lignans and Neoplasm-Metastasis

Currently cancer is the second leading cause of death globally and worldwide incidence and mortality rates of all cancers of males and females are rising tremendously. In spite of advances in chemotherapy and radiation, metastasis and recurrence are considered as the major causes of cancer related deaths. Hence there is a mounting need to develop new therapeutic modalities to treat metastasis and recurrence in cancers. A significant amount of substantiation from epidemiological, clinical and laboratory research highlights the importance of diet and nutrition in cancer chemoprevention. Enterolactone (EL) is a bioactive phenolic metabolite known as a mammalian lignan derived from dietary lignans. Here in we review the reported anti-cancer properties of EL at preclinical as well as clinical level. Several in-vivo and in-vitro studies have provided strong evidence that EL exhibits potent anti-cancer and/or protective properties against different cancers including breast, prostate, colo-rectal, lung, ovarian, endometrial, cervical cancers and hepatocellular carcinoma. Reported laboratory studies indicate a clear role for EL in preventing cancer progression at various stages including cancer cell proliferation, survival, angiogenesis, inflammation and metastasis. In clinical settings, EL has been reported to reduce risk, decrease mortality rate and improve overall survival particularly in breast, prostate, colon, gastric and lung cancer. Further, the in-vitro human cell culture studies provide strong evidence of the anticancer and antimetastatic mechanisms of EL in several cancers. This comprehensive review supports an idea of projecting EL as a promising candidate for developing anticancer drug or adjunct dietary supplements and nutraceuticals.

Topics: 4-Butyrolactone; Animals; Humans; Lignans; Neoplasm Metastasis; Neoplasms

The epithelial-to-mesenchymal transition (EMT) has received significant interest as a novel target in cancer prevention, metastasis, and resistance. The conversion of cells from an epithelial, adhesive state to a mesenchymal, motile state is one of the key events in the development of cancer metastasis. Polyphenols have been reported to be efficacious in the prevention of cancer and reversing cancer progression. Recently, the antimetastatic efficacy of polyphenols has been reported, thereby expanding the potential use of these compounds beyond chemoprevention. Polyphenols may affect EMT pathways, which are involved in cancer metastasis; for example, polyphenols increase the levels of epithelial markers, but downregulate the mesenchymal markers. Polyphenols also alter the level of expression and functionality of important proteins in other signaling pathways that control cellular mesenchymal characteristics. However, the specific proteins that are directly affected by polyphenols in these signaling pathways remain to be elucidated. The aim of this review is to analyze current evidence regarding the role of polyphenols in attenuating EMT-mediated cancer progression and metastasis. We also discuss the role of the most important polyphenol subclasses and members of the polyphenols in reversing metastasis and targeting EMT. Finally, limitations and future directions to improve our understanding in this field are discussed.

Topics: Chemoprevention; Epithelial-Mesenchymal Transition; Flavonoids; Humans; Hydroxybenzoates; Lignans; Neoplasm Metastasis; Polyphenols; Stilbenes

Cancer is a leading cause of death worldwide, and the numbers of new cancer cases are expected to continue to rise. The main goals of cancer therapy include removing the primary tumor, preventing the spread of distant metastases, and improving survival and quality of life for the patients. To attain these goals of cancer therapy, the combination of different chemotherapeutics, as opposed to the conventional single-agent treatment, is an emerging area of research. Given the potential risks of drug toxicity in such treatment, the focus is to have a second compound that increases the anticancer potential of the primary agent but which reduces toxicity. There is an ever growing interest in treatment with natural compounds, such as plant phytoestrogens, as an adjuvant cancer therapy along with conventional cancer therapy. The question remains whether or not adding these compounds to the cancer therapy regimen as a second agent would be beneficial, and if they are safe to be used among cancer patients. The current literature suggests that phytoestrogen treatment is capable of inducing G2/M cell cycle arrest in a number of cancer cell lines, as well as upregulating cell cycle inhibitory molecules. Phytoestrogen therapy has been shown to inhibit inflammation, angiogenesis and metastases in various IN VIVO tumor models, and pronounced benefits have been observed when combined with radiation therapy. The lack of side effects from phase I and II clinical trials of phytoestrogens in cancer therapy points towards their safety, but to further understand their added benefit clinical studies with large sample sizes are required. We have reviewed the recent research studies in these areas in an attempt to find evidence for their role in cancer therapy as well as safety.

