You Fangting, Li Cheng, Zhang Shicheng, Zhang Qiaoshan, Hu Zhiyuan, Wang Yuhui, Zhang Tong, Meng Qingming, Yu Rutong, Gao Shangfeng
Institute of Nervous System Diseases, Xuzhou Medical University, Xuzhou 221002, China; Department of Neurosurgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, China.
Institute of Nervous System Diseases, Xuzhou Medical University, Xuzhou 221002, China.
Biomed Pharmacother. 2023 Jun;162:114555. doi: 10.1016/j.biopha.2023.114555. Epub 2023 Mar 24.
The standard regimen treatment has improved GBM outcomes, but the survival rate of patients is still unsatisfactory. Temozolomide (TMZ) resistance is one of main reasons limiting the therapeutic efficacy of GBM. However, there are currently no TMZ-sensitizing drugs available in the clinic. Here we aimed to study whether the antidiabetic drug Sitagliptin can inhibit the survival, stemness and autophagy of GBM cells, and thus enhance TMZ cytotoxicity. We used CCK-8, EdU, colony formation, TUNEL and flow cytometry assays to assess cell proliferation and apoptosis; sphere formation and limiting dilution assays to measure self-renewal and stemness of glioma stem cells (GSCs); Western blot, qRT-PCR or immunohistochemical analysis to measure the expression of proliferation or stem cell markers; Western blot/fluorescent analysis of LC3 and other molecules to evaluate autophagy formation and degradation in glioma cells. We found that Sitagliptin inhibited proliferation and induced apoptosis in GBM cells and suppressed self-renewal and stemness of GSCs. The in vitro findings were further confirmed in glioma intracranial xenograft models. Sitagliptin administration prolonged the survival time of tumor-bearing mice. Sitagliptin could inhibit TMZ-induced protective autophagy and enhance the cytotoxicity of TMZ in glioma cells. In addition, Sitagliptin acted as a dipeptidyl peptidase 4 inhibitor in glioma as well as in diabetes, but it did not affect the blood glucose level and body weight of mice. These findings suggest that Sitagliptin with established pharmacologic and safety profiles could be repurposed as an antiglioma drug to overcome TMZ resistance, providing a new option for GBM therapy.
标准方案治疗改善了胶质母细胞瘤（GBM）的治疗效果，但患者的生存率仍不尽人意。替莫唑胺（TMZ）耐药是限制GBM治疗效果的主要原因之一。然而，目前临床上尚无TMZ增敏药物。在此，我们旨在研究抗糖尿病药物西他列汀是否能抑制GBM细胞的存活、干性和自噬，从而增强TMZ的细胞毒性。我们使用CCK-8、EdU、集落形成、TUNEL和流式细胞术检测来评估细胞增殖和凋亡；使用球体形成和极限稀释检测来测量胶质瘤干细胞（GSCs）的自我更新和干性；使用蛋白质免疫印迹法、qRT-PCR或免疫组织化学分析来测量增殖或干细胞标志物的表达；通过对LC3和其他分子进行蛋白质免疫印迹/荧光分析来评估胶质瘤细胞中的自噬形成和降解。我们发现西他列汀抑制GBM细胞的增殖并诱导其凋亡，同时抑制GSCs的自我更新和干性。体外研究结果在胶质瘤颅内异种移植模型中得到进一步证实。给予西他列汀可延长荷瘤小鼠的生存时间。西他列汀可抑制TMZ诱导的保护性自噬，并增强TMZ对胶质瘤细胞的细胞毒性。此外，西他列汀在胶质瘤中以及在糖尿病中均作为二肽基肽酶4抑制剂发挥作用，但不影响小鼠的血糖水平和体重。这些发现表明，具有既定药理特性和安全性的西他列汀可被重新用作抗胶质瘤药物以克服TMZ耐药性，为GBM治疗提供了新的选择。
