The ATR inhibitor VE-821 increases the sensitivity of gastric cancer cells to cisplatin
Background: Chemoresistance is a very common event after cancer chemotherapy, including gastric cancer (GC). Cisplatin continues to be reported to induce the DNA damage response (DDR), thus resulting in chemoresistance. VE-821, a particular inhibitor of ATR, has been shown to suppress a number of solid malignancies effectively. Our study aimed look around the aftereffect of VE-821 on improving the chemical sensitivity to cisplatin and clarify the possibility molecular mechanisms.
Methods: Cell viability and apoptosis of MKN-45 and AGS were measured by CCK8 and flow cytometry assay correspondingly. Western blotting was utilized to identify the expression of target proteins. TCGA database was utilized to evaluate the correlation between your ATR expression using the prognosis of GC patients. The viability of GC organoids was detected by Cell Titer Glo (CTG) through luminescence.
Results: Cisplatin inhibited the proliferation and caused apoptosis of GC cells having a relatively high IC50 value, and elevated the phosphorylation amounts of ATR-CHK1 and H2AX. VE-821 achieved exactly the same effects but by downregulating the phosphorylation quantity of a ATR-CHK1 path. Besides, greater ATR expression in GC tissues was positively correlated with greater pathological stage in GC patients. Interestingly, ATR inhibition reversed cisplatin-caused STAT3 activation that has been enhanced H2AX levels. Furthermore, VE-821 considerably sensitized GC cells to cisplatin, which two drugs had synergistic effects in GC cell lines, organoids, as well as in vivo.
Conclusion: Our results recommended VE-821 sensitized GC cells to cisplatin via reversing DDR activation. And VE-821 treatment can be a promising therapeutic technique for GC patients with cisplatin resistance.