lignans and Cell-Transformation--Neoplastic

Mammalian target of rapamycin (mTOR) has a pivotal role in carcinogenesis and cancer cell proliferation in diverse human cancers. In this study, we observed that epimagnolin, a natural compound abundantly found in Shin-Yi, suppressed cell proliferation by inhibition of epidermal growth factor (EGF)-induced G1/S cell-cycle phase transition in JB6 Cl41 cells. Interestingly, epimagnolin suppressed EGF-induced Akt phosphorylation strongly at Ser473 and weakly at Thr308 without alteration of phosphorylation of MAPK/ERK kinases (MEKs), extracellular signal-regulated kinase (ERKs), and RSK1, resulting in abrogation of the phosphorylation of GSK3β at Ser9 and p70S6K at Thr389. Moreover, we found that epimagnolin suppressed c-Jun phosphorylation at Ser63/73, resulting in the inhibition of activator protein 1 (AP-1) transactivation activity. Computational docking indicated that epimagnolin targeted an active pocket of the mTOR kinase domain by forming three hydrogen bonds and three hydrophobic interactions. The prediction was confirmed by using in vitro kinase and adenosine triphosphate-bead competition assays. The inhibition of mTOR kinase activity resulted in the suppression of anchorage-independent cell transformation. Importantly, epimagnolin efficiently suppressed cell proliferation and anchorage-independent colony growth of H1650 rather than H460 lung cancer cells with dependency of total and phosphorylated protein levels of mTOR and Akt. Inhibitory signaling of epimagnolin on cell proliferation of lung cancer cells was observed mainly in mTOR-Akt-p70S6K and mTOR-Akt-GSK3β-AP-1, which was similar to that shown in JB6 Cl41 cells. Taken together, our results indicate that epimagnolin potentiates as chemopreventive or therapeutic agents by direct active pocket targeting of mTOR kinase, resulting in sensitizing cancer cells harboring enhanced phosphorylation of the mTORC2-Akt-p70S6k signaling pathway.

Topics: Animals; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic; Chemoprevention; Drugs, Chinese Herbal; Epidermal Growth Factor; Extracellular Signal-Regulated MAP Kinases; G1 Phase Cell Cycle Checkpoints; Glycogen Synthase Kinase 3 beta; HEK293 Cells; Humans; JNK Mitogen-Activated Protein Kinases; Lignans; Lung Neoplasms; Mice; Molecular Docking Simulation; Phosphorylation; Protein Conformation; Proto-Oncogene Proteins c-akt; Ribosomal Protein S6 Kinases, 70-kDa; Ribosomal Protein S6 Kinases, 90-kDa; RNA Interference; RNA, Small Interfering; TOR Serine-Threonine Kinases

The incidence, risk factors, and outcomes of low-grade glioma patients who undergo malignant transformation (MT) in the era of temozolomide are not well known. This study evaluates these factors in a large group of World Health Organization grade 2 glioma patients treated at a tertiary-care institution.. Patient, tumor, and treatment factors were analyzed using an institutional review board-approved low-grade glioma database. Characteristics were compared using χ. Of a total of 599 patients, 124 underwent MT; 76 (61.3%) had biopsy-proven MT. The MT incidence was 21%, and the median time to MT was 56.4 months. The 5- and 10-year progression-free survival rates were 30.6% ± 4.2% and 4.8% ± 1.9%, respectively, for MT patients and 60% ± 2.4% and 38% ± 2.7%, respectively, for non-MT patients. The 5- and 10-year overall survival rates were 75% ± 4.0% and 46% ± 5.0%, respectively, for MT patients and 87% ± 1.7% and 78% ± 2.3%, respectively, for non-MT patients. On multivariate analysis, older age (P = .001), male sex (P = .004), multiple tumor locations (P = .004), chemotherapy alone (P = .012), and extent of resection (P = .045) remained significant predictors of MT.. MT affects survival. Risk factors include older age, male sex, multiple tumor locations, use of chemotherapy alone, and presence of residual disease. Our finding that initial interventions could affect the rate of MT is provocative, but these data should be validated using data from prospective trials. In addition to improving survival, future therapeutic efforts should focus on preventing MT.

Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Analysis of Variance; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Brain Neoplasms; Cell Transformation, Neoplastic; Chi-Square Distribution; Child; Child, Preschool; Female; Glioma; Glycosides; Humans; Incidence; Infant; Lignans; Male; Middle Aged; Progression-Free Survival; Risk Factors; Sex Factors; Statistics, Nonparametric; Temozolomide; Time Factors; Young Adult

Topics: AMP-Activated Protein Kinase Kinases; Animals; Biphenyl Compounds; Breast Neoplasms; Cell Line, Tumor; Cell Movement; Cell Transformation, Neoplastic; Female; Humans; Lignans; Mice; Neoplastic Stem Cells; Protein Serine-Threonine Kinases; STAT3 Transcription Factor; Xenograft Model Antitumor Assays

Obesity greatly influences risk, progression and prognosis of breast cancer. As molecular effects of obesity are largely mediated by adipocytokine leptin, finding effective novel strategies to antagonize neoplastic effects of leptin is desirable to disrupt obesity-cancer axis. Present study is designed to test the efficacy of honokiol (HNK), a bioactive polyphenol from Magnolia grandiflora, against oncogenic actions of leptin and systematically elucidate the underlying mechanisms. Our results show that HNK significantly inhibits leptin-induced breast-cancer cell-growth, invasion, migration and leptin-induced breast-tumor-xenograft growth. Using a phospho-kinase screening array, we discover that HNK inhibits phosphorylation and activation of key molecules of leptin-signaling-network. Specifically, HNK inhibits leptin-induced Wnt1-MTA1-β-catenin signaling in vitro and in vivo. Finally, an integral role of miR-34a in HNK-mediated inhibition of Wnt1-MTA1-β-catenin axis was discovered. HNK inhibits Stat3 phosphorylation, abrogates its recruitment to miR-34a promoter and this release of repressor-Stat3 results in miR-34a activation leading to Wnt1-MTA1-β-catenin inhibition. Accordingly, HNK treatment inhibited breast tumor growth in diet-induced-obese mouse model (exhibiting high leptin levels) in a manner associated with activation of miR-34a and inhibition of MTA1-β-catenin. These data provide first in vitro and in vivo evidence for the leptin-antagonist potential of HNK revealing a crosstalk between HNK and miR34a and Wnt1-MTA1-β-catenin axis.

Topics: Animals; Antineoplastic Agents, Phytogenic; beta Catenin; Biphenyl Compounds; Breast Neoplasms; Cell Movement; Cell Proliferation; Cell Transformation, Neoplastic; Cyclin D1; Drugs, Chinese Herbal; Female; Histone Deacetylases; Humans; Leptin; Lignans; Magnolia; MCF-7 Cells; Mice; Mice, Nude; Mice, Obese; MicroRNAs; Neoplasm Invasiveness; Obesity; Phosphorylation; Plant Extracts; Promoter Regions, Genetic; Repressor Proteins; RNA Interference; RNA, Small Interfering; Signal Transduction; Spheroids, Cellular; STAT3 Transcription Factor; Trans-Activators; Tumor Cells, Cultured; Wnt1 Protein; Xenograft Model Antitumor Assays

Mammalian target of rapamycin (mTOR), a serine/threonine protein kinase, forms two different complexes, complex 1 and 2, and plays a key role in the regulation of Akt signaling-mediated cell proliferation and transformation. This study reveals aschantin, a natural compound abundantly found in Magnolia flos, as a novel mTOR kinase inhibitor. Aschantin directly targeted the active pocket of mTOR kinase domain by competing with adenosine triphosphate (ATP), but not PI3K and PDK1. Aschantin inhibited epidermal growth factor (EGF)-induced full activation of Akt by phosphorylation at Ser473/Thr308, resulting in inhibition of the mTORC2/Akt and Akt/mTORC1/p70S6K signaling pathways and activation of GSK3β by abrogation of Akt-mediated GSK3β phosphorylation at Ser9. The activated GSK3β inhibited cell proliferation by c-Jun phosphorylation at Ser243, which facilitated destabilization and degradation of c-Jun through the ubiquitination-mediated proteasomal degradation pathway. Notably, aschantin treatment decreased c-Jun stability through inhibition of the mTORC2-Akt signaling pathway, which suppressed EGF-induced anchorage-independent cell transformation in non-malignant JB6 Cl41 and HaCaT cells and colony growth of LNCaP and MIAPaCa-2 cancer cells in soft agar. Altogether, the results show that aschantin targets mTOR kinase and destabilizes c-Jun, which implicate aschantin as a potential chemopreventive or therapeutic agent.

Topics: Animals; Benzodioxoles; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic; Epidermal Growth Factor; Gene Expression Regulation, Neoplastic; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Humans; Lignans; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Mice; Multiprotein Complexes; Phosphorylation; Proto-Oncogene Proteins c-akt; Signal Transduction; TOR Serine-Threonine Kinases

Mitogen-activated protein kinases play a key role in cell proliferation, cell cycle progression and cell transformation, and activated Ras/extracellular signal-regulated kinases (ERKs)/ribosomal S6 kinase 2 (RSK2) signaling pathways have been widely identified in many solid tumors. In this study, we found that magnolin, a compound found in the Magnolia species, directly targeted and inhibited ERK1 and ERK2 kinase activities with IC50 values of 87 and 16.5 nM by competing with adenosine triphosphate in an active pocket. Further, we demonstrated that magnolin inhibited epidermal growth factor (EGF)-induced p90RSKs phosphorylation at Thr359/Ser363, but not ERKs phosphorylation at Thr202/Tyr204, and this resulted in inhibition of cell proliferation by suppression of the G1/S cell cycle transition. Additionally, p38 kinases, Jun N-terminal kinases and Akts were not involved in the magnolin-mediated inhibitory signaling. Magnolin targeting of ERK1 and 2 activities suppressed the phosphorylation of RSK2 and downstream target proteins including ATF1 and c-Jun and AP-1, a dimer of Jun/Fos, and the transactivation activities of ATF1 and AP-1. Notably, ERKs inhibition by magnolin suppressed EGF-induced anchorage-independent cell transformation and colony growth of Ras(G12V)-harboring A549 human lung cancer cells and NIH3T3 cells stably expressing Ras(G12V) in soft agar. Taken together, these results demonstrated that magnolin might be a naturally occurring chemoprevention and therapeutic agent capable of inhibiting cell proliferation and transformation by targeting ERK1 and ERK2.

Topics: Animals; Blotting, Western; Cell Cycle; Cell Transformation, Neoplastic; Cells, Cultured; Drugs, Chinese Herbal; Embryo, Mammalian; Extracellular Signal-Regulated MAP Kinases; Fibroblasts; Fluorescent Antibody Technique; Humans; Immunoenzyme Techniques; Lignans; Mice; Mice, Knockout; NIH 3T3 Cells; ras Proteins; Ribosomal Protein S6 Kinases, 90-kDa; Signal Transduction

The aim of this study is to investigate whether HJC, isolated from Justicia procumbens for the first time, can suppress the proliferation and induce apoptosis of human leukemia K562 cells and finally clarify its related mechanism. The chemical structure of HJC was validated by LC-ESI-MS/MS, cytotoxicity was assayed using MTT, and apoptosis was investigated by flow cytometry. These assays indicated that HJC remarkably inhibited the growth in K562 cells by decreasing cell proliferation, reducing the SOD activity, enhancing ROS levels and inducing apoptosis. Activation of caspase-3 indicated that HJC may be inducing intrinsic and extrinsic apoptosis pathways and that HJC-induced apoptosis was caspase-dependent. This study suggests that HJC is a high-potency anti-tumor agent, and it induces apoptosis through a caspase-dependent pathway in human leukemia K562 cells. It also presents a potential alternative to leukemia therapy.

Topics: Acanthaceae; Antineoplastic Agents, Phytogenic; Apoptosis; Benzodioxoles; Caspase 3; Cell Transformation, Neoplastic; Depression, Chemical; Enzyme Activation; HL-60 Cells; Humans; K562 Cells; Leukemia; Lignans; Phytotherapy; Reactive Oxygen Species; Superoxide Dismutase

There is evidence that a mammalian lignan, enterolactone (ENL), decreases the proliferation rate of prostate cancer cells, although previous studies have used concentrations difficult to achieve through dietary modification. We have therefore investigated the anti-proliferative effects of ENL in an in vitro model of prostate tumourigenesis at concentrations reported to occur in a range of male populations.. The effects of 0.1 and 1 μM ENL on three markers of viability and proliferation (metabolic activity, growth kinetics, and cell cycle progression) were assessed in the RWPE-1, WPE1-NA22, WPE1-NB14, WPE1-NB11, WPE1-NB26, LNCaP, and PC-3 cell lines over 72 h. Based on these data, we quantified the expression levels of 12 genes involved in the control of DNA replication initiation using TaqMan real-time PCR in the WPE1-NA22, WPE1-NB14, WPE1-NB11, and WPE1-NB26 cell lines. ENL significantly inhibited the abnormal proliferation of the WPE1-NB14 and WPE1-NB11 cell lines and appears to be a consequence of decreased expression of abnormal chromatin licensing and DNA replication factor 1.. In contrast to previous studies, concentrations of ENL that are reported after dietary intervention restrict the proliferation of early-stage tumourigenic prostate cell lines by inhibiting the abnormal formation of complexes that initiate DNA replication.

