Synergistic antitumor effect with indoleamine 2,3-dioxygenase inhibition and temozolomide in a murine glioma model
Synergistic antitumor effect with indoleamine 2,3-dioxygenase inhibition and temozolomide in a murine glioma model
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DOI：
10.3171/2015.5.jns141901
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发表时间：
2016-06-01
影响因子：
4.1
通讯作者：
Kinouchi, Hiroyuki
中科院分区：
文献类型：
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作者：
Hanihara, Mitsuto;Kawataki, Tomoyuki;Kinouchi, Hiroyuki
目的 吲哚胺 2,3-双加氧酶 (IDO) 是色氨酸 (Trp) 代谢的关键酶，通过消耗色氨酸和代谢物犬尿氨酸的积累参与肿瘤源性免疫抑制，导致自然杀伤细胞失活并产生调节性 T 细胞 (Treg)。据报道，癌细胞中 IDO 的高表达与抗肿瘤免疫反应的抑制有关，并且与不良预后一致。因此，IDO可能是恶性癌症的治疗靶点。作者最近表明，IDO 表达在人胶质母细胞瘤和恶性变的继发性胶质母细胞瘤中显着增加，表明 IDO 靶向也可能对胶质瘤患者具有治疗潜力。本研究的目的是探讨IDO抑制剂的抗肿瘤作用，并探讨IDO抑制剂和替莫唑胺（TMZ）在小鼠胶质瘤模型中的协同作用。方法本研究包括小鼠胶质瘤GL261细胞和人胶质瘤U87细胞。作者使用 3 种小鼠模型来研究神经胶质瘤细胞生长：1）皮下异位模型，2）同基因颅内原位模型，3）同种异体颅内原位模型。 IDO 抑制是通过使用短发夹 RNA (shRNA) 敲低 GL261 细胞中的 IDO 以及口服 IDO 抑制剂 1-甲基-L-色氨酸 (1-MT) 来实现的。评估皮下模型中的肿瘤体积和颅内模型中的生存时间。结果在皮下模型中，口服1-MT显着抑制肿瘤生长，并且观察到1-MT和TMZ的协同抗肿瘤作用(p < 0.01)。与对照小鼠相比，颅内接种 IDO 敲低细胞的小鼠的存活期显着延长 (p < 0.01)。 结论 这些结果表明，IDO 表达与神经胶质瘤细胞的免疫抑制和肿瘤进展有关。因此，将 IDO 抑制与标准 TMZ 治疗相结合对于恶性神经胶质瘤患者来说可能是一种令人鼓舞的治疗策略。
OBJECTIVE Indoleamine 2,3-dioxygenase (IDO), a key enzyme of tryptophan (Trp) metabolism, is involved in tumor derived immune suppression through depletion of Trp and accumulation of the metabolite kynurenine, resulting in inactivation of natural killer cells and generation of regulatory T cells (Tregs). It has been reported that high expression of IDO in cancer cells is associated with suppression of the antitumor immune response and is consistent with a poor prognosis. Thus, IDO may be a therapeutic target for malignant cancer. The authors have recently shown that IDO expression is markedly increased in human glioblastoma and secondary glioblastoma with malignant change, suggesting that IDO targeting may also have therapeutic potential for patients with glioma. The aim of this study was to investigate the antitumor effect of IDO inhibition and to examine the synergistic function of IDO inhibitor and temozolomide (TMZ) in a murine glioma model.METHODS Murine glioma GL261 cells and human glioma U87 cells were included in this study. The authors used 3 mouse models to study glioma cell growth: 1) a subcutaneous ectopic model, 2) a syngeneic intracranial orthotopic model, and 3) an allogenic intracranial orthotopic model. IDO inhibition was achieved via knockdown of IDO in GL261 cells using short hairpin RNA (shRNA) and through oral administration of the IDO inhibitor, 1-methyl-L-tryptophan (1-MT). Tumor volume in the subcutaneous model and survival time in the intracranial model were evaluated.RESULTS In the subcutaneous model, oral administration of 1-MT significantly suppressed tumor growth, and synergistic antitumor effects of 1-MT and TMZ were observed (p < 0.01). Mice containing intracranially inoculated IDO knockdown cells had a significantly longer survival period as compared with control mice (p < 0.01).CONCLUSIONS These results suggest that IDO expression is implicated in immunosuppression and tumor progression in glioma cells. Therefore, combining IDO inhibition with standard TMZ treatment could be an encouraging therapeutic strategy for patients with malignant glioma.