4,5-Diphenyl-2-methyl picolinate induces cellular senescence by accumulating DNA damage and activating associated signaling pathways in gastric cancer

Aims Gastric cancer (GC) is a common cancer with a relatively low survival rate. Cellular senescence, a potent anti-cancer mechanism, is naturally occurred, and can be induced by chemotherapeutic agents. We sought to explore new compounds against GC cells by inducing cellular senescence. Main methods Primary screening of a library of N-heterocyclic compounds identified some with potent inhibitory effects on GC cells. Furthermore, in vitro effects of the most potent candidate compound on the proliferation and senescence of GC cells were studied by classical assays, including senescence-associated (SA)-β-galactosidase staining, and immunofluorescence; and in vivo effects of this compound was evaluated in a xenograft tumor mouse model. Key findings Among 43 tested compounds, 4,5-diphenyl-2-methyl picolinate (DMP) showed the highest inhibition effects on the growth of GC cells. In vitro experiments showed that DMP inhibited the proliferation by inducing senescence and DNA-damage associated protein markers and signaling pathways. In vivo experiment confirmed that DMP treatment inhibited tumor growth by promoting DNA-damage signaling. Significance This study set up a platform to identify senescence-inducing anti-cancer compounds, and uncovers that DMP exerted anticancer effects by inducing cellular senescence through targeting DNA damage and associated signaling pathways in GC cancer.