Topics: 4-Butyrolactone; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cell Transformation, Neoplastic; DNA Replication; Humans; Lignans; Male; Mitochondria; Prostatic Neoplasms; Real-Time Polymerase Chain Reaction

Honokiol, a small-molecule polyphenol isolated from magnolia species, is widely known for its therapeutic potential as an antiinflammatory, antithrombosis, and antioxidant agent, and more recently, for its protective function in the pathogenesis of carcinogenesis. In the present study, we sought to examine the effectiveness of honokiol in inhibiting migration and invasion of breast cancer cells and to elucidate the underlying molecular mechanisms.. Clonogenicity and three-dimensional colony-formation assays were used to examine breast cancer cell growth with honokiol treatment. The effect of honokiol on invasion and migration of breast cancer cells was evaluated by using Matrigel invasion, scratch-migration, spheroid-migration, and electric cell-substrate impedance sensing (ECIS)-based migration assays. Western blot and immunofluorescence analysis were used to examine activation of the liver kinase B1 (LKB1)-AMP-activated protein kinase (AMPK) axis. Isogenic LKB1-knockdown breast cancer cell line pairs were developed. Functional importance of AMPK activation and LKB1 overexpression in the biologic effects of honokiol was examined by using AMPK-null and AMPK-wild type (WT) immortalized mouse embryonic fibroblasts (MEFs) and isogenic LKB1-knockdown cell line pairs. Finally, mouse xenografts, immunohistochemical and Western blot analysis of tumors were used.. Analysis of the underlying molecular mechanisms revealed that honokiol treatment increases AMP-activated protein kinase (AMPK) phosphorylation and activity, as evidenced by increased phosphorylation of the downstream target of AMPK, acetyl-coenzyme A carboxylase (ACC) and inhibition of phosphorylation of p70S6kinase (pS6K) and eukaryotic translation initiation factor 4E binding protein 1 (4EBP1). By using AMPK-null and AMPK-WT (MEFs), we found that AMPK is required for honokiol-mediated modulation of pACC-pS6K. Intriguingly, we discovered that honokiol treatment increased the expression and cytoplasmic translocation of tumor-suppressor LKB1 in breast cancer cells. LKB1 knockdown inhibited honokiol-mediated activation of AMPK and, more important, inhibition of migration and invasion of breast cancer cells. Furthermore, honokiol treatment resulted in inhibition of breast tumorigenesis in vivo. Analysis of tumors showed significant increases in the levels of cytoplasmic LKB1 and phospho-AMPK in honokiol-treated tumors.. Taken together, these data provide the first in vitro and in vivo evidence of the integral role of the LKB1-AMPK axis in honokiol-mediated inhibition of the invasion and migration of breast cancer cells. In conclusion, honokiol treatment could potentially be a rational therapeutic strategy for breast carcinoma.

Topics: Adaptor Proteins, Signal Transducing; AMP-Activated Protein Kinase Kinases; AMP-Activated Protein Kinases; Animals; Antineoplastic Agents; Biphenyl Compounds; Breast Neoplasms; Cell Cycle Proteins; Cell Line, Tumor; Cell Movement; Cell Transformation, Neoplastic; Enzyme Activation; Female; Gene Expression; Humans; Lignans; Mice; Mice, Nude; Neoplasm Invasiveness; Phosphoproteins; Phosphorylation; Protein Processing, Post-Translational; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-akt; Ribosomal Protein S6 Kinases; Spheroids, Cellular; TOR Serine-Threonine Kinases; Tumor Burden; Xenograft Model Antitumor Assays

