Statins inhibit proliferation and cytotoxicity of a human leukemic natural killer cell line
Statins inhibit proliferation and cytotoxicity of a human leukemic natural killer cell line
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DOI：
10.1186/2050-7771-1-33
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发表时间：
2013-01-01
影响因子：
11.1
通讯作者：
Steele, Timothy A.
中科院分区：
文献类型：
--
作者：
Crosbie, Jon;Magnussen, Marc;Steele, Timothy A.
背景：自然杀伤细胞是人体抵御病毒感染细胞的第一道防线。就像所有的淋巴细胞一样，自然杀伤细胞恶性肿瘤可以发生，然而自然杀伤细胞白血病由于其对化疗药物的内在耐药性而非常难以治疗。随着对他汀类药物可能具有抗癌作用的认识，我们的研究主要集中在他汀类药物对YT-Indy自然杀伤细胞白血病细胞系的生长和细胞毒性的抑制作用。结果：我们的研究结果表明，几种他汀类化合物可以抑制YT-Indy细胞的增殖，扰乱细胞周期进程，并取消自然杀伤细胞的细胞毒性。由于自然杀伤细胞白血病的细胞毒性可能在这些患者的肺损伤中发挥作用，这是一个重要的发现。甲羟戊酸可恢复细胞毒性、增殖和细胞周期进程，表明他汀类药物的作用是通过抑制HMG辅酶A还原酶来实现的。甲羟戊酸途径的中间产物香叶基香叶基焦磷酸，而不是甲氧戊酸途径的其他中间产物，部分逆转了他汀类药物对YT-Indy增殖和细胞毒性的抑制。这些结果表明，甲羟戊酸途径后期产物的阻断可能解释了观察到的对YT-Indy增殖和细胞毒性的抑制作用。结论：他汀类药物可作为一种潜在的治疗人类自然杀伤细胞白血病的药物，可与化疗药物联合应用。
Background: Natural killer cells comprise the body's first line of defense against virus-infected cells. As is true of all lymphocytes, natural killer cell malignancies can develop, however natural killer cell leukemias can be very difficult to treat due to their intrinsic resistance to chemotherapeutic agents. With the recent understanding that statin drugs may have anti-cancer properties, our investigations have focused on the ability of statins to inhibit the growth and cytotoxicity of the YT-INDY natural killer cell leukemia cell line.Results: Our findings indicate that several statin compounds can inhibit YT-INDY proliferation disrupt cell cycle progression and abrogate natural killer cell cytotoxicity. Since natural killer cell leukemia cytotoxicity may play a role in the pulmonary damage seen in these patients, this is an important finding. Cytotoxicity, proliferation and cell cycle progression could be restored by the addition of mevalonate, signifying that the statin effects are brought about through HMG CoA reductase inhibition. The mevalonate pathway intermediate geranylgeranyl pyrophosphate, but not other intermediates in the mevalonate pathway, partially reversed statin-induced inhibition of YT-INDY proliferation and cytotoxicity. These results suggest that blockage of products made in the latter part of the mevalonate pathway may account for the observed inhibitory effects on YT-INDY proliferation and cytotoxicity. However, geranylgeranyl pyrophosphate could not reverse the statin-induced inhibition of the cell cycle.Conclusions: These results suggest that the statin drugs should be investigated as a potential therapeutic strategy for human natural killer cell leukemias possibly in combination with chemotherapeutic agents.