotal roles in myeloma pathogenesis and drug resistance. Novel agents targeting pathways critical to myeloma cell survival/proliferation and BM microenvironment that lead to overcome of drug resistance, remain an urgent need. In this study we investigated the effects and mechanisms of action of a sesquiterpene lactone 6-Oangeloylplenolin (6-OAP) on MM cells
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