One way to link chronic inflammation with cancer is through the intrinsic inflammatory pathway, in which genetic alterations that induce malignant transformation also produce a cancer-promoting, inflammatory microenvironment. Signal transducer and activator of transcription 3 (STAT3) contributes to the intrinsic inflammatory pathway in Barrett's esophagus. In human tumors, honokiol (a polyphenol in herbal teas) has growth-inhibitory and proapoptotic effects associated with suppressed activation of STAT3. We used human Barrett's epithelial and esophageal adenocarcinoma cell lines to determine effects of honokiol on cell number, necrosis, apoptosis, and anchorage-independent growth and to explore STAT3's role in those effects. We determined Ras activity and expression of phosphorylated ERK1/2, phosphorylated Akt, and phosphorylated STAT3 in the presence or absence of honokiol. Cells were infected with constitutively active Stat3-C to assess effects of honokiol-induced STAT3 inhibition on apoptosis. Honokiol decreased cell number and increased necrosis and apoptosis in transformed Barrett's cells, but not in nontransformed cells. In adenocarcinoma cells, honokiol also increased necrosis and apoptosis and decreased anchorage-independent growth. Within 30 min of honokiol treatment, transformed Barrett's cells decreased expression of phosphorylated STAT3; decreases in Ras activity and phosphorylated ERK1/2 expression were detected at 24 h. Infection with Stat3-C significantly reduced apoptosis after honokiol treatment. Honokiol causes necrosis and apoptosis in transformed Barrett's and esophageal adenocarcinoma cells, but not in nontransformed Barrett's cells, and the proapoptotic effects of honokiol are mediated by its inhibition of STAT3 signaling. These findings suggest a potential role for targeting the intrinsic inflammatory pathways as a therapeutic strategy to prevent Barrett's carcinogenesis.

Topics: Adenocarcinoma; Antineoplastic Agents, Phytogenic; Apoptosis; Barrett Esophagus; Biphenyl Compounds; Cell Line, Tumor; Cell Transformation, Neoplastic; Esophageal Neoplasms; Humans; Lignans; Signal Transduction; STAT3 Transcription Factor

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

To develop newer and more effective chemopreventive agents for skin cancer, we assessed the effect of honokiol, a phytochemical from the Magnolia plant, on ultraviolet (UV) radiation-induced skin tumorigenesis using the SKH-1 hairless mouse model. Topical treatment of mice with honokiol in a hydrophilic cream-based topical formulation before or after UVB (180 mJ/cm(2)) irradiation resulted in a significant protection against photocarcinogenesis in terms of tumor multiplicity (28-60%, P < 0.05 to <0.001) and tumor volume per tumor-bearing mouse (33-80%, P < 0.05 to 0.001, n = 20). Honokiol also inhibited and delayed the malignant progression of papillomas to carcinomas. To investigate the in vivo molecular targets of honokiol efficacy, tumors and tumor-uninvolved skin samples from the tumor-bearing mice were analyzed for inflammatory mediators, cell cycle regulators and survival signals using immunostaining, western blotting and enzyme-linked immunosorbent assay. Treatment with honokiol significantly inhibited UVB-induced expression of cyclooxygenase-2, prostaglandin E(2) (P < 0.001), proliferating cell nuclear antigen and proinflammatory cytokines, such as tumor necrosis factor-α (P < 0.001), interleukin (IL)-1β (P < 0.01) and IL-6 (P < 0.001) in the skin as well as in skin tumors. Western blot analysis revealed that honokiol: (i) inhibited the levels of cyclins D1, D2 and E and associated cyclin-dependent kinases (CDKs)2, CDK4 and CDK6, (ii) upregulated Cip/p21 and Kip/p27 and (iii) inhibited the levels of phosphatidylinositol 3-kinase and the phosphorylation of Akt at Ser(473) in UVB-induced skin tumors. Together, our results indicate that honokiol holds promise for the prevention of UVB-induced skin cancer by targeting inflammatory mediators, cell cycle regulators and cell survival signals in UVB-exposed skin.

Topics: Administration, Topical; Animals; Anti-Infective Agents; Biphenyl Compounds; Blotting, Western; Cell Cycle; Cell Transformation, Neoplastic; Cyclin-Dependent Kinases; Cyclooxygenase 2; Drugs, Chinese Herbal; Enzyme-Linked Immunosorbent Assay; Female; Immunoenzyme Techniques; Inflammation Mediators; Lignans; Magnolia; Mice; Mice, Hairless; Papilloma; Phosphatidylinositol 3-Kinases; Phosphorylation; Proto-Oncogene Proteins c-akt; Signal Transduction; Skin Neoplasms; Ultraviolet Rays

