Dietary flavonoid apigenin sensitizes malignant tumor cells to tumor necrosis factor-related apoptosis-inducing ligand

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Apigenin, one of the most common flavonoids, is widely distributed in many fruits and vegetables, including Chinese cabbage, bell pepper, garlic, celery and guava. Although some of flavonoids are mutagenic, apigenin has no mutagenic activity. Moreover, apigenin is expected to be a promising cancer preventive agent contained in foods. In the present study, we found a new function of apigenin, which might be useful for cancer therapy. Apigenin markedly induced the expression of death receptors 5 (DR5), which is also called TRAIL-R2. Apigenin partially prevented the degradation of DR5 protein, while apigenin very slightly increased DR5 mRNA and did not enhance promoter activity. These results indicate that the protein stabilization is one of the mechanisms of DR5 induction by apigenin. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is one of the most promising attractive candidates for cancer therapy due to its ability to selectively induce apoptosis in cancer cells, but not in normal cells. TRAIL induces apoptosis in cancer cells through its interaction with the death-domain containing receptor, DR5. Next, we found that apigenin synergistically enhanced TRAIL-induced apoptosis. These novel functions of apigenin were observed in human acute lymphoblastic leukemia Jurkat cells, prostate cancer DU145 cells and colon cancer DLD-1 cells that have inactivated p53 through point mutations. This suggests that apigenin can reduce the minimal effective dose and side effects of TRAIL, and that the combination of apigenin and TRAIL can induce apoptosis in malignant tumor cells in a p53-independent manner.

The combined use of apigenin and TRAIL at suboptimal concentrations induced Bid cleavage and the activation of caspase-8, -10, -9 and -3. Furthermore, human recombinant DR5/Fc chimera protein and caspase inhibitors dramatically inhibited apoptosis induced by the combination of apigenin and TRAIL. Although apigenin induced DR5 expression in a dose-dependent manner in malignant tumor cells, apigenin-mediated induction of DR5 expression was not observed in normal human peripheral blood mononuclear cells (PBMC). Moreover, apigenin did not sensitize normal human PBMC to TRAIL-induced apoptosis.Our results show the novel effects of apigenin and raise the possibility that combined treatment with apigenin and TRAIL can be used as a promising strategy for the treatment of malignant tumors.