lignans and vitexin

Topics: Amides; Apigenin; Benzodioxoles; Catechin; Chromatography, High Pressure Liquid; Coumarins; Dioxoles; Flavonoids; Furans; Hesperidin; Hydroxybenzoates; Lignans; Limit of Detection; Plant Leaves; Powders; Reproducibility of Results; Seasons; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry; Zanthoxylum

We have previously reported that the EVn-50 mixture of vitexins (lignan compounds) containing the purified vitexin (neolignan) compound, 6-hydroxy-4(4-hydroxy-3-methoxyphenyl)-3-hydroxymethyl‑7-methoxy-3,4-dihydro-2-naphthaldehyde, termed VB1, exhibits potent anticancer activity through the induction of apoptosis in several types of cancer cells, including MDA-MB‑231 cells. However, the exact molecular mechanisms by which VB1 induces apoptosis in MDA-MB‑231 cells have not yet been fully elucidated. In this study, to our knowledge, we provide for the first time mechanistic evidence that VB1-induced apoptosis in the human breast cancer line, MDA-MB-231, is associated with the generation of reactive oxygen species (ROS), the activation of caspases and the modulation of the expression of myeloid leukemia cell differentiation protein 1 (Mcl‑1), B cell lymphoma‑2 (Bcl-2) and Bcl-2-associated X (Bax) proteins. The silencing of Mcl-1 by RNA interference enhanced VB1-induced apoptosis. In addition, VB1 did not induce ROS generation or apoptosis in the immortalized non‑cancerous breast cell line, MCF-10A. Our findings reveal a novel mechanism underlying VB1-induced apoptosis, and highlight VB1 as a promising candidate for the therapy of human breast cancer.

Topics: Apigenin; Apoptosis; bcl-2-Associated X Protein; Breast Neoplasms; Caspases; Cell Line, Tumor; Cell Survival; Female; Gene Silencing; Humans; Lignans; Myeloid Cell Leukemia Sequence 1 Protein; Proto-Oncogene Proteins c-bcl-2; Reactive Oxygen Species

Previous studies have reported that vitexins induce cytotoxic effects. In the present study, we investigate a new native lignan vitexin 6 (VB6) in vitro to determine the molecular mechanism underlying its cytotoxicity. We screened and cultured several tumor cell lines and subsequently analyzed VB6 cytotoxicity against 14 different tumor cell lines using a 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay. The expression of proteins that regulate apoptosis and autophagy was determined using western blot analysis. VB6 showed an excellent cytotoxic effect against various cancer cell lines in vitro. It induced apoptosis and autophagy of cancer cells. VB6-induced apoptosis showed a time-dependent and concentration-dependent relationship with cleaved poly (ADP-ribose) polymerase, cleaved caspase-3, Bax upregulation, and Bcl-2 downregulation. The levels of Beclin-1 and LC3-II, which are markers for cell autophagy, gradually increased after VB6 treatment. Jun N-terminal kinase (JNK) phosphorylation was increased after VB6 treatment, accompanied by upregulation of P-Bcl-2 and P-C-Jun expression. Cotreatment with a JNK inhibitor significantly decreased VB6-induced cell death and downregulated P-Bcl-2, and cleaved PARP and Beclin-1 expression. The new native lignan VB6 inhibits cancer cell proliferation by activating the JNK pathway. We believe that VB6 could be a valuable chemotherapeutic drug after further evaluation.

Topics: Antineoplastic Agents, Phytogenic; Apigenin; Apoptosis; Autophagy; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drugs, Chinese Herbal; Ethnopharmacology; Humans; Inhibitory Concentration 50; JNK Mitogen-Activated Protein Kinases; Kinetics; Lignans; MAP Kinase Signaling System; Neoplasm Proteins; Neoplasms; Protein Kinase Inhibitors; Seeds; Vitex

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.. 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.. 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.. Vitexin is a class of nature lignan compounds, whose action and anticancer effect is mediated by the mechanisms different from the classic lignans. Vitexin-induced antitumor effect and cytotoxic activity is exerted through proapoptotic process, which is mediated by a decreased Bcl-2/Bax ratio and activation of caspases.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apigenin; Apoptosis; Cell Proliferation; Female; Flavonoids; HeLa Cells; Humans; Lignans; Male; Mice; Mice, Nude; Models, Biological; Neoplasms; Rats; Rats, Sprague-Dawley; Tumor Burden; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Previously, we isolated two new dibenzylbutyrolactone-type lignans, named phenaxolactones and, from the leaves of Phenax angustifolius Wedd. (Urticaceae). In this investigation three new dibenzylbutyrolactone lignans (phenaxolactones), together with phenaxolactone, and flavones vitexin, isovitexin, were isolated from Phenax rugosus Wedd. leaves collected in Santa Ana, Costa Rica. The structures were elucidated using 1D and 2D NMR spectroscopy as well as mass spectrometry. Phenaxolactones and flavones and were evaluated for their inhibitory activity against HIV-1MN in infected C8166 cells. The most promising compound was phenaxolactone with an EC50 value of 3.0 microM, no cytotoxicity at 112 microM and a therapeutic index value of 37.3.

Topics: 4-Butyrolactone; Anti-HIV Agents; Apigenin; Chemistry, Pharmaceutical; Costa Rica; Ethanol; Geography; Lactones; Lignans; Plant Extracts; Plant Leaves; Structure-Activity Relationship; Technology, Pharmaceutical; Urticaceae