Topics: Animals; Antineoplastic Agents, Phytogenic; Cell Cycle; Chemotherapy, Adjuvant; Humans; Inflammation; Isoflavones; Lignans; Mice; Neoplasm Metastasis; Neoplasms; Neovascularization, Pathologic; Phytoestrogens; Randomized Controlled Trials as Topic

Topics: Cell Adhesion; Extracellular Matrix; Humans; Integrins; Lignans; Neoplasm Invasiveness; Neoplasm Metastasis; Signal Transduction; Stomach Neoplasms

Osteosarcoma represents one of the most devastating cancers due to its high metastatic potency and fatality. Osteosarcoma is insensitive to traditional chemotherapy. Identification of a small molecule that blocks osteosarcoma progression has been a challenge in drug development. Phillygenin, a plant-derived tetrahydrofurofuran lignin, has shown to suppress cancer cell growth and inflammatory response. However, how phillygenin plays functional roles in osteosarcoma has remained unveiled. In this study, we showed that phillygenin inhibited osteosarcoma cell growth and motility in vitro. Further mechanistic studies indicated that phillygenin blocked STAT3 signaling pathway. Phillygenin led to significant downregulation of Janus kinase 2 and upregulation of Src homology region 2 domain-containing phosphatase 1. Gene products of STAT3 regulating cell survival and invasion were also inhibited by phillygenin. Therefore, our studies provided the first evidence that phillygenin repressed osteosarcoma progression by interfering STAT3 signaling pathway. Phillygenin is a potential candidate in osteosarcoma therapy.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Humans; Janus Kinase 2; Lignans; Neoplasm Metastasis; Osteosarcoma; Protein Tyrosine Phosphatase, Non-Receptor Type 6; Signal Transduction; STAT3 Transcription Factor

Sesamin-treated human oral cancer cell lines FaDu, HSC-3, and Ca9-22 were subjected to a wound-healing assay. Furthermore, Western blotting was performed to assess the effect of sesamin on the expression levels of matrix metalloproteinase (MMP)-2 and proteins of the MAPK signaling pathway, including p-ERK1/2, P-p38, and p-JNK1/2. In addition, we investigated the association between MMP-2 expression and the MAPK pathway in sesamin-treated oral cancer cells. Sesamin inhibited cell migration and invasion in FaDu, Ca9-22, and HSC-3 cells and suppressed MMP-2 at noncytotoxic concentrations (0 to 40 μM). Furthermore, sesamin significantly reduced p38 MAPK and JNK phosphorylation in a dose-dependent manner in FaDu and HSC-3 cells.. These results indicate that sesamin suppresses the migration and invasion of HNSCC cells by regulating MMP-2 and is thus a potential antimetastatic agent for treating HNSCC.

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Movement; Cell Survival; Dioxoles; Head and Neck Neoplasms; Humans; Lignans; MAP Kinase Kinase 4; MAP Kinase Signaling System; Matrix Metalloproteinase 2; Neoplasm Metastasis; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Squamous Cell Carcinoma of Head and Neck; Zanthoxylum

Magnolol (Mag), an effective natural compound isolated from the stem bark of Magnolia officinalis, was found to have the potential for antitumor activity by inducing apoptosis in tumor cells. However, the effect of Mag on renal carcinoma cells and its molecular mechanism are unexplored. Our study provided evidence that Mag induced apoptosis in 786-O and OS-RC-2 cell lines via the mitochondrial pathway and cell cycle arrest. In this work, we found that Mag induced morphological changes and inhibited the proliferation of 786-O and OS-RC-2 cells in a dose- and time-dependent manner but exerted no notable inhibitory effects on normal human renal proximal tubular (HK-2) cells. Treatment with Mag suppressed the migration and invasion ability of renal carcinoma cells. Moreover, Mag caused the openness of mPTP, the accumulation of intracellular ROS and decreased △Ψm, leading to mitochondrial dysfunction. However, pretreatment with the antioxidant N-acetyl cysteine (NAC) reversed the apoptosis induced by Mag and decreased the generation of ROS. In addition, the increased proportion of the G1/G0 phase indicated that Mag caused cell cycle arrest. Further analyses suggested that magnolol-induced apoptosis was related to the abnormal expression of p53, Bax, Bcl-2, cytochrome c and caspase activation. Together, the results above revealed that Mag had antitumor effects in renal carcinoma cells via ROS production as well as cell cycle arrest and the apoptotic mitochondrial pathway was suppressed in part by NAC.

Topics: Apoptosis; Apoptosis Regulatory Proteins; Biphenyl Compounds; Cell Cycle; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Movement; Cell Proliferation; Humans; Inhibitory Concentration 50; Kidney Neoplasms; Lignans; Membrane Potential, Mitochondrial; Mitochondria; Neoplasm Metastasis; Reactive Oxygen Species

