Pitavastatin Is Anti-Leukemic in a Bone Marrow Microenvironment Model of B-Lineage Acute Lymphoblastic Leukemia.
Pitavastatin Is Anti-Leukemic in a Bone Marrow Microenvironment Model of B-Lineage Acute Lymphoblastic Leukemia.
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Pitavastatin是B-Linege急性淋巴细胞白血病的骨髓微环境模型中的抗白血病。
DOI：
10.3390/cancers14112681
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发表时间：
2022-05-28
期刊：
影响因子：
5.2
通讯作者：
Gibson, Laura F.
中科院分区：
文献类型：
--
作者：
Piktel, Debbie;Nair, Rajesh R.;Rellick, Stephanie L.;Geldenhuys, Werner J.;Martin, Karen H.;Craig, Michael D.;Gibson, Laura F.
化疗后的化疗耐药是B细胞急性淋巴细胞性白血病(ALL)的一个负面预后指标，需要寻找新的治疗方法。通过将ALL细胞与骨髓基质细胞共同培养，我们建立了一种耐化疗的ALL模型。利用这一模型，我们发现降脂药物匹拉伐他汀在这种化疗耐药共培养模型中具有抗白血病活性。我们的数据表明，匹伐他汀可能是一种新的治疗方案，用于化疗耐药、复发ALL的再利用。在治疗B细胞急性淋巴细胞白血病(ALL)方面缺乏完全的治疗成功，部分原因是骨髓微环境中具有耐药性的细胞亚群。最近，胆固醇合成抑制剂倍他伐他汀(Pitavastatin，PIT)被证明在急性髓系白血病中具有活性，这促使我们在支持耐药ALL人群的体外共培养模型中对其进行评估。由于多种活性生存信号的上调，我们使用磷酸化蛋白图谱来评估脂类代谢活性化合物在这些化疗耐药细胞中的使用。在与基质细胞的共培养中，发生了向合成代谢过程的转变，这一点在显示脂质含量增加的检测中得到了进一步证实。在共培养模型中，与标准化疗药物阿糖胞苷(Ara-C)相比，在共培养模型中用匹伐他汀处理REH白血病细胞导致的白血病细胞死亡率显著高于标准护理化疗药物阿糖胞苷(Ara-C)。我们的数据表明，使用匹伐他汀作为一种可能的替代治疗策略，以改善化疗耐药的复发ALL患者的预后。
Chemoresistance after chemotherapy is a negative prognostic indicator for B-cell acute lymphoblastic leukemia (ALL), necessitating the search for novel therapies. By growing ALL cells together with bone marrow stromal cells, we developed a chemoresistant ALL model. Using this model, we found that the lipid lowering drug pitavastatin had antileukemic activity in this chemoresistant co-culture model. Our data suggests that pitavastatin may be a novel treatment option for repurposing in chemoresistant, relapse ALL. The lack of complete therapeutic success in the treatment of B-cell acute lymphoblastic leukemia (ALL) has been attributed, in part, to a subset of cells within the bone marrow microenvironment that are drug resistant. Recently, the cholesterol synthesis inhibitor, pitavastatin (PIT), was shown to be active in acute myeloid leukemia, prompting us to evaluate it in our in vitro co-culture model, which supports a chemo-resistant ALL population. We used phospho-protein profiling to evaluate the use of lipid metabolic active compounds in these chemo-resistant cells, due to the up-regulation of multiple active survival signals. In a co-culture with stromal cells, a shift towards anabolic processes occurred, which was further confirmed by assays showing increased lipid content. The treatment of REH leukemia cells with pitavastatin in the co-culture model resulted in significantly higher leukemic cell death than exposure to the standard-of-care chemotherapeutic agent, cytarabine (Ara-C). Our data demonstrates the use of pitavastatin as a possible alternative treatment strategy to improve patient outcomes in chemo-resistant, relapsed ALL.
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影响因子：
9
作者：
通讯作者：
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影响因子：
3.5
作者：
CARLING, D;ZAMMIT, VA;HARDIE, DG
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HARDIE, DG
影响因子：
50.3
作者：
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Jeremias I
影响因子：
3.7
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通讯作者：
Baigent C
影响因子：
20.3
作者：
Doughty, Cheryl A.;Bleiman, Blair F.;Chiles, Thomas C.
通讯作者：
Chiles, Thomas C.