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Prostate cancer is the most commonly diagnosed malignant disease in U.S. men and the second leading cause of death in this population. Studies on epidemiology, genetics, and molecular pathogenesis of prostate cancer strongly suggest that activation of PI3 kinase (PI3K)/Akt and mammalian target of rapamycin (mTOR) pathways play important roles in the development of this disease. Dual inhibition of both of these pathways may provide a novel and effective treatment for this disease. Certain herbal extracts have long been considered effective in the prevention or treatment of prostate cancer. Liquidambar styraciflua L., known as sweet gum, contains lupine and oleanane-type triterpenoids and has shown potential in inhibiting the proliferation of multiple human cancer cell lines. We examined the anticancer activity of a methanolic fraction of sweet gum (LIS-100) in human prostate cancer and its associated mechanism(s). The anti-proliferative effect of sweet gum extract was tested against human prostate cancer (PC3, LNCaP, DU145), human colon HCT116, human pancreatic cancer (PANC-1, BxPC3 and AsPC-1), and human non-small cell lung cancer A549 cells. Our preliminary study demonstrated that LIS-100 inhibited the proliferation of multiple cell lines with IC50 values ranging from 1.85 to 31.25 μg/ml although it was most potent against prostate cancer (IC50 1.85 and 2.75 μg/ml for PC3 and LNCaP cells, respectively). LIS-100 inhibits proliferation of PC3 cells through G2/M cell cycle arrest at low concentrations (10-50 μg/ml), but induced apoptosis at higher concentration (125 μg/ml). It inhibited cyclin D1 expression, Stat3 and restored the tumor suppressor Rb protein function in PC3 cells. Additionally, LIS-100 (2.5 μg/ml) altered the phosphorylation of multiple cell signaling proteins, especially those associated with PI3K/Akt/mTOR pathways. LIS-100 not only inhibited phosphorylation of the effector of mTOR, p70S6 kinase at ser389, and ribosomal S6 protein at Ser235/236, it also inhibited the phosphorylation of Akt and eIF4E in both PC3 and LNCaP cells, yet increased the tumor suppressor protein eIF4BP1. These modulations were concentration-dependent. In comparison to a known mTOR inhibitor (rapamycin derivative) which enhances cell survival pathways, such as PI3K-Akt and 4lF4E, this extract has the ability to inhibit both PI3k/Akt and mTOR pathways. When the extract was administered orally to CD-1 mice, no signs of toxicity were observed even at doses as high as 500 mg/kg. Additionally, the extract inhibited the growth of PC3 xenograft by 46% and 64% when it was administered at 250 mg/kg orally and 50 mg/kg intraperitonially, respectively. Taken together, our research suggests that sweet gum has important potential to inhibit the proliferation of human prostate cancer cells through, at least partially, dual inhibition of PI3K/AKt and mTOR pathways.

99th AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA