lignans and Lung-Neoplasms

lignans has been researched along with Lung-Neoplasms* in 79 studies

Reviews

3 review(s) available for lignans and Lung-Neoplasms

ArticleYear
Use of honokiol in lung cancer therapy: a mini review of its pharmacological mechanism.
    Journal of Asian natural products research, 2023, Volume: 25, Issue:11

    Honokiol (3',5-di-(2-propenyl)-1,1'-biphenyl-2,2'-diol) is a biologically active natural product derived from

    Topics: Apoptosis; Biphenyl Compounds; Cell Line, Tumor; Lignans; Lung Neoplasms; Signal Transduction

2023
Hyaluronic acid-modified liposomal honokiol nanocarrier: Enhance anti-metastasis and antitumor efficacy against breast cancer.
    Carbohydrate polymers, 2020, May-01, Volume: 235

    In an effort to enhance antitumor and anti-metastasis of breast cancer, honokiol (HNK) was encapsulated into hyaluronic acid (HA) modified cationic liposomes (Lip). The prepared HA-Lip-HNK had a spherical shape with a narrow size distribution. The enhanced antitumor efficacy of HA-Lip-HNK was investigated in 4T1 cells in vitro, wherein flow cytometry and confocal microscopy analysis revealed its HA/CD44-mediated greater cellular internalization. As anticipate, the significant cytotoxicity of the HA-Lip-HNK was also observed in 4T1 tumor spheroids. Furthermore, the superior prevention of tumor metastasis by HA-Lip-HNK was verified by in vitro anti-invasion, wound healing and anti-migration assessments, and in vivo bioluminescence imaging in pulmonary metastasis model. Finally, compared with unmodified liposomes, the HA-Lip-HNK exhibited higher tumor accumulation, and achieved a tumor growth inhibition rate of 59.5 %. As a result, the HA-Lip-HNK may serve as a promising tumor-targeted drug delivery strategy for the efficient therapy of metastatic breast cancer.

    Topics: Animals; Antineoplastic Agents; Apoptosis; Biphenyl Compounds; Breast Neoplasms; Cell Movement; Cell Proliferation; Disease Models, Animal; Drug Carriers; Drug Delivery Systems; Drug Screening Assays, Antitumor; Hyaluronic Acid; Injections, Intravenous; Lignans; Lung Neoplasms; Mice; Nanoparticles; Particle Size; Surface Properties

2020
Controlling the master-upstream regulation of the tumor suppressor LKB1.
    Oncogene, 2018, Volume: 37, Issue:23

    The tumor suppressor LKB1 is an essential serine/threonine kinase, which regulates various cellular processes such as cell metabolism, cell proliferation, cell polarity, and cell migration. Germline mutations in the STK11 gene (encoding LKB1) are the cause of the Peutz-Jeghers syndrome, which is characterized by benign polyps in the intestine and a higher risk for the patients to develop intestinal and extraintestinal tumors. Moreover, mutations and misregulation of LKB1 have been reported to occur in most types of tumors and are among the most common aberrations in lung cancer. LKB1 activates several downstream kinases of the AMPK family by direct phosphorylation in the T-loop. In particular the activation of AMPK upon energetic stress has been intensively analyzed in various diseases, including cancer to induce a metabolic switch from anabolism towards catabolism to regulate energy homeostasis and cell survival. In contrast, the regulation of LKB1 itself has long been only poorly understood. Only in the last years, several proteins and posttranslational modifications of LKB1 have been analyzed to control its localization, activity and recognition of substrates. Here, we summarize the current knowledge about the upstream regulation of LKB1, which is important for the understanding of the pathogenesis of many types of tumors.

    Topics: AMP-Activated Protein Kinase Kinases; AMP-Activated Protein Kinases; Biphenyl Compounds; Calcium-Binding Proteins; Gene Expression Regulation, Neoplastic; Genes, Tumor Suppressor; Humans; Lignans; Lung Neoplasms; Lysosomes; Mutation; Peutz-Jeghers Syndrome; Phosphorylation; Protein Serine-Threonine Kinases; Sumoylation; Ubiquitination

2018

Trials

1 trial(s) available for lignans and Lung-Neoplasms

ArticleYear
Schisandrin B attenuates cancer invasion and metastasis via inhibiting epithelial-mesenchymal transition.
    PloS one, 2012, Volume: 7, Issue:7

