Combination of levetiracetam and IFN-α increased temozolomide efficacy in MGMT-positive glioma
Combination of levetiracetam and IFN-α increased temozolomide efficacy in MGMT-positive glioma
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左乙拉西坦和 IFN-α 组合可增加替莫唑胺治疗 MGMT 阳性神经胶质瘤的疗效
DOI：
10.1007/s00280-020-04169-y
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发表时间：
2020-10-19
影响因子：
3
通讯作者：
Chen, Zhong-Ping
中科院分区：
文献类型：
--
作者：
Ni, Xiang-Rong;Guo, Cheng-Cheng;Chen, Zhong-Ping
胶质瘤，尤其是胶质母细胞瘤（GBM）是最具侵袭性的脑恶性肿瘤，其标准治疗常因替莫唑胺（TMZ）耐药而无效。TMZ耐药的逆转可能改善胶质瘤患者的预后。我们以前发现干扰素-α（IFN-α）和抗癫痫药物左乙拉西坦（LEV）分别可以使胶质瘤对TMZ增敏。在这项研究中，我们进一步研究了LEV和IFN-α相结合，以提高TMZ的疗效的效率。方法我们评估是否LEV和IFN-α可以增加TMZ的疗效与MGMT阳性和MGMT阴性的胶质瘤细胞系在体外的集落形成试验和细胞活力测定。采用皮下移植瘤和原位移植瘤小鼠模型，观察TMZ、TMZ + IFN-α、TMZ + LEV或TMZ + LEV + IFN-α治疗后的肿瘤生长和小鼠存活。结果IFN-α、LEV和TMZ联合应用对MGMT阳性细胞系（U138、GSC-1、U118和T98 G）的抗肿瘤活性最好。TMZ + LEV + IFN-α在体外对MGMT阳性细胞系的TMZ + LEV或TMZ + IFN-α效率进一步明显增加，而对阴性细胞系（SKMG-4、U87、U373和U251）的TMZ + LEV或TMZ + IFN-α效率无明显增加，这在皮下小鼠模型（U138、GSC-1与SKMG-4、U87相比）和体内原位模型（GSC-1）中也观察到。引人注目的是，LEV和IFN-α与TMZ的组合显著延长了具有原位GSC-1胶质瘤的小鼠的存活。结论LEV和IFN-α联合应用可明显抑制MGMT阳性胶质瘤细胞的MGMT表达，是克服TMZ耐药的最佳方法。
PurposeGlioma, especially glioblastoma (GBM), is the most aggressive malignant brain tumor and its standard therapy is often ineffective because of temozolomide (TMZ) resistance. Reversal of the TMZ resistance might improve the prognosis of glioma patients. We previously found that interferon-α (IFN-α) and anti-epileptic drug levetiracetam (LEV) could sensitize glioma to TMZ, respectively. In this study, we further investigated the efficiency of combining of LEV and IFN-α for improving the efficacy of TMZ.MethodsWe evaluated whether LEV and IFN-α could increase TMZ efficacy using colony formation assay and cell viability assay with MGMT-positive and MGMT-negative glioma cell lines in vitro. Subcutaneous xenografts and orthotopic xenografts mice models were used in vivo to observe the tumor growth and mice survival upon treatments with TMZ, TMZ + IFN-α, TMZ + LEV, or TMZ + LEV + IFN-α. The expression levels of MGMT, markers of pro-apoptotic and anti-apoptotic in tumor samples were analyzed by Western blotting.ResultsThe combinational use of IFN-α, LEV, and TMZ showed the best anti-tumor activity in MGMT-positive cell lines (U138, GSC-1, U118, and T98 G). TMZ + LEV + IFN-α further obviously increased TMZ + LEV or TMZ + IFN-α efficiency in MGMT-positive cell lines, while not in negative cell lines (SKMG-4, U87, U373, and U251) in vitro, which were also observed in subcutaneous mice models (U138, GSC-1 compared to SKMG-4, U87) and orthotopic models (GSC-1) in vivo. Strikingly, the combination of LEV and IFN-α together with TMZ significantly prolonged the survival of mice with orthotopic GSC-1 glioma. Furthermore, we confirmed that the combination of LEV and IFN-α enhanced the inhibition of MGMT and the activation of apoptosis in U138 tumor on the basis of TMZ treatment.ConclusionsThe combination use of LEV and IFN-α could be an optimal method to overcome TMZ resistance through obvious MGMT inhibition in MGMT-positive glioma.