Chemoresistance contributes to relapse in high-risk neuroblastoma. Cancer cells acquire resistance through multiple mechanisms, including drug efflux pumps. In neuroblastoma, multidrug resistance-associated protein-1 (MRP1/ efflux pump expression correlates with worse outcomes. These pumps are regulated by PIM kinases, a family of serine–threonine kinases, overexpressed in neuroblastoma. We hypothesized PIM kinase inhibition would sensitize neuroblastoma cells by modulating MRP1. Kocak database query evaluated , and expression in neuroblastoma patients. SK-N-AS and SK-N-BE(2) cells were treated with doxorubicin or the pan-PIM kinase inhibitor, AZD1208. Flow cytometry assessed intracellular doxorubicin accumulation. AlamarBlue assay measured viability. The lethal dose 50% (LD) of each drug and combination indices (CI) were calculated and isobolograms constructed to determine synergy. Kocak database query demonstrated positive correlation between genes and . PIM kinase inhibition increased intracellular doxorubicin accumulation in both cell lines, suggesting PIM kinase regulation of MRP1. Isobolograms showed synergy between AZD1208 and doxorubicin. The correlation between and gene expression suggests PIM kinases may contribute to neuroblastoma chemotherapeutic resistance. PIM kinase inhibition increased intracellular doxorubicin accumulation. Combination treatment with AZD1208 and doxorubicin decreased neuroblastoma cell viability in a synergistic fashion. These findings support further investigations of PIM kinase inhibition in neuroblastoma. Basic Science Research. NA.

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PIM 激酶抑制使神经母细胞瘤对阿霉素敏感

化疗耐药导致高危神经母细胞瘤复发。癌细胞通过多种机制获得耐药性，包括药物外排泵。在神经母细胞瘤中，多药耐药相关蛋白 1（MRP1/ 外排泵表达与较差的结果相关。这些泵受 PIM 激酶（丝氨酸-苏氨酸激酶家族，在神经母细胞瘤中过度表达）调节。我们假设 PIM 激酶抑制会使神经母细胞瘤细胞敏感通过调节 MRP1。Kocak 数据库查询评估了 和在神经母细胞瘤患者中的表达。用阿霉素或泛 PIM 激酶抑制剂 AZD1208 处理 SK-N-AS 和 SK-N-BE(2) 细胞。流式细胞术评估细胞内阿霉素积累. AlamarBlue 测定法测量活力。计算每种药物的致死剂量 50% (LD) 和组合指数 (CI)，并构建等效线图以确定协同作用。Kocak 数据库查询证明基因与 之间呈正相关。PIM 激酶抑制增加细胞内阿霉素积累两种细胞系，表明 PIM 激酶对 MRP1 的调节。等效线图显示 AZD1208 和阿霉素之间的协同作用。和基因表达之间的相关性表明 PIM 激酶可能导致神经母细胞瘤化疗耐药。 PIM 激酶抑制增加了细胞内阿霉素的积累。 AZD1208 和阿霉素联合治疗以协同方式降低神经母细胞瘤细胞的活力。这些发现支持对神经母细胞瘤中 PIM 激酶抑制的进一步研究。基础科学研究。不适用。