Overcoming temozolomide (TMZ) resistance in glioma cancer cells remains a major challenge to the effective treatment of the disease. Increasing TMZ efficacy for patients with glioblastoma (GBM) is urgently needed because TMZ treatment is the standard chemotherapy protocol for adult patients with glioblastoma. O⁶-methylguanine-DNA-methyltransferase (MGMT) overexpression is associated with TMZ resistance, and low MGMT is a positive response marker for TMZ therapy. Here, we used 3 glioma cell lines (SF767, U373, and LN229), which had different levels of TMZ sensitivity. We found TMZ sensitivity is positively correlated with MGMT expression and multidrug-resistance protein ABC subfamily G member 2 (ABCG2) in these cells. CK2-STAT3 signaling and Hippo-YAP signaling are reported to regulate MGMT expression and ABCG2 expression, respectively. We combined CK2 inhibitor CX-4945 and YAP inhibitor verteporfin with TMZ treatment. We found that CX-4945 but not verteporfin can sensitize TMZ-resistant cells SF767 to TMZ and that CX-4945 and TMZ combinational treatment was effective for glioma treatment in mouse models compared with TMZ alone.

Implications

A combination of CK2 inhibitor with TMZ may improve the therapeutic efficiency of TMZ toward GBM with acquired resistance.

中文翻译：

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CX-4945抑制酪蛋白激酶II，但非Verteporfin抑制Yes-associated蛋白（YAP）增强替莫唑胺在成胶质细胞瘤中的抗肿瘤功效。

克服神经胶质瘤癌细胞中的替莫唑胺（TMZ）耐药性仍然是有效治疗该疾病的主要挑战。由于成年胶质母细胞瘤患者的标准化疗方案是TMZ治疗，因此迫切需要提高胶质母细胞瘤（GBM）患者的TMZ疗效。Ø ⁶-甲基鸟嘌呤-DNA-甲基转移酶（MGMT）的过表达与TMZ耐药有关，而低MGMT是TMZ治疗的阳性反应标志物。在这里，我们使用了3种胶质瘤细胞系（SF767，U373和LN229），它们具有不同水平的TMZ敏感性。我们发现TMZ敏感性与这些细胞中的MGMT表达和多药耐药蛋白ABC亚家族G成员2（ABCG2）正相关。据报道，CK2-STAT3信号和Hippo-YAP信号分别调节MGMT表达和ABCG2表达。我们将CK2抑制剂CX-4945和YAP抑制剂韦替泊芬与TMZ治疗相结合。我们发现CX-4945而非verteporfin可以使TMZ耐药细胞SF767对TMZ敏感，并且与单独使用TMZ相比，CX-4945和TMZ联合治疗在小鼠模型中对神经胶质瘤治疗有效。

含意

CK2抑制剂与TMZ的组合可提高TMZ对GBM的治疗效率，并获得耐药性。