In vitro cytotoxicity of the novel antimyeloma agents perifosine, bortezomib and lenalidomide against different cell lines
In vitro cytotoxicity of the novel antimyeloma agents perifosine, bortezomib and lenalidomide against different cell lines
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DOI：
10.1007/s10637-010-9576-2
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发表时间：
2012-04-01
影响因子：
3.4
通讯作者：
Blau, Igor W.
中科院分区：
文献类型：
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作者：
Schmidt-Hieber, Martin;Dabrowski, Robert;Blau, Igor W.
新型AKT抑制剂perifosine是一种合成烷基磷脂，目前正在临床试验中研究用于治疗不同的血液学和肿瘤学恶性肿瘤。采用台盼蓝染色、流式细胞术检测活化的半胱天冬酶、膜联蛋白V测定、免疫组织化学研究（KI-67和半胱天冬酶-3染色）和未成熟髓样信息（IMI）技术研究哌立福新、硼替佐米和来那度胺对6种恶性血液病细胞系的体外细胞毒性。哌立福新和硼替佐米在所有测试的细胞系中诱导浓度和时间依赖性细胞毒性。哌立福新与硼替佐米共同孵育24小时后，联合效力为25%至75%，联合指数为1.13至0.22，在很大程度上发挥了相加或协同作用。在使用任何试验检测的所有细胞系中，来那度胺触发的细胞毒性均较低（与阴性对照相比，小于10%）。最后，哌立福新，而不是硼替佐米或来那度胺，显着增加了在IMI通道中检测到的细胞数量。哌立福新和硼替佐米-而不是来那度胺-通过半胱天冬酶激活触发实质性细胞毒性，并且主要以相加或协同作用起作用。IMI技术可能是一个有用的工具，用于研究药物的细胞毒性，如perifosine，主要与细胞膜相互作用。
The novel AKT inhibitor perifosine, a synthetic alkylphospholipid, is currently being investigated in clinical trials for the treatment of different hematological and oncological malignancies. The in vitro cytotoxicity of perifosine, bortezomib and lenalidomide against 6 cell lines derived from hematological malignancies was investigated using trypan blue staining, flow cytometry-based detection of activated caspases, Annexin V assays, immunohistochemistry studies (KI-67 and caspase-3 staining) and the immature-myeloid-information (IMI) technique. Perifosine and bortezomib induced concentration- and time-dependent cytotoxicity in all cell lines tested. Perifosine together with bortezomib largely exerted additive or synergistic effects with combination indices ranging from 1.13 to 0.22 for combined efficacies of 25% to 75% after 24-hour incubation. Lenalidomide-triggered cytotoxicity was low in all cell lines tested with any assay (less than 10% compared to the negative control). Finally, perifosine, but not bortezomib or lenalidomide, significantly increased the number of cells detected in the IMI channel. Perifosine and bortezomib- but not lenalidomide- trigger substantial cytotoxicity by caspase activation and mainly act additively or synergistically. The IMI technique might be a useful tool for studying cytotoxicity of agents like perifosine that interact mainly with the cellular membrane.