Small Compound 6-<italic>O</italic>-Angeloylplenolin Induces Mitotic Arrest and Exhibits Therapeutic Potentials in Multiple Myeloma
Menée in vitro et in vivo, cette étude évalue le potentiel thérapeutique d'un composé appelé 6-OAP dans le myélome multiple
Background Multiple 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-<italic>O</italic>-angeloylplenolin (6-OAP) on MM cells.</p> </sec> <sec> <title>Methodology/Principal Findings</title> <p>MM 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 <italic>in vivo</italic> 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.</p> </sec> <sec> <title>Conclusions/Significance</title> <p>These results indicate that 6-OAP is a new cell cycle inhibitor which shows therapeutic potentials for MM.</p> </sec>
PLOS ONE 2011