    Metastasis is the major cause of cancer related death and targeting the process of metastasis has been proposed as a strategy to combat cancer. Therefore, to develop candidate drugs that target the process of metastasis is very important. In the preliminary studies, we found that schisandrin B (Sch B), a naturally-occurring dibenzocyclooctadiene lignan with very low toxicity, could suppress cancer metastasis.. BALB/c mice were inoculated subcutaneously or injected via tail vein with murine breast cancer 4T1 cells. Mice were divided into Sch B-treated and control groups. The primary tumor growth, local invasion, lung and bone metastasis, and survival time were monitored. Tumor biopsies were examined immuno- and histo-pathologically. The inhibitory activity of Sch B on TGF-β induced epithelial-mesenchymal transition (EMT) of 4T1 and primary human breast cancer cells was assayed.. Sch B significantly suppressed the spontaneous lung and bone metastasis of 4T1 cells inoculated s.c. without significant effect on primary tumor growth and significantly extended the survival time of these mice. Sch B did not inhibit lung metastasis of 4T1 cells that were injected via tail vein. Delayed start of treatment with Sch B in mice with pre-existing tumors did not reduce lung metastasis. These results suggested that Sch B acted at the step of local invasion. Histopathological evidences demonstrated that the primary tumors in Sch B group were significantly less locally invasive than control tumors. In vitro assays demonstrated that Sch B could inhibit TGF-β induced EMT of 4T1 cells and of primary human breast cancer cells.. Sch B significantly suppresses the lung and bone metastasis of 4T1 cells via inhibiting EMT, suggesting its potential application in targeting the process of cancer metastasis.

    Topics: Animals; Antineoplastic Agents; Bone Neoplasms; Breast Neoplasms; Cell Line, Tumor; Cyclooctanes; Epithelial-Mesenchymal Transition; Female; Humans; Lignans; Lung Neoplasms; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Invasiveness; Neoplasm Transplantation; Polycyclic Compounds; Transplantation, Heterologous; Xenograft Model Antitumor Assays

2012

Other Studies

75 other study(ies) available for lignans and Lung-Neoplasms

ArticleYear
Novel lignans from Zanthoxylum nitidum and antiproliferation activity of sesaminone in osimertinib-resistant non-small cell lung cancer cells.
    Bioorganic chemistry, 2023, Volume: 134

    Seven previously undescribed tetrahydrofuran lignans with different configurations and unusual isopentenyl substitutions, nitidumlignans D-J (corresponding to compounds 1, 2, 4, 6, 7, 9 and 10), along with 14 known lignans, were isolated from Zanthoxylum nitidum. Notably, compound 4 is an uncommon naturally occurring furan-core lignan derived from tetrahydrofuran aromatization. The antiproliferation activity of the isolated compounds (1-21) was determined in various human cancer cell lines. The structure-activity study revealed that the steric positioning and chirality of the lignans exert important effects on their activity and selectivity. In particular, compound 3 (sesaminone) exhibited potent antiproliferative activity in cancer cells, including acquired osimertinib-resistant non-small-cell lung cancer (HCC827-osi) cells. Compound 3 also inhibited colony formation and induced the apoptotic death of HCC827-osi cells. The underlying molecular mechanisms revealed that 3 downregulated the activation of the c-Met/JAK1/STAT3 and PI3K/AKT/mTOR signaling pathways in the HCC827-osi cells. In addition, the combination of 3 and osimertinib exhibited synergistic effects on the antiproliferative activity against HCC827-osi cells. Overall, these findings inform the structure elucidation of novel lignans isolated from Z. nitidum, and sesaminone was identified as a potential compound for exerting antiproliferative effects on osimertinib-resistant lung cancer cells.

    Topics: Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Furans; Humans; Lignans; Lung Neoplasms; Phosphatidylinositol 3-Kinases; Zanthoxylum

2023
Phytoestrogens and lung cancer risk: a nested case-control study in never-smoking Chinese women.
    The American journal of clinical nutrition, 2022, 03-04, Volume: 115, Issue:3

