Inhibitory effect of simvastatin on the proliferation of human myeloid leukaemia cells in severe combined immunodeficient (SCID) mice
Inhibitory effect of simvastatin on the proliferation of human myeloid leukaemia cells in severe combined immunodeficient (SCID) mice
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DOI：
10.1046/j.1365-2141.1998.00783.x
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发表时间：
1998-07-01
影响因子：
6.5
通讯作者：
Millar, JL
中科院分区：
文献类型：
--
作者：
Clutterbuck, RD;Millar, BC;Millar, JL
用来自人HL 60成髓细胞白血病细胞系的细胞静脉内接种SCID小鼠，然后用3-羟基-3-甲基戊二酰辅酶A（HMG CoA）还原酶抑制剂辛伐他汀处理。通过皮下持续输注，通过随后的存活HL 60细胞体外集落形成和流式细胞术来测量药物的作用。在两个独立的实验中，接受辛伐他汀的小鼠骨髓中的克隆形成性HL 60细胞的数量与对照小鼠相比减少了65%和68%。在两项实验中，同时暴露于体内辛伐他汀的正常小鼠骨髓祖细胞的克隆形成数量均未受到影响。骨髓和脾细胞的流式细胞仪分析证实了这些结果，显示辛伐他汀已减少这些组织中的人白血病细胞的百分比分别为70%和88%.Data表明，辛伐他汀对急性髓系白血病细胞在体外的选择性作用。可以扩展到这个体内模型，HL 60携带N-ras突变。在进一步的体外研究中，酮康唑（一种焦磷酸法呢酯合成后胆固醇生物合成的抑制剂）对HL 60菌落发育的影响与辛伐他汀相似。此外，N-ras突变的原发性急性髓性白血病（AML）细胞群体的克隆形成性对辛伐他汀并不比没有突变的群体更敏感。这些数据表明，辛伐他汀对AML细胞增殖的抑制可能不依赖于RAS信号通路。
SCID mice were inoculated intravenously with cells from the human HL60 myeloblastic leukaemia cell line and then treated with the 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitor, simvastatin. by subcutaneous continuous infusion, The effect of the drug was measured by subsequent colony formation of surviving HL60 cells in vitro and flow cytometry., The number elf clonogenic HL60 cells was reduced in the bone marrow of mice that received simvastatin compared with control mice by 65% and 68% in two separate experiments. The number of clonogenic, normal, murine, bone marrow progenitor cells concomitantly exposed to simvastatin in vivo, was not affected in either experiment. Flow cytometric analysis of bone marrow and spleen cells confirmed these results by showing that simvastatin had reduced the percentage of human leukaemia cells in these tissues by 70% and 88% respectively.The data show that the reported selective effect of simvastatin against acute myeloid leukaemia cells in vitro. can be extended to this in vivo model, HL60 bears an N-ras mutation. In further in vitro studies, ketoconazole, an inhibitor of cholesterol biosynthesis post farnesyl pyrophosphate synthesis, had a similar effect to simvastatin on HL60 colony development. Furthermore, the clonogenicity of a population of N-ras mutated, primary acute myeloid leukaemia (AML) cells was no more sensitive to simvastatin than a population without the mutation. The data suggest that the inhibition of AML cell proliferation by simvastatin may be independent of the RAS signalling pathway.