Abstract 3800: Dietary agent α-Mangostin inhibits growth of pancreatic cancer BxPC3 and PANC1 cells and arrests the cell cycle in G0/G1 phase: Involvement of Ras, Hedgehog, NF-kB, and STAT3 signaling networks

Abstract

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.

Anticarcinogenic Effects of α-Mangostin: A Review

“…In other cancer cells, α-MG was reported to arrest the cell cycle at the S phase [78], G0/G1 phase [25,79], or G2/M phase [80]. In addition, α-MGʼs antiproliferative activity might also be ascribed to its direct inhibition of DNA synthesis by diminishing DNA polymerases and topoisomerases.…”

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“…This work provides new insights into the molecular basis of α-MGʼs antiproliferative activity outside its role in the p53-p21axis. In other cancer cells, α-MG was reported to arrest the cell cycle at the S phase [78], G0/G1 phase [25,79], or G2/M phase [80]. In addition, α-MGʼs antiproliferative activity might also be ascribed to its direct inhibition of DNA synthesis by diminishing DNA polymerases and topoisomerases.…”