    Since several lines of evidence suggest that estrogens may be involved in lung carcinogenesis, it has been hypothesized that intake of phytoestrogens, similar in molecular structure to mammalian estrogens, may be associated with lung cancer development.. The aim was to prospectively evaluate the association between phytoestrogen exposure and lung cancer risk in never-smoking women.. We conducted a nested case-control study within a population-based prospective cohort study of women. A total of 478 incident lung cancer cases and their individually matched controls were identified among never-smoking women after a mean follow-up of 15.6 years. Habitual intake of and internal exposure to phytoestrogens were assessed by repeated dietary surveys and urinary biomarkers, respectively. ORs and 95% CIs for lung cancer were estimated in conditional logistic regression models.. After adjustment for potential confounders, a moderate intake of dietary isoflavones was inversely associated with lung cancer risk in never-smoking women, with the OR for the second quartile vs. the lowest quartile of intake being 0.52 (95% CI: 0.35, 0.76). Further increasing intake did not convey additional benefits, with ORs (95% CI) for the third and fourth quartiles of 0.53 (0.36, 0.78) and 0.47 (0.31, 0.72), respectively (P-overall < 0.001 and P-nonlinearity = 0.006). A similar association was seen when exposure to isoflavones was assessed by urinary biomarkers. ORs (95% CI) for the second, third, and fourth quartiles compared with the lowest quartile of urinary isoflavone excretion were 0.57 (0.39, 0.83), 0.64 (0.44, 0.92), and 0.60 (0.41, 0.86), respectively. The inverse association reached a plateau beyond the second quartile, with P-overall = 0.04 and P-nonlinearity = 0.15. Urinary excretion of gut-microbiota-derived metabolites of lignans was not related to lung cancer risk.. This study suggests that moderately increasing intake of isoflavone-rich foods is associated with lower risk of lung cancer in never-smoking women.

    Topics: Biomarkers; Case-Control Studies; China; Female; Humans; Isoflavones; Lignans; Lung; Lung Neoplasms; Phytoestrogens; Prospective Studies; Risk Factors; Smoking

2022
Schisandrin B suppresses osteosarcoma lung metastasis
    Oncology reports, 2022, Volume: 47, Issue:3

    Topics: Animals; Antineoplastic Agents; Apoptosis; beta Catenin; Bone Neoplasms; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cyclooctanes; Disease Models, Animal; Humans; Lignans; Lung Neoplasms; Mice; Osteosarcoma; Phosphatidylinositol 3-Kinases; Polycyclic Compounds; Proto-Oncogene Proteins c-akt; Wnt Signaling Pathway

2022
PCAT19 Regulates the Proliferation and Apoptosis of Lung Cancer Cells by Inhibiting miR-25-3p via Targeting the MAP2K4 Signal Axis.
    Disease markers, 2022, Volume: 2022

    Both PCAT19 and miR-25-3p have been reported in lung cancer studies, but whether there is a correlation between the two and whether they jointly regulate the progress of lung cancer have not been reported yet. Therefore, this study carried out a further in-depth research. The expression of PCAT19 was detected in lung cancer (LC) tissues and cells by quantitative real-time polymerase chain reaction (qRT-PCR). The effect of PCAT19 on tumor growth was detected in a tumor-bearing model of nude mice. PCAT19-transfected cells were treated with Honokiol and anisomycin. The effects of PCAT19 on proliferation, apoptosis, and cycle of LC cells were investigated by biomolecule experiments. The effects of PCAT19 on the expressions of mitogen-activated protein kinase- (MAPK-) related proteins were evaluated by western blotting. The expression of PCAT19 was decreased in LC tissues and related to patient survival, tumor size, and pathology. In addition, upregulation of PCAT19 hindered LC cell proliferation, miR-25-3p expression, and the activation of extracellular regulated protein kinases (ERK) 1/2, p38, and c-Jun N-terminal kinase (JNK), while facilitating LC cell apoptosis. Furthermore, upregulation of PCAT19 reversed the effects of Honokiol and anisomycin on promoting cell proliferation and inhibiting cell apoptosis. Collectively, our findings show that upregulated PCAT19 suppresses proliferation yet promotes the apoptosis of LC cells through modulating the miR-25-3p/MAP2K4 signaling axis.

    Topics: Animals; Anisomycin; Apoptosis; Biphenyl Compounds; Cell Line, Tumor; Cell Movement; Cell Proliferation; Gene Expression Regulation, Neoplastic; Humans; Lignans; Lung Neoplasms; MAP Kinase Kinase 4; Mice; Mice, Nude; MicroRNAs; RNA, Long Noncoding

2022
Magnolol Induces Apoptosis Through Extrinsic/intrinsic Pathways and Attenuates NF-κB/STAT3 Signaling in Non-small-cell Lung Cancer Cells.
    Anticancer research, 2022, Volume: 42, Issue:8

    Non-small-cell lung cancer (NSCLC) is the most common type of lung cancer worldwide, and treatment outcomes are still poor. Magnolol, a hydroxylated biphenyl isolated from Magnolia officinalis, was found to be effective against hepatocellular carcinoma via inactivating nuclear-factor-kappa B (NF-B) signaling. However, whether magnolol targets not only NF-B but also other factors in NSCLC and may contribute to the suppression of tumor progression is unclear.. Cell viability, flow cytometry, and western blotting assays were used to identify the mechanism of magnolol action in human lung adenocarcinoma cell lines A549 and CL1-5-F4.. Our results indicated that magnolol induced cytotoxicity through extrinsic/intrinsic apoptosis signaling and suppressed phosphorylation of signal transducer and activator of transcription 3 (STAT3)/NF-B and expression of their downstream proteins.. Magnolol not only induced extrinsic and intrinsic apoptosis signaling but also inactivated STAT3/NF-B and attenuated their signaling of epithelial-mesenchymal transition and metastasis-related protein expression in NSCLC.

    Topics: Apoptosis; Biphenyl Compounds; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Humans; Lignans; Lung Neoplasms; NF-kappa B; STAT3 Transcription Factor

2022
A multidimensional biosensor system to guide LUAD individualized treatment.
    Journal of materials chemistry. B, 2021, 10-06, Volume: 9, Issue:38

    Lung cancer, mainly non-small cell lung cancer (NSCLC), has been a global health problem, leading to maximum cancer death. Across adenocarcinoma patients, significant genetic and phenotypic heterogeneity was identified as responsible for individual cancer drug resistance, driving an urgent need for individualized treatment. High expectation has been set on individualized treatment for better responses and extended survival. There are pressing needs for and significant advantages of testing dosages and drugs directly on patient-specific cancer cells for preclinical drug testing and personalized drug selection. Monitoring the drug response based on patient-derived cells (PDCs) is a step toward effective drug development and individualized treatment. Despite the dependence on optical labels, optical equipment, and other complex manual operation, we here report a multidimensional biosensor system to guide adenocarcinoma individualized treatment by integrating 2D and 3D PDC models and cellular impedance biosensors. The cellular impedance biosensors were applied to quantitate drug response in 2D and 3D environments. Compared with 2D plate culture, 3D cultured cells were found to show higher resistance to anti-cancer drugs. Cell-cell, cell-ECM, and mechanical interactions in the 3D environment led to stronger drug resistance. The

    Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Biosensing Techniques; Biphenyl Compounds; Cell Culture Techniques; Cell Movement; Cell Proliferation; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Humans; Lignans; Lung Neoplasms; Male; Mice; Mice, Nude; Piperidines; Precision Medicine; Quinazolines; Tumor Cells, Cultured

2021
Enhanced antitumour efficacy of functionalized doxorubicin plus schisandrin B co-delivery liposomes via inhibiting epithelial-mesenchymal transition.
    Journal of liposome research, 2021, Volume: 31, Issue:2

    Non-small cell lung cancer (NSCLC) is a malignant cancer characterized by easy invasion, metastasis and poor prognosis, so that conventional chemotherapy cannot inhibit its invasion and metastasis. Doxorubicin (DOX), as a broad-spectrum antitumour drug, cannot be widely used in clinic because of its poor targeting, short half-life, strong toxicity and side effects. Therefore, the aim of our study is to construct a kind of PFV modified DOX plus schisandrin B liposomes to solve the above problems, and to explore its potential mechanism of inhibiting NSCLC invasion and metastasis. The antitumour efficiency of the targeting liposomes was carried out by cytotoxicity, heating ablation, wound healing, transwell, vasculogenic mimicry channels formation and metastasis-related protein tests

    Topics: Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cyclooctanes; Doxorubicin; Epithelial-Mesenchymal Transition; Humans; Lignans; Liposomes; Lung Neoplasms; Polycyclic Compounds; Vascular Endothelial Growth Factor A

2021
Synergistic killing effect of paclitaxel and honokiol in non-small cell lung cancer cells through paraptosis induction.
    Cellular oncology (Dordrecht), 2021, Volume: 44, Issue:1

    Paclitaxel is an anticancer drug for the treatment of non-small cell lung cancer (NSCLC). However, drug-resistance remains a major problem. Honokiol is a natural component which has been found to exhibit anti-tumor activity. Paclitaxel and honokiol have been reported to be able to induce paraptosis. The aim of this study was to investigate whether honokiol can reverse paclitaxel resistance by inducing paraptosis in NSCLC cells.. NSCLC cell lines H1650 (paclitaxel-sensitive), H1299 and H1650/PTX (intrinsic and acquired paclitaxel-resistant, respectively) were used to assess the cytotoxic effects of paclitaxel and honokiol. Light and transmission electron microscopy were performed to detect cytoplasmic vacuolation. In vitro cell viability and clonogenic survival assays, as well as in vivo xenograft assays were conducted to test synergistic killing effects of paclitaxel and honokiol on NSCLC cells. Western blotting, flow cytometry and immunofluorescence were performed to evaluate paraptosis-regulating mechanisms.. Combination of honokiol and paclitaxel may represent a novel strategy for the treatment of paclitaxel-resistant NSCLC.

    Topics: Animals; Apoptosis; Biphenyl Compounds; Calcium; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Drug Synergism; Endoplasmic Reticulum Stress; Humans; Lignans; Lung Neoplasms; Male; Mice, Inbred BALB C; Mice, Nude; Microtubule-Associated Proteins; Mitochondria; Paclitaxel; Proteasome Endopeptidase Complex; Ubiquitin-Activating Enzymes; Vacuoles

2021
α-Conidendrin inhibits the expression of intercellular adhesion molecule-1 induced by tumor necrosis factor-α in human lung adenocarcinoma A549 cells.
    European journal of pharmacology, 2021, Jan-05, Volume: 890

    α-Conidendrin is a lignan isolated from Taxus wallichiana and other species. In the present study, we demonstrated that α-conidendrin inhibited the cell-surface expression of intercellular adhesion molecule-1 (ICAM-1) induced by tumor necrosis factor-α (TNF-α) at an IC

    Topics: A549 Cells; Adenocarcinoma of Lung; Cell Survival; Chromans; Cyclooxygenase 2; E-Selectin; Human Umbilical Vein Endothelial Cells; Humans; Intercellular Adhesion Molecule-1; Lignans; Lung Neoplasms; Promoter Regions, Genetic; Signal Transduction; Tetrahydronaphthalenes; Transcription Factor RelA; Tumor Necrosis Factor-alpha

2021
Synthesis and evaluation of new compounds bearing 3-(4-aminopiperidin-1-yl)methyl magnolol scaffold as anticancer agents for the treatment of non-small cell lung cancer via targeting autophagy.
    European journal of medicinal chemistry, 2021, Jan-01, Volume: 209

    Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Autophagy; Biphenyl Compounds; Carcinoma, Non-Small-Cell Lung; Cell Cycle Checkpoints; Cell Line, Tumor; Drug Screening Assays, Antitumor; Female; Humans; Lignans; Lung Neoplasms; Magnolia; Mice, Inbred BALB C; Plant Extracts; Solubility; Structure-Activity Relationship

2021
Augment the efficacy of eradicating metastatic lesions and tumor proliferation in breast cancer by honokiol-loaded pH-sensitive targeted lipid nanoparticles.
    Colloids and surfaces. B, Biointerfaces, 2021, Volume: 207

    Topics: Animals; Antineoplastic Agents; Biphenyl Compounds; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Female; Humans; Hydrogen-Ion Concentration; Lignans; Lipids; Lung Neoplasms; Mice; Mice, Inbred BALB C; Nanoparticles

2021
Sesamin suppresses NSCLC cell proliferation and induces apoptosis via Akt/p53 pathway.
    Toxicology and applied pharmacology, 2020, 01-15, Volume: 387

    Non-small cell lung cancer (NSCLC) is the most common type of lung cancer with a disappointing prognosis. The aim of this study was to investigate the anticancer effect of sesamin and the underlying mechanism. The MTT assay was used to detect the proliferation of NSCLC cells. The cell cycle and apoptosis were analyzed by flow cytometry. The protein levels of Akt, p-Akt (Ser473), p53, cyclin D1, CDK2, MDM2, p-MDM2 (Ser166) were detected by western blotting. The expression of p-Akt (Ser473), p53 and Ki67 in vivo was analyzed by IHC. Histopathologic analyses of major organs (heart, liver, spleen, lung and kidney) were performed by H&E staining. The results show that sesamin suppressed cell proliferation and induced apoptosis of NSCLC cells (A549 and H1792) in a dose-dependent manner. Treatment with sesamin caused cell cycle arrest at G1 phase and inhibited cyclin D1 and CDK2 expression. In addition, sesamin inhibited Akt activity and upregulated p53 expression both in vivo and in vitro. When Akt and p53 were suppressed by LY294002 and PFTα, respectively, sesamin exerted no additional effects. The in vivo results mostly matched the in vitro findings. Specifically, sesamin exerted little damage to major organs. Taken together, this study demonstrates that sesamin suppresses NSCLC cell proliferation by induction of G1 phase cell cycle arrest and apoptosis via Akt/p53 pathway. Therefore, sesamin may be a promising adjuvant treatment for NSCLC therapy.

    Topics: Animals; Apoptosis; Benzothiazoles; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Chromones; Dioxoles; Female; G1 Phase Cell Cycle Checkpoints; Humans; Lignans; Lung Neoplasms; Mice; Morpholines; Proto-Oncogene Proteins c-akt; Signal Transduction; Toluene; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays

2020
A cocktail of betulinic acid, parthenolide, honokiol and ginsenoside Rh2 in liposome systems for lung cancer treatment.
    Nanomedicine (London, England), 2020, Volume: 15, Issue:1

    Topics: A549 Cells; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Betulinic Acid; Biphenyl Compounds; Cell Proliferation; Cisplatin; Ginsenosides; Humans; Lignans; Liposomes; Lung Neoplasms; Mice; Neoplasm Invasiveness; Pentacyclic Triterpenes; Sesquiterpenes; Triterpenes; Xenograft Model Antitumor Assays

2020
Overcoming acquired resistance of EGFR-mutant NSCLC cells to the third generation EGFR inhibitor, osimertinib, with the natural product honokiol.
    Molecular oncology, 2020, Volume: 14, Issue:4

    The development of acquired resistance to osimertinib (Osim) (AZD9291 or TAGRISSO

    Topics: Acrylamides; Aniline Compounds; Animals; Antineoplastic Agents, Phytogenic; Biphenyl Compounds; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Drug Resistance, Neoplasm; Drug Synergism; ErbB Receptors; Humans; Lignans; Lung Neoplasms; Mice, Nude; Mutation; Protein Kinase Inhibitors

2020
Gomisin A ameliorates metastatic melanoma by inhibiting AMPK and ERK/JNK-mediated cell survival and metastatic phenotypes.
    Phytomedicine : international journal of phytotherapy and phytopharmacology, 2020, Volume: 68

    Gomisin A (G.A), a lignan compound extracted from the fruits of Schisandra chinensis, is known to exert anti-tumor effects on hepatocarcinoma and colorectal cancer cells. Suppression of proliferation and metastatic abilities of cancer cells are some effective cancer treatment methods.. The objective of this study is to investigate the effects of G.A on metastatic melanoma, and the mechanism by which it affects metastatic melanoma.. The anti-proliferative and anti-metastatic effects of G.A were observed in in vitro and in vivo.. WST assay and flow cytometry were conducted to investigate the effect of G.A on proliferation, cell cycle arrest, and apoptosis in metastatic melanoma cell lines. Migration and invasion abilities of G.A-treated melanoma cells were observed by wound healing and invasion assays.. G.A (25-100 μM) decreased the viability of melanoma cells by inducing cell cycle arrest and apoptosis. These anti-proliferative effects of G.A were found to be mediated by AMPK, ERK, and JNK activation. G.A (5-20 μM) decreased the migration and invasion of melanoma cells by suppressing epithelial-mesenchymal transition (EMT). Consequently, G.A (2-50 mg/kg) inhibited lung metastasis by suppressing EMT and inducing cell cycle arrest and apoptosis in melanoma cells.. These results conclude that G.A has the potential to reduce metastatic melanoma through its anti-proliferative and anti-metastatic effects.