Honokiol is a natural product extracted from herbal plants such as the Magnolia species which have been shown to exhibit anti-tumor and anti-metastatic properties. However, the effects of honokiol on thyroid cancers are largely unknown.. To determine whether honokiol might be useful for the treatment of thyroid cancer and to elucidate the mechanism of toxicity of honokiol, we analyzed the impact of honokiol treatment on differential protein expression in human thyroid cancer cell line ARO using lysine-labeling two-dimensional difference gel electrophoresis (2D-DIGE) combined with mass spectrometry (MS).. This study revealed 178 proteins that showed a significant change in expression levels and also revealed that honokiol-induced cytotoxicity in thyroid cancer cells involves dysregulation of cytoskeleton, protein folding, transcription control and glycolysis.. Our work shows that combined proteomic strategy provides a rapid method to study the molecular mechanisms of honokiol-induced cytotoxicity in thyroid cancer cells. The identified targets may be useful for further evaluation as potential targets in thyroid cancer therapy.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Biphenyl Compounds; Cell Line, Tumor; Cell Survival; Cytoskeleton; Electrophoresis, Gel, Two-Dimensional; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Glycolysis; Humans; Lignans; Magnolia; Mass Spectrometry; Neoplasm Metastasis; Plant Extracts; Protein Processing, Post-Translational; Proteome; Proteomics; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Thyroid Neoplasms

Treatment effect of chemotherapy for aggressive non-small-cell lung cancer (NSCLC) is usually unsatisfactory for non-selective distributions of anticancer drugs, generation of vasculogenic mimicry (VM) channels, high metastasis and recurrence rate. Therefore, we developed a kind of dequalinium (DQA) modified paclitaxel plus honokiol micelles in this study to destroy VM channels and inhibit tumour metastasis. In vitro assays indicated that the targeting paclitaxel micelles with ideal physicochemical characteristics could exhibit not only the powerful cytotoxicity on Lewis lung tumour (LLT) cells but also the effective suppression on VM channels and tumour metastasis. Action mechanism studies manifested that DQA modified paclitaxel plus honokiol micelles could activate apoptotic enzymes caspase-3 and caspase-9 as well as down-regulate FAK, PI3K, MMP-2 and MMP-9. In vivo assays indicated that polymeric micelles could increase selective accumulation of chemotherapeutic drugs at tumour sites and showed a conspicuous antitumour efficacy. Hence, the DQA modified paclitaxel plus honokiol micelles prepared in this study provided a potential treatment strategy for NSCLC.

Topics: Animals; Antineoplastic Agents; Apoptosis; Biphenyl Compounds; Carcinoma, Non-Small-Cell Lung; Cell Adhesion; Cell Line, Tumor; Cell Survival; Dequalinium; Drug Interactions; Drug Liberation; Humans; Lignans; Lung Neoplasms; Mice; Micelles; Neoplasm Metastasis; Paclitaxel; Temperature; Xenograft Model Antitumor Assays

To concurrently suppress multidrug resistance (MDR) and metastasis of breast cancer cells, paclitaxel (PTX) and honokiol (HNK) were coencapsulated into pH-sensitive polymeric micelles based on poly(2-ethyl-2-oxazoline)-poly(d,l-lactide) (PEOz-PLA). The physicochemical properties of dual drug-loaded PEOz-PLA micelles were characterized in size, drug loading and in vitro release. The efficiency of MDR reversal for the micelles was testified by synergetic enhancement of cytotoxicity and uptake by MCF-7/ADR cells. The flow cytometry and fluorescence polarization measurement results reinforced the conclusion that down-regulation of P-gp expression and increase of plasma membrane fluidity appeared to be possible mechanisms of MDR reversal by dual drug-loaded PEOz-PLA micelles. Further, the efficient inhibition of tumor metastasis by dual drug-loaded PEOz-PLA micelles was demonstrated by in vitro anti-invasion and anti-migration assessment in MDA-MB-231 cells and in vivo bioluminescence imaging in nude mice. The suppression of MDR and metastasis by the micelles was assigned to synergistic effects of pH-triggered drug release and HNK/PEOz-PLA-aroused P-gp inhibition, and pH-triggered drug release and PTX/HNK-aroused MMPs inhibition, respectively. In conclusion, our findings strengthen the usefulness of co-delivery of PTX and HNK by pH-responsive polymeric micelles for suppression of tumor MDR and metastasis.. Multidrug resistance (MDR) and metastasis are considered to be two of the major barriers for successful chemotherapy. The combination of a chemotherapeutic drug with a modulator has emerged as a promising strategy for efficiently treating MDR cancer and preventing tumor metastasis. Herein, a dual drug (paclitaxel and honokiol)-loaded pH-sensitive polymeric micelle system based on PEOz-PLA was successfully fabricated to ensure that tumor MDR and metastasis could be concurrently suppressed, therefore achieving distinguishing endo/lysosomal pH from physiological pH by accelerating drug release and then enhancing the cytotoxicity of paclitaxel to drug-resistant tumor cells MCF-7/ADR by increasing cellular uptake of paclitaxel, preventing in vitro invasion and migration for MDA-MB-231 cells and in vivo metastasis in nude mice. Further, the mechanism of MDR reversal by dual drug-loaded PEOz-PLA micelles was elucidated to be down-regulation of P-gp expression and increase of plasma membrane fluidity of MCF-7/ADR cells. The present findings strengthen the usefulness of co-delivery of PTX and HNK by pH-responsive polymeric micelles for suppression of tumor MDR and metastasis.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biphenyl Compounds; Breast Neoplasms; Drug Delivery Systems; Female; Humans; Lignans; MCF-7 Cells; Neoplasm Metastasis; Paclitaxel

