Study on the synthesis, characterization, and antitumor mechanism investigation of QZQ-01115 via targeting sphingosine kinase 2

Sphingosine kinase 2 (SphK2) is an oncogenic enzyme that plays an essential role in the development of oral squamous cell carcinoma (OSCC). Therefore, development of SphK2 inhibitors is of great significance for the treatment of OSCC. In this study, we synthesized a series of thiazolidinediones and screened compounds with good inhibitory activity against CAL-27 using cytotoxicity assay. The compounds were further investigated in vitro using a series of in vitro experiments such as Western blot and qPCR were used to investigate the in vivo anti-tumor mechanisms, and in vivo investigation was applied by using a nude mouse ectopic tumor model. The results showed that four new compounds were successfully synthesized, and among which the compound named QZQ-01115 showed the best inhibitory activity against CAL-27 at the concentration of 5.84 ± 0.042 μM. Further mechanistic studies showed that QZQ-01115 could inhibit the proliferation, migration and invasion of CAL-27 cells at a concentration of 4 μM-6 μM. QZQ-01115 affected the PI3K/Akt signaling pathway by influencing the levels of S1P and ceramides in CAL-27, which in turn affected the mTOR/p70S6K, resulting in the blockage of protein synthesis and the blockage of cell cycle at the G0/G0 level. Apoptosis was promoted by down-regulating Bcl-2 and up-regulating Bax. The in vivo results showed that QZQ-01115 reduced the volume and weight of xenograft tumors in nude mice. The induction of Apoptosis by QZQ-01115 was further determined by HE staining and immunohistochemical analysis. These results suggest that QZQ-01115 may be a potential candidate for the treatment of OSCC.

Apoptosis; CAL-27; Ceramide signaling; PI3K/AKT signaling pathway; QZQ-01115; Sphingosine kinase 2.