Synergistic interaction between tetrandrine and chemotherapeutic agents and influence of tetrandrine on chemotherapeutic agent-associated genes in human gastric cancer cell lines

Tetrandrine (Tet), a bis-benzylisoquinoline alkaloid that was isolated from the dried root of Hang-Fang-Chi (Stephania tetrandra S. Moore), is well known as processing a marked antitumor effect in vitro and in vivo. The aim of this study was to assess the interaction between tetrandrine and chemotherapeutic agents widely used in gastric cancer treatment, and to investigate the influence of tetrandrine on chemotherapeutic agent-associated gene expression and apoptosis. Synergistic interaction on human gastric cancer BGC-823 and MKN-28 cells was evaluated using the combination index (CI) method. The double staining with both Annexin-V-FITC and PI was employed to distinguish the apoptotic cells from living cells. Expression of chemotherapeutic agent-associated genes, i.e., excision repair cross-complementing 1 (ERCC1), thymidylate synthase (TS), class III beta-tubulin (beta-tubulin III) and tau, of BGC-823 cells with or without tetrandrine treatment were measured by real-time quantitative PCR. Tetrandrine had a synergistic effect on the cytotoxicity of chemotherapeutic agents in both two gastric cancer cell lines. The combination of tetrandrine and chemotherapeutic agents could also induce apoptosis in a synergistic manner. Tetrandrine could suppress the mRNA expression of ERCC1, TS, beta-tubulin III and tau. Most prominently, ERCC1, TS and beta-tubulin III mRNA levels were markedly suppressed at 0.29-, 0.12- and 0.60-fold, respectively, by the presentation of tetrandrine. Tetrandrine appears a promising candidate for combining with three chemotherapeutic agents. The possible mechanisms might be the synergistic apoptotic effect and the downregulation of chemotherapeutic agent-associated genes.