Arctigenin is a bioactive lignan isolated from the seeds of Arctium lappa L. which has been widely used as a diuretic and a diaphoretic in Traditional Chinese Medicine. In the present study, the authors investigated the effects of arctigenin on tumor migration and invasion in aggressive human breast cancer cells. The MTT assay results showed that arctigenin did not show a significant cytotoxic effect on the cell viability of MDA-MB-231 cells. However, wound healing migration and Boyden chamber invasion assays demonstrated that arctigenin significantly inhibited in vitro migration and invasion of the MDA-MB-231 cells. Furthermore, gelatin zymography results showed that arctigenin reduced the activity of MMP-2 and MMP-9. Western blot analysis results demonstrated that the expression of MMP-2, MMP-9 and heparanase proteins was significantly downregulated following the treatment of arctigenin. Finally, the antiangiogenic activity of arctigenin was also examined by the chick embryo chorioallantoic membrane (CAM) assay. Arctigenin treatment significantly inhibited angiogenesis in the CAM. In conclusion, the results revealed that arctigenin significantly inhibited the migration and invasion of MDA-MB-231 cells by downregulating MMP-2, MMP-9 and heparanase expression. However, further studies are still necessary to investigate the exact mechanisms involved and to explore signal transduction pathways to better understand the biological mechanisms.

Topics: Animals; Arctium; Breast Neoplasms; Cell Line, Tumor; Cell Movement; Chick Embryo; Down-Regulation; Female; Furans; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Glucuronidase; Humans; Lignans; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Neoplasm Metastasis

At present, there is no specific anti-metastasis drug in HCC treatment. Drugs used for primary HCC tumors and tumor metastasis are very similar, among which cytotoxic drugs are prevalent, such as cisplatin, doxorubicin and 5-FU. The EGFR pathway plays an important role in promoting hepatocellular carcinoma (HCC) metastasis. Hence, development of non-toxic anti-metastasis drugs, such as EGFR or downstream pathways inhibitors, is of great importance. In our present study, we found non-toxic dose of liposomal honokiol (LH) could inhibit the HCC metastasis by destabilizing EGFR and inhibiting the downstream pathways. Non-toxic dose of LH significantly inhibited the motility, migration and lamellipodia formation of HepG2 cells in vitro and decreased extravasation of HepG2 cells in a novel metastasis model of transgenic zebrafish. In two lung metastasis models (HepG2 and B16F10) and a spontaneous metastasis model of HepG2 cells, LH remarkably inhibited pulmonary metastasis and regional lymph nodes metastasis without obvious toxicity. Further study showed that destabilizing EGFR and inhibiting the downstream pathways were the main mechanisms of non-toxic dose of LH on metastasis inhibition. Our results provide the preclinical rationale and the underlying mechanisms of LH to suppress HCC metastasis, implicating LH as a potential therapeutic agent to block HCC metastasis without severe side effects.

Topics: Animals; Antineoplastic Agents; Apoptosis; Biphenyl Compounds; Carcinoma, Hepatocellular; cdc42 GTP-Binding Protein; Cell Cycle; Cell Line, Tumor; Cell Movement; Cell Proliferation; Disease Models, Animal; ErbB Receptors; Female; Hep G2 Cells; Heterografts; Humans; Lignans; Liver Neoplasms; MAP Kinase Signaling System; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Melanoma, Experimental; Mice; Neoplasm Metastasis; Neoplasm Staging; Protein Stability; rac1 GTP-Binding Protein; Signal Transduction; Zebrafish

Arctigenin is a plant lignan extracted from Arctium lappa that has been shown to have estrogenic properties. In spite of the health benefits of phytoestrogens reducing the risk of osteoporosis, heart disease, and menopausal symptoms, its benefits against the risk of breast cancer have not been fully elucidated. Thus, we investigated the effects of arctigenin on metastasis of breast cancer using both estrogen receptor (ER)-positive MCF-7 and ER-negative MDA-MB-231 human breast cancer cell lines to see if the effects are dependent on the status of ER expression. In ER-positive MCF-7 cells, arctigenin efficiently inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced cell migration and invasion. The activity of crucial metastatic protease matrix metalloprotease (MMP)-9 in gelatin zymography was also efficiently decreased by arctigenin, as well as its mRNA expression. Notably, arctigenin exhibited similar anti-metastatic effects even in ER-negative MDA-MB-231 cells, suggesting that the anti-metastatic effects of arctigenin were not exerted via the ER. The upstream signaling pathways involved in the regulation of MMP-9 and urokinase plasminogen activator (uPA) were analyzed using western blotting. The activation of Akt, NF-κB and MAPK (ERK 1/2 and JNK 1/2) was found to be inhibited. Taken together, these data suggest that arctigenin confers anti-metastatic effects by inhibiting MMP-9 and uPA via the Akt, NF-κB and MAPK signaling pathways on breast cancer, regardless of ER expression. Therefore, we propose that the intake of arctigenin could be an effective supplement for breast cancer patients.