    Topics: AMP-Activated Protein Kinases; Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Cyclooctanes; Dioxoles; Epithelial-Mesenchymal Transition; Extracellular Signal-Regulated MAP Kinases; Humans; Lignans; Lung Neoplasms; MAP Kinase Kinase 4; Melanoma; Mice, Inbred C57BL; Xenograft Model Antitumor Assays

2020
Arctigenin, a novel TMEM16A inhibitor for lung adenocarcinoma therapy.
    Pharmacological research, 2020, Volume: 155

    TMEM16A plays critical roles in physiological process and may serve as drug targets for diverse diseases. Recently, TMEM16A has started to be regarded as potential primary lung adenocarcinoma targets. Here, we identified that arctigenin, a natural compound, is a novel TMEM16A inhibitor, and it can suppress lung adenocarcinoma growth through inhibiting TMEM16A both in vitro and in vivo. Our data also showed that the IC

    Topics: Adenocarcinoma of Lung; Animals; Anoctamin-1; Antineoplastic Agents; Cell Line; Furans; Humans; Lignans; Lung Neoplasms; MAP Kinase Signaling System; Mice, Inbred BALB C

2020
Enhanced antitumor efficacy using epirubicin and schisandrin B co-delivery liposomes modified with PFV via inhibiting tumor metastasis.
    Drug development and industrial pharmacy, 2020, Volume: 46, Issue:4

    As a malignant tumor, breast cancer is very prone to metastasis. Chemotherapy is one of the most common means for treating breast cancer. However, due to the serious metastasis and the poor targeting effect of traditional chemotherapeutic drugs, even after years of efforts, the therapeutic effect is still unsatisfied. Therefore, in this study, we constructed a kind of PFV modified epirubicin plus schisandrin B liposomes to solve the above disadvantages.

    Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Cell Movement; Chick Embryo; Chorioallantoic Membrane; Cyclooctanes; Epirubicin; Female; Humans; Lignans; Liposomes; Lung Neoplasms; Mice; Neoplasm Invasiveness; Polycyclic Compounds; Xenograft Model Antitumor Assays

2020
Radiosensitization of NSCLC cells to X-rays and carbon ions by the CHK1/CHK2 inhibitor AZD7762, Honokiol and Tunicamycin.
    Radiation and environmental biophysics, 2020, Volume: 59, Issue:4

    Although radiotherapy, especially carbon-ion radiotherapy, is an effective treatment modality against non-small-cell lung cancer (NSCLC), studies using radiation combined with sensitizer for improving the efficacy of radiotherapy are still needed. In this work, we aimed to investigate in NSCLC A549 and H1299 cell lines the effects of different linear energy transfer (LET) radiations combined with diverse sensitizing compounds. Cells pretreated with the CHK1/CHK2 inhibitor AZD7762, Honokiol or Tunicamycin were irradiated with low-LET X-rays and high-LET carbon ions. Cell survival was assessed using the clonogenic cell survival assay. Cell cycle distribution and apoptosis were measured with flow cytometry, and DNA double strand break (DSB) and repair were detected using γ-H2AX immunofluorescence staining. Our results revealed that AZD7762, Honokiol and Tunicamycin demonstrated low cytotoxicity to NSCLC cells and a pronounced radiosensitizing effect on NSCLC cells exposed to carbon ions than X-rays. Unrepaired DNA DSB damages, the abrogation of G2/M arrest induced by irradiation, and finally apoptotic cell death were the main causes of the radiosensitizing effect. Thus, our data suggest that high-LET carbon ion combined with these compounds may be a potentially effective therapeutic strategy for locally advanced NSCLC.

    Topics: Antineoplastic Agents; Apoptosis; Biphenyl Compounds; Carbon; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Checkpoint Kinase 1; Checkpoint Kinase 2; DNA Breaks, Double-Stranded; G2 Phase Cell Cycle Checkpoints; Humans; Ions; Lignans; Linear Energy Transfer; Lung Neoplasms; Protein Kinase Inhibitors; Radiation Tolerance; Radiation-Sensitizing Agents; Thiophenes; Tunicamycin; Urea; X-Rays

2020
[Preparation and evaluation of schisandrin B-loaded F127 modified lipid-polymer nanoparticles for inhibition of breast cancer lung metastasis].
    Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica, 2020, Volume: 45, Issue:21

