AB53. Diallyltrisulfide inhibits NF-κB activation and suppressestumor growth through metallothionein2A elevation in gastric cancer cells

Background: Diallyltrisulfide (DATS), a novel component of garlic, induces apoptosis and suppresses tumor growth in gastric cancer (GC). Using the differential display technique, we identified a cDNA fragment, encoding Metallothionein 2A (MT2A) mRNA. However, the roles of MT2A induced by DATS in human GC are not fully understood.

Methods: Cell viability assays, colony formation assays, and apoptosis assays were used to analyze the effects of ectopic expression of MT2A induced by DATS in BGC823 cells. Nude mice were injected BGC823 cells to assess the role of DATS or MT2A in tumor growth in vivo and to evaluate the effects of chemical agents on tumor growth. Polymerase chain reaction, Western blotting, immunofluorescence and immunohistochemistry (IHC), electrophoretic mobility shift assay and chromatin immunoprecipitation analyses were employed to establish the mechanism for MT2A induced by DATS on the inhabition of nuclear factor-κB (NF-κB) pathway. IHC was performed on primary tumor specimens from GC patients (n=258) to determine the relationship between MT2A and NF-κB-mediated overall survival.

Results: MT2A expression markedly decreased in GC, restoration of MT2A, suppressed cell growth in vitro and in vivo. Ectopic expression of MT2A treated by DATS resulted in apoptosis through inhibition of the NF-κB pathway and reduction of NF-κB-mediated transcription. Combination with chemotherapy, DATS could increase the effectiveness of chemotherapy drugs in vitro and in vivo.

Conclusions: DATS mediate the elevation of MT2A to suppress tumor growth, and therapeutic targeting of MT2A and/or NF-κB pathways may be an effective way to enhance the therapeutic activity of anticancer drugs against GC.

Keywords: Diallyltrisulfide; metallothionein 2A; NF-κB pathway; apoptosis; gastric cancer