Aspirin enhances the cytotoxic activity of bortezomib against myeloma cells via suppression of Bcl-2, survivin and phosphorylation of AKT.
Aspirin enhances the cytotoxic activity of bortezomib against myeloma cells via suppression of Bcl-2, survivin and phosphorylation of AKT.
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阿司匹林通过抑制 Bcl-2、生存素和 AKT 磷酸化增强硼替佐米对骨髓瘤细胞的细胞毒活性
DOI：
10.3892/ol.2016.5472
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发表时间：
2017-02
期刊：
影响因子：
2.9
通讯作者：
Chen GA
中科院分区：
文献类型：
--
作者：
Ding JH;Yuan LY;Chen GA
在我们以前的研究中，发现阿司匹林（阿萨）在体内和体外都具有抗骨髓瘤作用。多发性骨髓瘤（MM）对硼替佐米（BTZ）的耐药部分是由于BTZ诱导的AKT激活和Survivin上调，这两个作用分别是阿萨在胃癌和卵巢癌中的靶点。因此，本研究探讨了阿萨和BTZ在MM中的相互作用，并进一步阐明了潜在的机制。分别用2.5 mM阿萨、10 nM BTZ和阿萨+BTZ处理含有N-和K-Ras突变的MM1.S和RPMI-8226细胞系不同的持续时间。测定细胞的增殖和凋亡，并在MM细胞中检查阿萨和BTZ相互作用的潜在机制。与单独使用任何一种药物相比，阿萨+BTZ处理以时间依赖性方式导致MM1.S和RPMI-8226细胞的增殖抑制率和凋亡率更高。药物相互作用试验显示阿萨和BTZ对骨髓瘤细胞的累加效应。阿萨单独抑制磷酸化AKT（p-AKT）和生存素的水平，而BTZ单独增加p-AKT和生存素的水平。值得注意的是，阿萨显著降低BTZ诱导的p-AKT和Survivin的上调。与单独使用任何一种药物相比，阿萨+BTZ治疗显著抑制Bcl-2水平。阿萨可能通过抑制AKT磷酸化、Survivin和Bcl-2增强BTZ对骨髓瘤细胞的抗骨髓瘤活性，表明阿萨+BTZ治疗MM的潜力，特别是对于BTZ难治性/复发性MM病例。
In our previous study, it was found that aspirin (ASA) exerted antimyeloma actions in vivo and in vitro. The resistance to bortezomib (BTZ) in multiple myeloma (MM) is partly due to AKT activation and the upregulation of survivin induced by BTZ, which are the targets of ASA in gastric and ovarian cancer, respectively. Thus, the present study investigated the interaction between ASA and BTZ in MM and further clarified the underlying mechanisms. MM1.S and RPMI-8226 cell lines harboring the N- and K-Ras mutations, respectively, were treated with 2.5 mM ASA, 10 nM BTZ and ASA+BTZ for different durations. The proliferation and apoptosis of the cells were determined, and the underlying mechanisms governing the interaction of ASA and BTZ were examined in the MM cells. Treatment with ASA+BTZ caused higher rates of proliferative inhibition and apoptosis in the MM1.S and RPMI-8226 cells in time-dependent manner, compared with either agent alone. A drug interaction assay revealed the additive effect of ASA and BTZ on the myeloma cells. ASA alone inhibited the levels of phosphorylated AKT (p-AKT) and survivin, whereas BTZ alone augmented the levels of p-AKT and survivin. Of note, ASA markedly decreased the upregulation of p-AKT and survivin induced by BTZ. Treatment with ASA+BTZ significantly suppressed the level of Bcl-2, compared with either agent alone. ASA may potentiate the antimyeloma activity of BTZ against myeloma cells via suppression of AKT phosphorylation, survivin and Bcl-2, indicating the potential of ASA+BTZ in treating MM, particularly for cases of BTZ-refractory/relapsed MM.