Topics: Breast Neoplasms; Cell Line, Tumor; Cell Movement; Female; Furans; Gene Expression; Gene Expression Regulation, Neoplastic; Humans; Lignans; Matrix Metalloproteinase 9; MCF-7 Cells; Neoplasm Metastasis; Phytoestrogens; Receptors, Estrogen; Signal Transduction; Urokinase-Type Plasminogen Activator

Tumour-associated fibroblasts (TAFs), as a functionally supportive microenvironment, play an essential role in tumour progression. Here we investigate the role of IL-25, an endogenous anticancer factor secreted from TAFs, in suppression of mouse 4T1 mammary tumour metastasis. We show that a synthetic dihydrobenzofuran lignan (Q2-3), the dimerization product of plant caffeic acid methyl ester, suppresses 4T1 metastasis by increasing fibroblastic IL-25 activity. The secretion of IL-25 from treated human or mouse fibroblasts is enhanced in vitro, and this activity confers a strong suppressive effect on growth activity of test carcinoma cells. Subsequent in vivo experiments showed that the anti-metastatic effects of Q2-3 on 4T1 and human MDA-MD-231 tumour cells are additive when employed in combination with the clinically used drug, docetaxel. Altogether, our findings reveal that the release of IL-25 from TAFs may serve as a check point for control of mammary tumour metastasis and that phytochemical Q2-3 can efficiently promote such anticancer activities.

Topics: 3T3 Cells; Animals; Antineoplastic Agents; Blotting, Western; Breast Neoplasms; Cell Line; Cell Line, Tumor; Cell Survival; Female; Fibroblasts; Humans; Interleukins; Lignans; Mammary Neoplasms, Experimental; MCF-7 Cells; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Structure; Neoplasm Metastasis; Survival Analysis; Tumor Burden; Xenograft Model Antitumor Assays

Arctigenin (ARC) has been shown to have an anti-cancer effect in various cell types and tissues. However, there have been no studies concerning metastatic colorectal cancer (CRC). In this study, we investigated the anti-metastatic properties of ARC on colorectal metastasis and present a potential candidate drug. ARC induced cell cycle arrest and apoptosis in CT26 cells through the intrinsic apoptotic pathway via MAPKs signaling. In several metastatic phenotypes, ARC controlled epithelial-mesenchymal transition (EMT) through increasing the expression of epithelial marker E-cadherin and decreasing the expressions of mesenchymal markers; N-cadherin, vimentin, β-catenin, and Snail. Moreover, ARC inhibited migration and invasion through reducing of matrix metalloproteinase-2 (MMP-2) and MMP-9 expressions. In an experimental metastasis model, ARC significantly inhibited lung metastasis of CT26 cells. Taken together, our study demonstrates the inhibitory effects of ARC on colorectal metastasis.

Topics: Animals; Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Cell Survival; Colorectal Neoplasms; Drug Screening Assays, Antitumor; Female; Furans; Lignans; Lung Neoplasms; Mice; Mice, Inbred BALB C; Neoplasm Metastasis

Malignant glioma is the aggressive tumor in the brain and is characterized by high morbidity, high mortality. The main purpose of the present study was to investigate the therapeutic effects of Schisandrin B on glioma cells and preliminary explore the possible mechanism underlying anti-metastasis of Schisandrin B.. Two glioma cell lines, U251 and U87, were used in present study. The ability of metastasis of glioma cells was evaluated using transwell migration assay and invasion assay. Expression of Akt, mTOR, MMP-2 and MMP-9 was determined using Western blotting. Antagonist or agonist was used to activated or inactivated signal molecules.. Schisandrin B suppressed cell migration and invasion in manner of dose dependent as well as inhibited expression of p-Akt, p-mTOR and MMP-9. Activation of PI3K by 740Y-P treatment leaded to upregulation of p-Akt, mTOR and MMP-9; inactivation of mTOR by Rapamycin treatment inhibited expression MMP-9 while activation of mTOR by l-Leucine treatment enhanced MMP-9 expression in Schisandrin B incubated cells. Anti-migration and invasion action of Schisandrin B was also reversed by mTOR activation.. Our findings demonstrate that Schisandrin B can suppress migration and invasion of glioma cell via PI3K/Akt-mTOR-MMP-9 signaling pathway.

