Cancer Therapy: Preclinical Vitexins, Nature-Derived Lignan Compounds, Induce Apoptosis and Suppress Tumor Growth

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) Lignans are a group of complex polyphenolic antioxidants found in plants. Lignans such as secoisolariciresinol (SDG) found high in flaxseed, have antitumor effect. Clinical studies suggest that lignans are one of the most promising classes of dietary agents for testing in cancer prevention (1–3). In particular, lignan may prevent hormone-dependent diseases such as breast cancer and prostate cancer. Several lignans have been extensively investigated in preclinical tumor xenograft models, prospective and case-control epidemiologic studies, and in some clinical trials (1–7). Many of the dietary plant lignans are converted by intestinal microbiota to mammalian metabolites of END and ENL (8–11). Mammalian lignans have been thought to be themajor biologically active lignan, and suggested to be associated with low risk of cancer (4). Although there is no randomized clinical trial data that exist, indicating that lignan can reduce cancer growth, there are several biomarker-based neoadjuvant trials indicating that dietary intake of flaxseed lignan can inhibit tumor cell proliferation and induce apoptosis (2, 5). The ability to inhibit tumor growth kinetics in a neoadjuvant setting has previously been used as a measure of an agent's effectiveness in clinical circumstances (12–14). One neoadjuvant study, in a randomized double-blind placebo-controlled clinical trial, examined the effects of dietary flaxseed on tumor biological markers in postmenopausal patients with newly diagnosed breast cancer (5). In this study, patients were randomized to daily intake of either a 25-gram flaxseed-containing muffin or Authors' Affiliations: Central South University, Changsha, Hunan Province, China; Department of Radiation Medicine, The Feinstein Institute for Medical Research, Long Island Jewish Medical Center, Albert Einstein College of Medicine, New Hyde Park, New York; Hunan Normal University; and Department of Oncology, Zhejiang University College of Medicine, Hangzhou, Zhejiang Province, China Received 3/16/09; revised 4/14/09; accepted 4/15/09; published OnlineFirst 8/11/09. Grant support: W81XWH-04-1-0569 and W81XWH-07-1-0375 from the United States ArmyMedical Research and Development Command, and a grant 2008SK2005 from the Key Projects in 2008 Science & Technology Pillar Program of Hunan Province. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Requests for reprints: Yingjun Zhou and Y. Eric Shi, Department of Radiation Medicine, Long Island Jewish Medical Center, New Hyde Park, NY 11040. Phone: 718-470-3086; Fax: 1-718-962-6675; E-mail: [email protected]. F 2009 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-09-0661 5161 Clin Cancer Res 2009;15(16) August 15, 2009 www.aacrjournals.org Cancer Research. on October 15, 2017. © 2009 American Association for clincancerres.aacrjournals.org Downloaded from Published OnlineFirst August 11, 2009; DOI: 10.1158/1078-0432.CCR-09-0661