Abstract
Prostate cancer (CaP) is one of the most commonly diagnosed cancers and a leading cause of cancer mortality in men in Western countries including the Unites States. Evidences suggest that androgen receptor (AR) mediated signaling plays a critical role in the development and progression of CaP. Hormonal therapies, mainlywith combinations of anti-androgens and androgen deprivation are the mainstay treatmentfor advanced disease. However, emergence of androgen resistance largely due to inefficient anti-hormone action limits their therapeutic usefulness. Thus, identification of non-toxic dietary agents capable of inhibiting AR signaling could have usefulness for the treatment of CaP. Recently, we have shown that a novel dietary anthocyanidin delphinidin induces apoptosis and inhibits growth of CaP cells in in vitro and in in vivo model systems (Cancer Research 2008, PMID: 18922932). In this study, we determined if delphinidin possesses anti-androgenic effect. By performing competitive ligand binding (FRET) assay, we observed that delphinidin acts as an AR ligand by competing with the high affinity labled AR agonist (Alarmone) to interact with the ligand binding domain of AR. We found that this physical interaction results in decrease in N-C terminus interaction of AR which results in a substantial decrease in AR stability. This interaction was found to inhibit AR-mediated transactivation of target genes including prostate specific antigen (PSA). To analyze the effect of delphinidin on observed decrease in AR transactivation function, transient transfections using two different androgen responsive reporters PSA-luc and MMTV-luc were carried out. Treatment of androgen sensitive LNCaP and 22R\#957;1 cells with androgen agonist R1881 led to induction of both the reporters in these cells. Co-treatment of LNCaP and 22R\#957;1 cells with delphinidin led to a dose-dependent decrease in AR transactivation as reflected by a decrease in the reporter activity. These results suggest that delphinidin interferes with the hormone-induced transactivation function of AR in both cells. In addition, treatment of LNCaP and 22R\#957;1 cells with delphinidin decreased AR protein levels by accelerating its degradation. Immunocytochemistry data revealed that delphinidin treatment to LNCaP and 22R\#957;1 cells inhibits agonist-induced nuclear translocation of AR. Delphinidin administration (2 mg, i.p. thrice weekly) to athymic male nude mice implanted with 22R\#957;1 cells resulted in a significant inhibition of tumor growth with concomitant decrease in AR protein expression and serumPSA levels. These data establish that delphinidin could function as an antagonist of AR signaling and provide further evidence that it could be used as a chemopreventive and chemotherapeutic agent in ongoing anti-hormone therapy of CaP.
Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 2699.
100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO
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