Pancreatic adenocarcinoma is one of the most fatal of all cancers and is ranked as the fourth most common cause of cancer related deaths among both men and women in the United States. It is estimated that 42,407 cases of pancreatic cancer (PaC) will be diagnosed in the United States alone in 2009 and 35,240 cancer related deaths are projected. The systemic toxicity caused by high doses of current chemotherapeutic drugs in PaC patients is of great concern, as it limits their use in patients. Since most of the chemotherapeutic agents generally target a specific pathway, they most often fail to inhibit growth of PaC in preclinical and clinical settings. Thus, there is a need to develop new novel non-toxic therapeutic agents which can either target the multiple oncogenic signaling pathways or target major pathways at multiple level. α-Mangostin a novel dietary natural agent isolated from the pericarp of Mangosteen fruit (Garcinia mangostana) has been shown to have anti-inflammatory, anti-carcinogenic and cardioprotective activities. However, no study exists examining the effects of α-Mangostin in the prevention and/or treatment of PaC. In this study, we present that α-Mangostin treatment of PaC PANC1 and BxPC3 cells results in dose-dependent decreases in cells viability and arrests PaC cells in G0/G1 phase of cell cycle. To understand the molecular mechanism of α-Mangostin for the inhibition of cell proliferation, we target the multiple signaling molecules which are aberrantly expressed and involved in survival, proliferation, initiation, development and chemoresistance of PaC cells. It has been reported that Sonic hedgehog (Shh) interacts with activated K-Ras and cooperates in initiation and maintenance of PaC. Western blot analysis showed that α-Mangostin treatment significantly inhibited the constitutive expression of K-Ras, Shh and transcription factor GLI-1 proteins in dose- and time-dependent manner in PaC cells suggesting that α-Mangostin targets Ras and Shh signalings molecules. Since NF-kB and Stat3 are another molecular targets in PaC, therefore, we next examined the effect of α-Mangostin in these transcription factors. We observed that α-Mangostin treatment of PaC cells not only inhibits the constitutive expression of of NF-kB and Stat3 proteins but also inhibits their phosphorylation. α-Mangostin treatment also elicited the inhibition of DNA-binding of Stat3 and NF-kB, suggesting inhibition in translocation of these transcription factors into the nucleus by α-Mangostin. Taken together, these results indicate that α-Mangostin is a novel multi-targeting dietary agent which could be developed as a natural dietary non-toxic agent for the prevention and treatment of PaC. (Support: R&D Funds, Department of Human Oncology, UW Madison, Madison, WI). 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 3800.

Prostate cancer (PCa) is one of the most commonly diagnosed cancers and leading cause of cancer related death in men in Western countries including the Unites States. Androgen receptor (AR)-mediated signaling plays a critical role in the development and progression of PCa. Most androgen independent (AI) prostate tumors continue to express AR as well as its target gene PSA, which indicates that these tumor cells maintain functional AR signaling. Evidence suggests that AR signaling is activated through androgen and androgen bypass mechanism. We believe that identification of non-toxic natural agents capable of blocking both androgen and non-androgen activation of AR signaling could be effective for the treatment of PCa. We have previously shown that a novel plant derived napthoquinone plumbagin (PL) induces apoptosis and inhibits growth of PCa cells in in vitro as well as in in vivo model systems (Cancer Research 2008, PMID: 18974148). We present here that PL inhibits both androgen and non-androgen activation of AR signaling in PCa cells. We observed that PL inhibits synthetic androgen methyltrienolone (R1881) induced growth of androgen-dependent (AD) LNCaP and AI C4-2 cells. PL treatment was found to inhibit protein levels of AR and AR-target gene PSA and accelerates AR degradation. To analyze the effect of PL on decreased AR transactivation, transient transfections using androgen responsive reporters PSA-luc were carried out. Treatment of LNCaP and C4-2 cells with R1881 led to induction of PSA reporter in these cells. Co-treatment of LNCaP and C4-2 cells with PL led to a dose-dependent decrease in AR transactivation as reflected by a decrease in the PSA reporter activity. These results suggest that PL interferes with androgen-induced transactivation function of AR. It has been reported that IL-6 signaling acts as a ligand for the activation of AR signaling. IL-6 induced phosphorylated Stat3 interacts with the N-terminal domain of AR and activates its target genes. We have previously shown that PL treatment inhibits Stat3 phosphorylation in PCa DU-145 cells xenograft tumor tissues (Cancer Research 2008, PMID: 18974148). Therefore, we hypothesized that PL treatment will inhibit Stat3 and AR N-terminal domain interaction in PCa cells. Reciprocal immunoprecipitation/blotting experiments revealed that PL treatment inhibited IL-6 induced interaction of Stat3 with AR N-terminal domain in both the PCa LNCaP and C4-2 cells. PL treatment also inhibited IL-6 induced Tyr 705 and Ser727 phosphorylation of Stat3. These results establish that PL has the potential to block the androgen and non-androgen activation of AR signaling in PCa and provide further evidence that PL could be used as a chemopreventive natural agent in ongoing anti-hormone therapy of PCa. (Support: NIH grants, CA35368). 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 3780.

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