Depending on their structure, some polyphenols (e.g. flavonoids) abundantly found in plant-derived beverages such as green tea can efficiently inhibit tyrosine kinase and serine/threonine kinase activities. Extra-virgin olive oil (EVOO - the juice of the olive obtained solely by pressing and consumed without any further refining process) is unique among other vegetable oils because of the high level of naturally occurring phenolic compounds. We explored the ability of EVOO polyphenols to modulate HER2 tyrosine kinase receptor-induced in vitro transformed phenotype in human breast epithelial cells. Using MCF10A normal breast epithelial cells retrovirally engineered to overexpress the wild-type sequence of human HER2, we further determined the relationship between chemical structures of EVOO-derived phenolics and their inhibitory activities on the tyrosine kinase activity of the HER2 oncoprotein. When the activation (phosphorylation) status of HER2 was semi-quantitatively measured the secoiridoids blocked HER2 signaling by rapidly reducing the activation status of the 1248 tyrosine residue (Y1248), the main autophosphorylation site of HER2. EVOO-derived single phenols tyrosol and hydroxytyrosol and the phenolic acid elenolic acid failed to significantly decrease HER2 tyrosine kinase activity. The anti-HER2 tyrosine kinase activity IC50 values were up to 5-times lower in the presence of EVOO-derived lignans and secoiridoids than in the presence of EVOO-derived single phenols and phenolic acids. EVOO polyphenols induced strong tumoricidal effects by selectively triggering high levels of apoptotic cell death in HER2-positive MCF10A/HER2 cells but not in MCF10A/pBABE matched control cells. EVOO lignans and secoiridoids prevented HER2-induced in vitro transformed phenotype as they inhibited colony formation of MCF10A/HER2 cells in soft-agar. Our current findings not only molecularly support recent epidemiological evidence revealing that EVOO-related anti-breast cancer effects primarily affect the occurrence of breast tumors over-expressing the type I receptor tyrosine kinase HER2 but further suggest that the stereochemistry of EVOO-derived lignans and secoiridoids might provide an excellent and safe platform for the design of new HER2 targeted anti-breast cancer drugs.

Topics: Apoptosis; Breast; Cell Transformation, Neoplastic; Cells, Cultured; Colony-Forming Units Assay; Enzyme-Linked Immunosorbent Assay; Flavonoids; Humans; Iridoids; Lignans; Olive Oil; Phenols; Plant Oils; Polyphenols; Protein-Tyrosine Kinases; Receptor, ErbB-2; Retroviridae

Two new compounds, an ent-isopimarane-type diterpene, 3alpha,12alpha-dihydroxy-ent-8(14),15-isopimaradien-18-al (1), and a dihydrobenzo[b]furan neolignan, (-)-trans-9-acetyl-4,9'-di-O-methyl-3'-de-O-methyldehydrodiconiferyl alcohol (2), along with five known compounds, 7,7'-dihydroxy-6,8'-bicoumarin (bicoumol) (3), 3,4-dimethoxycinnamaldehyde (4), 6-hydroxy-7-methoxycoumarin (isoscopoletin), N-butylaniline, and vanillin, have been isolated from an ethyl acetate-soluble extract of the stem wood of Euphorbiaquinquecostata. The structures of compounds 1 and 2 were elucidated on the basis of spectroscopic data interpretation, and single-crystal X-ray diffraction analysis was used to confirm the structure and relative stereochemistry of 1. The absolute configuration of 1 was established by a convenient Mosher ester procedure in which the sample was treated with MTPA chlorides in deuterated pyridine directly in NMR tubes. All isolates were evaluated for the induction of quinone reductase in Hepa1c1c7 hepatoma cells and for the inhibition of the transformation of murine epidermal JB6 cells.

Topics: Animals; Carcinoma, Hepatocellular; Cell Transformation, Neoplastic; Crystallography, X-Ray; Diterpenes; Epidermis; Euphorbia; Furans; Inhibitory Concentration 50; Lignans; Mice; Molecular Structure; Plant Stems; Plants, Medicinal; Quinone Reductases; Stereoisomerism; Tanzania; Tumor Cells, Cultured; Wood

Two lignans, asarinin (6) and xanthoxylol (7), were isolated from the radix of Asiasarum heterotropoides var. mandshuricum, which consist of a kampo prescription, Shouseiryu-to, as inhibitors of Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA). These lignans also exhibited remarkable inhibitory effects on a two-stage carcinogenesis test of mouse skin and pulmonary tumors. Furthermore, it was confirmed that these hydrophobic lignans dissolved in the water decoction of Shouseiryu-to, and these lignans might be among the active constituents of this kampo prescription in terms of its anti-tumor-promoting activity.

Topics: Animals; Anticarcinogenic Agents; Antigens, Viral; Cell Line; Cell Transformation, Neoplastic; Dioxoles; Female; Furans; Lignans; Lung Neoplasms; Mice; Mice, Inbred ICR; Phenols; Skin Neoplasms; Tetradecanoylphorbol Acetate