Arsenic sulfide, the main component of realgar, a traditional Chinese medicine, induces apoptosis of gastric cancer cells in vitro and in vivo

Abstract

Background

Arsenic sulfide (As ₄S ₄), the main component of realgar, a traditional Chinese medicine, has shown antitumor efficacy in several tumor types, especially for acute promyelocytic leukemia. In this study, we aimed to explore the efficacy and mechanism of As ₄S ₄ in gastric cancer.

Methods

The effect of As ₄S ₄ on cell proliferation and apoptosis of gastric cancer cells was investigated by MTT assay, 4′,6-diamidino-2-phenylindole (DAPI) staining, and annexin V–fluorescein isothiocyanate/propidium iodide staining using gastric cancer cell lines AGS (harboring wild-type p53) and MGC803 (harboring mutant p53) in vitro. The expression of apoptosis-related proteins was measured by Western blotting, real-time polymerase chain reaction, and immunohistochemistry analysis. Mouse xenograft models were established by inoculation with MGC803 cells, and the morphology and the proportion of apoptotic cells in tumor tissues were detected by hematoxylin and eosin staining and TdT-mediated dUTP nick end labeling (TUNEL) assay, respectively.

Results

As ₄S ₄ inhibited the proliferation and induced apoptosis of AGS and MGC803 cells in a time- and dose-dependent manner. As ₄S ₄ upregulated the expression of Bax and MDM2 while downregulated the expression of Bcl-2. The expression of p53 increased significantly in the AGS cells but did not readily increase in the MGC803 cells, which harbored mutant p53. Pifithrin-α, a p53 inhibitor, blocked the modulation of As ₄S ₄ on AGS cells, but not on MGC803 cells. Using xenograft as a model, we showed that As ₄S ₄ suppressed tumor growth and induced apoptosis in vivo and that the expression of p53 increased accordingly.

Conclusion

As ₄S ₄ is a potent cytotoxic agent for gastric cancer cells, as it induced apoptosis both in vitro and in vivo through a p53-dependent pathway. Our data indicate that As ₄S ₄ may have therapeutic potential in gastric cancer.