Abstract 5649: Highly synergistic anti-tumor efficacy induced by the combination of two natural dietary agents, luteolin and EGCG: Role of p53 phosphorylation, stabilization and translocation

Abstract

Abstract Natural dietary agents have drawn a great deal of attention for cancer prevention and therapy because of their wide safety margin and easy availability. However, single agent intervention has failed to bring the expected outcome in clinical trials in many instances; therefore, combinations of chemopreventive agents are gaining increasing attention. In the present study, we have investigated a combinatorial approach using two natural dietary polyphenols, luteolin and EGCG, and found that combination of the two compounds at low doses (at which almost no apoptosis was observed after single agent treatment) tremendously increased apoptosis (50-70%) in both head and neck and lung cancer cell lines (a panel of 11 cell lines tested). This combination also significantly inhibited growth of head and neck cancer Tu212 and lung cancer A549 xenografts as compared with either of the single agents (P value < 0.05). Ki-67 and TUNEL staining of the xenografted tumor tissues also showed statistically significant decrease in the number of Ki-67 and increase in TUNEL positive cells after combined treatment with luteolin and EGCG as compared with single agent treatment or untreated control. Further mechanistic study showed that the combination-induced both mitochondria-dependent and -independent apoptosis varying among cell lines. Although the combination was effective against cell lines regardless of their p53 status, those with wild-type p53 were much more sensitive to the treatment than those with mutant or no p53. Ablation of p53 using shRNA strongly inhibited apoptosis (>50%) as evidenced by decreased PARP and caspase 3 cleavage. Moreover, we found more efficient stabilization and phosphorylation of p53 at Ser15 by the combination as compared with either single agent, particularly when the basal p53 levels were low. In addition, we observed mitochondrial translocation of p53 after treatment with luteolin or the combination of EGCG and luteolin. Taken together, our results, for the first time, suggest that combination of luteolin and EGCG has synergistic/additive growth inhibitory effects both in vitro and in vivo via a p53-dependent pathway and will provide an important rationale for chemoprevention or treatment trials using this combination. This research was supported by the National Cancer Institute award 5 P50 CA128613 SPORE in Head and Neck Cancer (ARA, JCB, TM, FRK, ZGC and DMS). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5649.