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Luteolin is a common flavonoid present widely in varieties of fruits and vegetables. Our previous studies have demonstrated the sensitization activity of luteolin on cancer cell apoptosis induced by TNFa or TRAIL. In this study, we further examined the effect of luteolin on cancer cell killing induced by cisplatin, an important cancer chemotherapeutic agent. First we found that luteolin is able to enhance the cell-killing effects of cisplatin by inducing apoptosis in human cancer cells. Interestingly, luteolin sensitizes cisplatin-induced apoptosis only in p53 wide-type cancer cells, such as human colorectal cancer HCT116 and human hepatoma HepG2, but not in p53 mutant cancer cells, such as HT29 and Hep3B. Consistently, knockdown of p53 gene by siRNA in p53 wide-type cancer cells significantly attenuated the sensitization activity of luteolin. Next, a rapid elevation of p53 protein level in luteolin-treated cells was observed, without evident increase in p53 mRNA level, suggesting that luteolin is capable of regulating p53 expression posttranscriptionally. Further mechanistic study revealed that luteolin acts as a proteasome inhibitor to prolong the half-life of p53 protein. Subsequently, we observed enhanced p53 and Bax mitochondrial translocation, Bax conformational changes and cytochrome c release, which all contribute to apoptotic cell death in cells treated with luteolin and cisplatin. Finally, we tested the synergistic effect of luteolin and cisplatin in a nude mice xenograft model. While injection of luteolin (i.p. 40 mg/kg body weight, 3 times per week for 3 weeks) had no significant effect on the growth of xenografted HCT116 cells, luteolin enhances the therapeutic activity of cisplatin, demonstrated by significant reduction of tumor size and weight. In conclusion, data from this study provides experimental evidence to support the potential application of luteolin as a chemosensitizer in cancer chemotherapy.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]