Topics: Antineoplastic Agents, Phytogenic; Brain Neoplasms; Cell Line, Tumor; Cell Movement; Cyclooctanes; Dose-Response Relationship, Drug; Glioma; Humans; Lignans; Matrix Metalloproteinase 9; Neoplasm Invasiveness; Neoplasm Metastasis; Phosphatidylinositol 3-Kinases; Polycyclic Compounds; Proto-Oncogene Proteins c-akt; Signal Transduction; TOR Serine-Threonine Kinases

A lignan-rich diet is associated with a lower risk of human breast cancer. Enterolactone, an active polyphenol metabolites of lignan, was reported to have an antitumor effect. We investigated the mechanism for the effect of enterolactone against human breast cancer. Cellular changes, and associated genes induced by enterolactone, were investigated in MDA-MB-231 cells. Enterolactone showed an antiproliferative effect, and its IC50 was 261.9 ± 10.5 μM for a treatment period of 48 hr. The mRNA levels of the genes related to cell proliferation, Ki67, PCNA, and FoxM1, were reduced. Enterolactone induced accumulation of cells in the S phase, and a lower expression of Cyclin E1, Cyclin A2, Cyclin B1, and Cyclin B2 genes. There were almost no changes in the transcription levels of the genes that participate in G0/G1 phase regulation, CDK4, CDK6, and Cyclin D1. Furthermore, enterolactone interfered with the cytoskeleton by downregulating phosphorylation of the FAK/paxillin pathway, inhibiting migration and invasion of cells. The results suggest that enterolactone exerts an antitumor effect by regulating the expression of genes associated with cell proliferation and the cell cycle and by blocking the FAK/paxillin signaling pathway. These findings provide new insights into the molecular mechanisms behind the antitumor effect of enterolactone.

Topics: 4-Butyrolactone; Breast Neoplasms; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cyclins; Cytoskeleton; Focal Adhesion Kinase 1; Forkhead Box Protein M1; Forkhead Transcription Factors; Gene Expression; Humans; Ki-67 Antigen; Lignans; Neoplasm Invasiveness; Neoplasm Metastasis; Paxillin; Proliferating Cell Nuclear Antigen; RNA, Messenger; S Phase; Signal Transduction

Breast cancer frequently spreads to bone. The interaction between bone metastases and microenvironment, referred as the "vicious cycle", increases both tumor burden and bone destruction. Therefore, inhibition at any point in this "vicious cycle" can reduce malignant osteolytic lesions in patients with advanced breast cancer. In this study, we evaluated whether tetrahydrofurofuran-type lignans derived from Magnoliae Flos, commonly used in traditional Asian medicine to treat inflammatory diseases, could block breast cancer-mediated bone loss. Aschatin, fargesin, lirioresinol B dimethyl ether, and magnolin at noncytotoxic concentrations suppressed mRNA expression and secretion of osteolytic factor PTHrP in MDA-MB-231 metastatic human breast cancer cells. Fargesin inhibited TGF-β-stimulated cell viability, migration, and invasion and decreased TGF-β-induced PTHrP production in MDA-MB-231 cells. In addition, these lignans reduced RANKL/OPG ratio in PTHrP-treated hFOB1.19 human osteoblastic cells and inhibited RANKL-mediated osteoclast differentiation in mouse bone marrow macrophages. Aschatin, fargesin, lirioresinol B dimethyl ether, and magnolin substantially reduced bone-resorbing activity of osteoclasts by inhibiting MMP-9 and cathepsin K activities. Furthermore, orally administered fargesin inhibited tumor growth and cancer-mediated bone destruction in mice with MDA-MB-231 cells injected into calvarial tissues. Aschatin, fargesin, lirioresinol B dimethyl ether, and magnolin blocked initiation and progression of the "vicious cycle" between breast cancer metastases and bone microenvironment by inhibiting PTHrP production in breast cancer cells and osteoclastic bone resorption. Therefore, these tetrahydrofurofuran-type lignans have the potential to serve as beneficial agents to prevent and treat cancer-induced bone destruction in breast cancer patients.

Topics: Animals; Benzodioxoles; Bone Resorption; Breast Neoplasms; Cell Line, Tumor; Female; Furans; Gene Expression Regulation, Neoplastic; Humans; Lignans; Lignin; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Metastasis; Osteoblasts; Osteoclasts; Osteoprotegerin; Parathyroid Hormone-Related Protein; RANK Ligand; RNA, Messenger

