Combination statin and chemotherapy inhibits proliferation and cytotoxicity of an aggressive natural killer cell leukemia.
Combination statin and chemotherapy inhibits proliferation and cytotoxicity of an aggressive natural killer cell leukemia.
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DOI：
10.1186/s40364-018-0140-0
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发表时间：
2018
影响因子：
11.1
通讯作者：
Steele TA
中科院分区：
文献类型：
--
作者：
Henslee AB;Steele TA
侵袭性自然杀伤细胞白血病是一种毁灭性的疾病，诊断后患者的平均生存时间不到2个月。由于P-糖蛋白介导的肿瘤细胞耐药，大多数形式的化疗效果有限，因此需要新的治疗策略。最近发现他汀类药物可以抑制各种肿瘤细胞的生长。我们研究了他汀类药物介导的甲羟戊酸通路抑制对细胞增殖、肿瘤诱导的细胞毒性、细胞周期进展和ERK MAP激酶信号转导通路激活的影响。流式细胞仪检测细胞毒性和细胞周期变化，Western blotting检测ERK MAP激酶活性。通过Student t检验评估统计学显著性。发现氟伐他汀和阿托伐他汀抑制细胞生长和肿瘤诱导的细胞毒性。这些作用通过加入甲羟戊酸逆转，表明药物对甲羟戊酸途径的影响。这两种药物通过引起G 0/G1期细胞百分比的显著增加以及细胞周期的S期和G2/M期的减少来影响细胞周期进程。低浓度的他汀类药物能够消除ERK MAP激酶途径的激活，其通常在侵袭性自然杀伤细胞白血病中被组成性激活，并且在肿瘤介导的细胞毒性中很重要。与单独使用任何一种药物相比，在化疗中加入他汀类药物会增强对细胞生长和细胞毒性的抑制作用;可以想象，这种联合治疗会使一些患者受益。这些研究表明，抑制甲羟戊酸途径可能会提供一个更有效的治疗这种致命的疾病时，结合化疗。鉴于数百万人目前正在服用他汀类药物以降低胆固醇水平，他汀类药物的风险特征及其副作用是众所周知的。我们的研究表明，这可能是有益的，探索他汀类药物联合化疗治疗侵袭性自然杀伤细胞白血病。
Aggressive natural killer cell leukemia is a devastating disease, with an average patient survival time of less than 2 months following diagnosis. Due to P-glycoprotein-mediated resistance of the tumor cells most forms of chemotherapy are of limited efficacy, therefore new treatment strategies are needed. Statin drugs have recently been found to inhibit the growth of various tumor cell types. We investigated the effects of statin drug-mediated mevalonate pathway inhibition on cell proliferation, tumor-induced cytotoxicity, cell cycle progression and ERK MAP kinase signal transduction pathway activation. Flow cytometry was used to perform the cytotoxicity and cell cycle analyses and Western blotting was used to investigate ERK MAP kinase activation. Statistical significance was assessed by Student’s t-test. Fluvastatin and atorvastatin were found to inhibit cell growth and tumor-induced cytotoxicity. These effects were reversed by the addition of mevalonate, signifying that the impact of the drugs were on the mevalonate pathway. Both drugs affected cell cycle progression by causing a significant increase in the percentage of cells in the G0/G1 phase and a reduction in the S phase and the G2/M phases of the cell cycle. Low concentrations of statin drugs were able to abrogate ERK MAP kinase pathway activation, which is typically constitutively activated in aggressive natural killer cell leukemias and important in tumor-mediated cytotoxicity. Addition of statins to chemotherapy caused enhanced inhibition of cell growth and cytotoxicity, compared to either agent alone; a combination therapy that could conceivably benefit some patients. These investigations suggest that inhibiting the mevalonate pathway might provide a more effective therapy against this deadly disease when combined with chemotherapy. Given that millions of people are currently taking statin drugs to lower cholesterol levels, the risk profile for statin drugs and their side effects are well-known. Our studies suggest that it may be beneficial to explore statin-chemotherapy combination in the treatment of aggressive natural killer cell leukemias.
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