Abstract 3699: Novel combinatorial strategies for cancer chemoprevention using polymethoxyflavones from orange and atorvastatin

Abstract

Abstract Cancer is a complex disease, and multiple aberrant molecular events are driving forces for cancer progression. It is difficult to control cancer progression by a single agent. We investigated a novel approach to inhibit cancer cell growth by using polymethoxyflavones (PMFs, isolated from aged orange peel) and atorvastatin (Lipitor, a commonly used cholesterol-lowering drug) in combination. The goal is to identify combination regimen that can produce synergy in inhibiting human cancer cell growth. Our results on multiple colon and lung cancer cells demonstrated that permethoxylated PMFs, namely nobiletin and tangeretin, can synergistically interact with atorvastatin and produced much stronger inhibitory effects than either agent alone. On the other hand, the hydroxylated PMFs, namely 5-hydroxy nobiletin (5HN) and 5-hydroxy tangeretin (5HT) showed different interaction profiles with atorvastatin, i.e., 5HN produced strong synergy with atorvastatin while 5HT did not. Further mechanistic study demonstrated that the combination treatment with 5HN and atorvastatin for 24 hr caused extensive cell population accumulation in G0/G1 phase; whereas at 48 hr or longer, apoptosis was induced significantly. Our results also demonstrated that the combinational effects of 5HN and atorvastatin were associated with increased levels of p21Cip1/Waf1, and p27Kip1; decreased levels of CDK-2, CDK-4,CDK-6,Cyclin D1, Mcl-1 and hyper-phosphorylated Rb(Ser 780); and activation of caspase cascade. More importantly, we investigated the inhibitory effects of PMFs/atorvastatin combinations in an NNK-induced mouse lung tumorigenesis model, and our results demonstrated that dietary administration of nobiletin and 5HN in combination with atorvastatin caused potent inhibition of lung tumor formation in A/J mice. These inhibitory effects were much stronger than those produced by singular nobiletin, 5HN, or atorvastatin treatments at much higher doses. The isobologram-based statistic analysis confirmed that nobiletin, 5HN and atorvastatin produced strong synergy in inhibiting lung tumorigenesis in mice. In conclusion, the present work provided promising leads for future investigation on the novel combination of PMFs and atorvastatin as novel strategy for cancer chemoprevention. (This study was supported in part by NIH-CA139174, AICR-#10A044, CEAR pilot grant, and USDA Special Grant on Bioactive Foods). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3699. doi:10.1158/1538-7445.AM2011-3699