Inhibition of endogenous hydrogen sulfide biosynthesis enhances the anti-cancer effect of 3,3'-diindolylmethane in human gastric cancer cells

Aims: 3,3'-Diindolylmethane (DIM) has limited anti-cancer effects in gastric cancer. Hydrogen sulfide (H₂S) plays an important role in the tumor development and therapy, cystathionine-β-synthase (CBS) and cystathionine-γ-lyase (CSE), two key endogenous H₂S biosynthesis enzymes, can affect endogenous H₂S levels and alter cancer treatment. Our main objective was to investigate whether the aminooxyacetic acid (AOAA) and DL-Propargylglycine (PAG), two specific inhibitors of CBS and CSE, could assist DIM to play a stronger anti-cancer effects in gastric cancer BGC-823 and SGC-7901 cells.

Materials and methods: Cell proliferation was assayed by MTT and cell colony-forming assay, apoptosis and migration were detected by Hoechst staining, scratch test. Western blot was used to evaluate the expression of proteins related to proliferation, apoptosis and migration.

Key findings: Combination of AOAA or PAG with DIM synergistically inhibited proliferation and migration, increased apoptosis in gastric cancer cells. The p38-p53 axis was also further activated by the combination of AOAA or PAG with DIM. Exogenous H₂S from sodium hydrosulfide, attenuated the efficacy of DIM in cancer cells by reducing the activation level of p38-p53 axis. Taken together, AOAA or PAG inhibited the expression of endogenous H₂S biosynthesis enzymes and effectively enhanced susceptibility of gastric cancer to DIM through activating p38-p53 axis.

Significance: The current study highlight more precise requirements for the clinical application of action concentrations about sulfur-containing anti-cancer drugs, and open a new way to enhance the sensitivity of DIM in chemotherapy of gastric cancer.

Keywords: 3,3′-Diindolylmethane; Aminooxyacetic acid; DL-propargylglycine; Gastric cancer.