Large increases in the use of both aspirin and NSAIDs were observed over a 5 year period. The increase may be the result of increasing media attention reporting that regular aspirin use lowers the risk of CVD and related deaths, and may also prevent cancer. Moreover, safety concerns related to alternative medications such as acetaminophen and selective COX-2 inhibitors may influence users of these drugs to switch to aspirin and NSAIDs.

Purpose: Lignans such as secoisolariciresinol diglucoside in flaxseed, are metabolizes to bioactive mammalian lignans of END and ENL. Because mammalian lignans have chemical structural similarity to the natural estrogen, they are thought to behave like selective estrogen receptor modulators and therefore have anticancer effect against hormone-related cancers. We isolated a series of lignan compounds, named as Vitexins, from the seed of Chinese herb Vitex Negundo. Experimental Design: We purified several Vitexin lignan compounds. Cytotoxic and antitumor effects were analyzed in cancer cells and in tumor xenograft models. In vivo metabolism of Vitexins was determined in rat. Results: Contrasts to the classic lignans, Vitexins were not metabolized to END and ENL. A mixture of Vitexins EVn-50 and purified Vitexin compound 6-hydroxy-4-(4-hydroxy-3-methoxyphenyl)-3-hydroxymethyl-7-methoxy-3, 4-dihydro-2-naphthaldehyde have cytotoxic effect on breast, prostate, and ovarian cancer cells and induces apoptosis with cleavage in poly ADP ribose polymerase protein, up-regulation of Bax, and down-regulation of Bcl-2. This induction of apoptosis seems to be mediated by activation of caspases because inhibition of caspases activity significantly reduced induced apoptosis. We showed a broad antitumor activity of EVn-50 on seven tumor xenograft models including breast, prostate, liver, and cervical cancers. Consistent with in vitro data, EVn-50 treatment induced apoptosis, down-regulated of Bcl-2, and up-regulated Bax in tumor xenografts. Conclusion: Vitexin is a class of nature lignan compounds, whose action and anticancer effect is mediated by the mechanisms different from the classic lignans. Vitexininduced antitumor effect and cytotoxic activity is exerted through proapoptotic process, which is mediated by a decreased Bcl-2/Bax ratio and activation of caspases. (Clin Cancer Res 2009;15(16):5161-9)

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Vitexins, isolated from the seeds of the Chinese herb Vitex negundo, is known to exert antitumor activity in cancer xenograft models and cell lines. The aim of the current study was to examine whether the Akt/forkhead box protein O3a (FOXO3a) pathway mediates the biological effects of purified vitexin compound 1 (VB-1) in hepatocellular carcinoma (HCC) cells. The effect of VB-1 on the viability of the HCC cell lines HepG2, Hep3B, Huh-7 and the human embryonic liver cells L-02 was investigated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Growth inhibition was assessed by clonogenic assay, and cell cycle arrest was investigated using flow cytometry. Inhibition of angiogenesis was evaluated using a matrigel in vitro HUVEC tube formation assay. The effects on the Akt/FOXO3a pathway were detected by western blotting. VB-1 suppressed the proliferation of HepG2, Hep3B, Huh-7 cells, but had little effect on L-02 cells. VB-1 inhibited anchorage-dependent and -independent HepG2 cell growth in a concentration-dependent manner by induction of cell cycle arrest at G1/G0. VB-1 also reduced the secretion of vascular endothelial growth factor (VEGF), resulting in the inhibition of endothelial tube formation. Phosphorylated Akt and its downstream effector FOXO3a were downregulated in VB-1-treated HepG2 cells. Knockdown of Akt1 by small interfering RNA (siRNA) enhanced growth inhibition, and silencing FOXO3a by siRNA attenuated this action. VB-1 inhibited growth and induced cell cycle arrest at G1/G0 by regulating the Akt/FOXO3a pathway. The findings suggested that VB-1 is a potentially promising candidate for the treatment of HCC.

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