2. Academic Validation
  3. Sitagliptin inhibits the survival, stemness and autophagy of glioma cells, and enhances temozolomide cytotoxicity

Sitagliptin inhibits the survival, stemness and autophagy of glioma cells, and enhances temozolomide cytotoxicity

  • Biomed Pharmacother. 2023 Mar 24;162:114555. doi: 10.1016/j.biopha.2023.114555.
Fangting You 1,  Cheng Li 1,  Shicheng Zhang 1,  Qiaoshan Zhang 1,  Zhiyuan Hu 1,  Yuhui Wang 1,  Tong Zhang 2,  Qingming Meng 2,  Rutong Yu 3,  Shangfeng Gao 4
Affiliations

Affiliations

  • 1 Institute of Nervous System Diseases, Xuzhou Medical University, Xuzhou 221002, China; Department of Neurosurgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, China.
  • 2 Institute of Nervous System Diseases, Xuzhou Medical University, Xuzhou 221002, China.
  • 3 Institute of Nervous System Diseases, Xuzhou Medical University, Xuzhou 221002, China; Department of Neurosurgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, China. Electronic address: yu.rutong@163.com.
  • 4 Institute of Nervous System Diseases, Xuzhou Medical University, Xuzhou 221002, China; Department of Neurosurgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, China. Electronic address: gaoshangfeng@xzhmu.edu.cn.
PMID: 36966667 DOI: 10.1016/j.biopha.2023.114555
Abstract

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.

Keywords

Autophagy; Glioblastoma; Glioma stem cell; Sitagliptin; Temozolomide.

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