Guangzhou Institute of Biomedicine and Health and State Key Laboratory of Biomembrane and Membrane Biotechnology, Chinese Academy of Sciences, Beijing, China.
PLoS One. 2011;6(7):e21930. doi: 10.1371/journal.pone.0021930. Epub 2011 Jul 6.
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-O-angeloylplenolin (6-OAP) on MM cells.
METHODOLOGY/PRINCIPAL FINDINGS: 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 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/SIGNIFICANCE: These results indicate that 6-OAP is a new cell cycle inhibitor which shows therapeutic potentials for MM.
多发性骨髓瘤（MM）是一种细胞周期失调的疾病，而细胞周期调节可能是 MM 治疗的靶点。在这项研究中，我们研究了倍半萜内酯 6-O-当归酰基大根香叶烯内酯（6-OAP）对 MM 细胞的作用及其作用机制。
方法/主要发现：将 MM 细胞暴露于 6-OAP 中，并分析细胞周期分布。通过 U266 细胞中的特异性 siRNA 分析测试 cyclin B1 在 6-OAP 引起的有丝分裂阻滞中的作用。将 MM.1S 细胞与白细胞介素-6（IL-6）、胰岛素样生长因子-I（IGF-I）或骨髓基质细胞（BMSCs）共孵育，并用 6-OAP 处理。评估 6-OAP 加其他药物对 MM.1S 细胞的影响。分别在荷 U266 细胞的裸鼠和 Sprague-Dawley 大鼠中测试 6-OAP 的体内治疗效果和药代动力学特征。我们发现，6-OAP 抑制了地塞米松敏感和地塞米松耐药细胞系和原发性 CD138+ MM 细胞的增殖。6-OAP 导致有丝分裂停滞，伴随着纺锤体组装检查点的激活和 cyclin B1 的泛素化和随后的蛋白酶体降解的阻断。6-OAP 与硼替佐米联合使用可诱导增强的细胞毒性，同时使 ERK1/2 失活，JNK1/2 和 Casp-8/-3 激活。6-OAP 通过分别抑制 Jak2/Stat3 和 Akt，克服了 IL-6 和 IGF-I 对 MM 细胞的保护作用。6-OAP 抑制了 BMSCs 促进的 MM 细胞扩增和 TNF-α诱导的 NF-κB 信号。此外，6-OAP 在裸鼠中表现出强大的抗 MM 活性，并在大鼠中具有良好的药代动力学特性。
结论/意义：这些结果表明，6-OAP 是一种新的细胞周期抑制剂，对 MM 具有治疗潜力。