Cancer metastasis is a major cause for cancer-related death and inhibiting cancer metastasis is an alternative way to treat cancer. Several lines of reported evidence suggest that NADPH oxidase 4 (NOX4) is a potential target for intervention of cancer metastasis, as the reactive oxygen species (ROS) generated by this enzyme plays important roles in TGF-β signaling, an important inducer of cancer metastasis. Here we show (1) that TGF-β induces ROS production in breast cancer 4T1 cells and enhances cell migration and that the effect of TGF-β depends on NOX4 expression, (2) that knockdown of NOX4 via RNAi significantly decreases the migration ability of 4T1 cells in the presence or absence of TGF-β and significantly attenuates distant metastasis of 4T1 cells to lung and bone, (3) that Schisandrin B (Sch B), a naturally occurring dibenzocyclooctadiene lignan with very low toxicity, is a novel NOX inhibitor and its IC50 toward NOX4 is 9.3μM, and (4) that Sch B suppresses TGF-β-induced and NOX4-associated ROS production in 4T1 cells and inhibits TGF-β-enhanced cell migration. Similar to NOX4 knockdown observed in this study, Sch B significantly attenuated 4T1 cells distant metastasis to lung and bone in our recently published study. In line with previous reports, the study suggests that pharmacologically targeting NOX4 may be a potential approach to disrupt cancer metastasis.

Topics: Animals; Blotting, Western; Cell Line, Tumor; Cyclooctanes; Female; Humans; Lignans; Mice; Mice, Inbred BALB C; Microscopy, Confocal; NADPH Oxidase 4; NADPH Oxidases; Neoplasm Metastasis; Polycyclic Compounds; Reactive Oxygen Species; Signal Transduction; Transforming Growth Factor beta

Overexpression of the HER2 oncogene contributes to tumor cell invasion, metastasis and angiogenesis and correlates with poor prognosis. Magnolol has been reported to exhibit anti-tumor activities. However, the molecular mechanism of action of magnolol has not been investigated in HER2-positive cancer cells. Therefore, we examined the anti-cancer effects of magnolol on HER2-overexpressing ovarian cancer cells. Magnolol treatment caused a dose-dependent inhibition of HER2 gene expression at the transcriptional level, potentially in part through suppression of NF-κB activation. Treatment of HER2-overexpressing ovarian cancer cells with magnolol down-regulated the HER2 downstream PI3K/Akt signaling pathway, and suppressed the expression of downstream target genes, vascular endothelial growth factor (VEGF), matrix metalloproteinase 2 (MMP2) and cyclin D1. Consistently, magnolol-mediated inhibition of MMP2 activity could be prevented by co-treatment with epidermal growth factor. Migration assays revealed that magnolol treatment markedly reduced the motility of HER2-overexpressing ovarian cancer cells. Furthermore, magnolol-induced apoptosis in HER2-overexpressing ovarian cancer cells was characterized by the up-regulation of cleaved poly(ADP-ribose) polymerase (PARP) and activated caspase 3. These findings suggest that magnolol may act against HER2 and its downstream PI3K/Akt/mTOR-signaling network, thus resulting in suppression of HER2-mediated transformation and metastatic potential in HER2-overexpressing ovarian cancers. These results provide a novel mechanism to explain the anti-cancer effect of magnolol.

Topics: Biphenyl Compounds; Caspase 3; Cell Growth Processes; Cell Line, Tumor; Cell Transformation, Neoplastic; Cyclin D1; Down-Regulation; Female; Gene Expression Regulation, Neoplastic; Genes, erbB-2; Humans; Lignans; Neoplasm Metastasis; Ovarian Neoplasms; Phosphatidylinositol 3-Kinases; Poly(ADP-ribose) Polymerases; Proto-Oncogene Proteins c-akt; Receptor, ErbB-2; Signal Transduction; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A

Magnolol, a hydroxylated biphenyl compound isolated from the root and stem bark of Magnolia officinalis, has been reported to have anticancer activity, but little is known about its molecular mechanisms of action. Increased expression of cyclooxygenase-2 (COX-2), a key enzyme in arachidonic acid metabolism, has been identified in many cancer types. Matrix metalloproteinases (MMPs) are enzymes involved in various steps of metastasis development. The objective of this study was to study the effects of magnolol on cancer invasion and metastasis using PC-3 human prostate carcinoma cells. Cellular proliferation was determined by MTT colorimetric assay. Magnolol inhibited cell growth in a dose-dependent manner. In an invasion assay conducted in Transwell chambers, magnolol showed 33 and 98% inhibition of cancer cell at 10 microM and 20 microM concentrations, respectively, compared to the control. The expression of MMP-2/-9 and COX-1/-2 was assessed by gelatin zymography and Western blot respectively. The protein and mRNA levels of both MMP-2 and MMP-9 were down-regulated by magnolol treatment in a dose-dependent manner. These results demonstrate the antimetastatic properties of magnolol in inhibiting the adhesion, invasion, and migration of PC-3 human prostate cancer cells.

