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

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.

 

Comments：

The study suggests that Sitagliptin, an antidiabetic drug, may have the potential to be repurposed as an antiglioma drug to enhance the therapeutic efficacy of Temozolomide (TMZ) in GBM treatment. The researchers used various in vitro and in vivo assays to evaluate the effects of Sitagliptin on GBM cells, including proliferation, apoptosis, stemness, and autophagy. The results showed that Sitagliptin inhibited the survival and stemness of GBM cells, induced apoptosis, and enhanced the cytotoxicity of TMZ by inhibiting protective autophagy. The drug also prolonged the survival time of tumor-bearing mice without affecting their blood glucose level and body weight.

The findings of this study suggest that Sitagliptin has the potential to be used as a novel therapeutic agent for GBM treatment. However, further studies are needed to evaluate the efficacy and safety of Sitagliptin in clinical trials.

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