Gambogic acid induced tumor cell apoptosis by T lymphocyte activation in H22 transplanted mice

Multiple lines of evidence have demonstrated that gambogic acid (GA) is an efficient apoptosis inducing agent. However, the mechanisms of GA induced apoptosis have been controversial, despite the tremendous effort made during recent years. Here we report a novel mechanism through which GA induces cell apoptosis. Instead of dealing with tumor cells directly, GA first activates inactive T lymphocytes, which in turn triggers cancer cell apoptosis. This is supported by the observation that GA inhibited tumor growth and extended the survival time of mice bearing H22 tumor. cDNA microarray analysis indicated that 22.92% of the 48 genes that were affected with GA treatment were immune related genes. RT-PCR assay revealed that GA up-regulated MHC-II and TCR transcriptions, implicating that GA activates T lymphocytes to induce tumor cell apoptosis in vivo. HE staining showed that T lymphocytes penetrated into tumor tissues after GA administration. Western blotting revealed that GA enhanced CD4+ and CD8+ expressions. Annexin-V/PI double-staining and DNA ladder assays confirmed that GA induced tumor cell apoptosis. In summary, this report demonstrated, for the first time, that GA mainly activates T lymphocytes to induce cancer cell apoptosis in H22 transplanted mice.