Topics: Biphenyl Compounds; Cell Adhesion; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cyclooxygenase 1; Cyclooxygenase 2; Down-Regulation; Gene Expression Regulation, Neoplastic; Humans; Lignans; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Neoplasm Invasiveness; Neoplasm Metastasis; Prostatic Neoplasms

Both epidemiological and experimental evidence is accumulating to show that a lignan-rich diet may reduce the risk of human breast cancer. Possible anti-cancer effects of dietary lignans on hepatomas or hepatoma cells have not been the topic of earlier studies. In the present study, we examined the effect of 7-hydroxymatairesinol (HMR) and its mammalian metabolite, enterolactone (ENL), on AH109A hepatoma cell proliferation and invasion in vitro. HMR and ENL inhibited the proliferation and invasion of AH109A hepatoma cells in vitro. The 50% inhibitory concentration (IC50) of hepatoma cell proliferation was lower for ENL (10 microM) than HMR (> 200 microM). Likewise, IC50 of hepatoma cell invasion was lower for ENL (9 microM) than HMR (144 microM). ENL suppressed hepatoma cell proliferation by accumulating cells in G1 phase and elongating doubling time of these cells, and by increasing the rate of apoptosis. Subsequently, we investigated in vivo the effect of dietary HMR and ENL on growth and metastasis of AH109A hepatomas in rats. Both of these compounds reduced the growth and metastasis of solid AH109A hepatomas in rats. These in vitro and in vivo findings suggest that HMR has inhibitory activities on tumor growth and metastasis in the hepatoma-bearing rats, and that this anti-tumor effect is mediated at least partially by ENL, a metabolite of HMR.

Topics: 4-Butyrolactone; Animals; Apoptosis; Cell Cycle; Cell Division; Cell Line, Tumor; Dose-Response Relationship, Drug; Inhibitory Concentration 50; Lignans; Liver Neoplasms, Experimental; Male; Neoplasm Invasiveness; Neoplasm Metastasis; Rats; Tumor Cells, Cultured

Our previous studies have shown that dietary flaxseed (FS) can reduce the growth and metastasis of human estrogen receptor negative (ER-) breast cancer in nude mice. The aims of our study were to determine (i) whether the tumor inhibitory effect of FS was due to its oil (FO), lignan secoisolariciresinol diglycoside (SDG), or both components, and (ii) whether the effect on tumor growth was related to increased lipid peroxidation. Athymic nude mice were orthotopically injected with ER- breast cancer cells (MDA-MB-435) and 8 weeks later were fed either the basal diet (BD) or BD supplemented with 10% FS, SDG, FO, or combined SDG and FO (SDG + FO) for 6 weeks. The SDG and FO levels were equivalent to the amounts in the 10% FS. Compared to the BD group, the tumor growth rate was significantly lower (p < 0.05) in the FS, FO, and SDG + FO groups, in concordance with decreased cell proliferation and increased apoptosis; however, these did not significantly relate to the lipid peroxidation, indexed as malonaldehyde (MDA), in the primary tumors. Lung metastasis incidence was reduced (16-70%) by all treatments, significantly in the FS and SDG + FO groups. The distant lymph node metastasis was significantly decreased (52%) only in the FO group. Although the total metastasis incidence was lowered (42%) significantly only in the SDG + FO group, all treatment groups did not differ significantly. In conclusion, FS reduced the growth and metastasis of established ER- human breast cancer in part due to its lignan and FO components, and not to lipid peroxidation.

Topics: Animals; Breast Neoplasms; Cell Line, Tumor; Female; Flax; Humans; Lignans; Linseed Oil; Mice; Neoplasm Metastasis; Neoplasm Transplantation; Receptors, Estrogen; Transplantation, Heterologous

Flaxseed has been shown to reduce the metastasis of estrogen receptor negative (ER-) human breast cancer in nude mice. This study determined whether enterodiol (ED) and enterolactone (EL), metabolites of plant lignans exceptionally rich in flaxseed, and tamoxifen (TAM), alone or in combination, can influence the various steps of metastasis, that is, breast cancer cell adhesion, invasion and migration, of two ER- human breast cancer cell lines, MDA-MB-435 and MDA-MB-231. The inhibition by ED, EL or TAM (1-5 microM) of cell adhesion to Matrigel or extracellular matrices, fibronectin, laminin, and type IV collagen, as well as cell invasion was dose dependent in both cell lines. When ED, EL and TAM were combined at 1 microM, a greater inhibitory effect on cell adhesion and invasion was observed than with either compound alone. ED and EL at doses of 0.1-10 microM reduced cell migration, but TAM had no effect at 0.1 and 1 microM, and exhibited a stimulatory effect at 10 microM. It is concluded that lignans and TAM, alone or in combination, can inhibit the steps involved in the metastasis cascade. Although more investigations are required, the study also suggests that the intake of the lignan-rich flaxseed may not antagonize the effect of TAM in ER- breast cancer cells.

Topics: 4-Butyrolactone; Antineoplastic Agents; Breast Neoplasms; Cell Adhesion; Cell Line, Tumor; Cell Movement; Female; Humans; Lignans; Neoplasm Invasiveness; Neoplasm Metastasis; Phytotherapy; Receptors, Estrogen; Tamoxifen