Abstract

Background: Gastric Cancer (GC) is the fourth most common malignant tumor worldwide. This study aimed to investigate the effect of a combination of Cryptotanshinone (CTS) and Trifluorothymidine (FTD) on GC.

Methods: The effect of the combined or separate use of FTD and CTS on HGC-27 and AGS cells was detected using the CCK8 assay. The combined index of FTD and CTS was calculated using Compusyn software. Additionally, we applied flow cytometry to study the cell cycle and apoptosis and investigated the amount of FTD incorporated into DNA by immunofluorescence assay. Protein expression was monitored by western blotting (WB). Furthermore, the effect of TAS-102 in combination with CTS was studied in a xenograft nude mouse model.

Results: FTD and CTS inhibited the proliferation of GC cells in a dose-dependent manner. The combination of FTD and CTS showed synergistic anticancer effects in HGC-27 and AGS cells. Our mechanistic studies indicate that FTD blocks HGC-27 cells at the G2/M phase, CTS blocks HGC-27 cells at the G1/G0 phase, while FTD combined with CTS mainly blocks HGC-27 cells at the G2 phase. The combination of FTD and CTS significantly increases apoptosis. CTS increased the incorporation of FTD into the DNA. FTD activated STAT3 (Signal Transducer and Activator of Transcription 3) phosphorylation, whereas CTS downregulated p-STAT3. Interestingly, the combination of CTS and FTD reduced the STAT3 phosphorylation induced by FTD. In vivo, the combination of TAS-102 with CTS was significantly more potent than TAS-102 alone in tumor growth inhibition.

Conclusions: FTD combined with CTS has a synergistic anti-gastric cancer effect in vitro and in vivo and is a promising treatment option for advanced GC.