    In the current study, schisandrin B(SchB)-loaded F127 modified lipid-polymer hybrid nanoparticles(SchB-F-LPNs) were developed to improve the inhibition of breast cancer lung metastasis. Modified nanoprecipitation method was used to prepare SchB-F-LPNs. The nanoparticles were spherical in shape with shell-core structure by TEM observation. SchB-F-LPNs showed a mean particle size of(234.60±6.11) nm with zeta potential of(-5.88±0.49) mV. XRD results indicated that SchB existed in the nanoparticles in an amorphous state. The apparent permeability coefficient through porcine mucus of F-LPNs was 1.43-fold of that of LPNs as shown in the in vitro mucus penetration study. The pharmacokinetics study showed that the C_(max) of SchB was(369.06±146.94) μg·L~(-1),(1 121.34±91.65) μg·L~(-1) and(2 951.91±360.53) μg·L~(-1) respectively in SchB suspensions group, SchB-LPNs group and SchB-F-LPNs group after oral administration in rats. With SchB suspensions as the reference formulation, the relative bioavailability of SchB-F-LPNs was 568.60%. SchB-F-LPNs inhibited the morphological change during transforming growth factor-β1(TGF-β1)-induced epithelial-mesenchymal transition. In addition, SchB-F-LPNs significantly decreased the number of metastatic pulmonary nodules in 4 T1 tumor-bearing mice, suggesting that SchB-F-LPNs may inhibit the metastasis of breast cancer. These results reveal the promising potential of SchB-F-LPNs in treatment of breast cancer lung metastasis.

    Topics: Animals; Cyclooctanes; Lignans; Lipids; Lung Neoplasms; Mice; Nanoparticles; Polycyclic Compounds; Polyethylenes; Polymers; Polypropylenes; Rats; Swine

2020
Evaluation of the anti-cancer potential of Cedrus deodara total lignans by inducing apoptosis of A549 cells.
    BMC complementary and alternative medicine, 2019, Oct-24, Volume: 19, Issue:1

    Cedrus deodara (Roxb.) Loud (normally called as deodar), one out of four species in the genus Cedrus, exhibits widely biological activities. The Cedrus deodara total lignans from the pine needles (CTL) were extracted. The aim of the study was to investigate the anticancer potential of the CTL on A549 cell line.. We extracted the CTL by ethanol and assessed the cytotoxicity by CCK-8 method. Cell cycle and apoptosis were detected by a FACS Verse Calibur flow cytometry.

    Topics: A549 Cells; Antineoplastic Agents; Apoptosis; Cedrus; Cell Cycle; Cell Proliferation; Humans; Lignans; Lung Neoplasms; Plant Extracts; Plant Leaves

2019
Suppression of cyclooxygenase 2 increases chemosensitivity to sesamin through the Akt‑PI3K signaling pathway in lung cancer cells.
    International journal of molecular medicine, 2019, Volume: 43, Issue:1

    Safe, affordable and efficacious agents are urgently required for cancer prevention. Sesamin, a lipid‑soluble lignan from sesame (Sesamum indicum) displays anticancer activities through an unknown mechanism. In the present study, the anticancer activity of sesamin via cyclooxygenase 2 (COX2) was investigated in lung cancer. Quantitative polymerase chain reaction was performed to determine the mRNA expression levels of COX2 in cells, while western blot analysis was used to determine its protein expression levels. Cell proliferation was evaluated by Cell Counting Kit‑8 assay, while apoptosis and cell cycle analyses were conducted by flow cytometry. The results indicated that COX2 expression was upregulated in lung cancer cell lines compared with human normal lung epithelial cell line BEAS‑2B and sesamin was demonstrated to decrease the levels of COX2, inhibit the proliferation of lung cancer cells and promote their apoptosis in a concentration‑dependent manner. Furthermore, decreased COX2 expression potentiated sesamin‑induced apoptosis and G1‑phase arrest, which was correlated with the suppression of gene products associated with cell apoptosis (Bcl‑2 and Bax) and the cell cycle (cyclin E1). In addition, cotreatment with the COX2 inhibitor CAY10404 and sesamin downregulated the expression of downstream molecules of COX2 [including interleukin (IL)1β, IL6 and tumor necrosis factor α] compared with CAY10404 or sesamin alone. Furthermore, cotreatment with sesamin and CAY10404 markedly reduced the levels of phosphorylated protein kinase B (pAkt) and phosoinositide 3 kinase (PI3K) in three lung cancer cell lines. PI3K expression was observed to be under the control of COX2, possibly forming a negative feedback loop. In addition, PI3K depletion induced apoptosis and G1‑phase arrest in A549 cells. These results suggested that sesamin blocked the pAkt‑PI3K signaling pathway by downregulating the expression of COX2, therefore resulting in cell cycle arrest and increased apoptosis in vitro. In conclusion, inhibition of COX2 increased the sensitivity of lung cancer cells to sesamin by modulating pAkt‑PI3K signaling. These results may aid the development of more selective agents to overcome cancer.

    Topics: Apoptosis; Cell Cycle Checkpoints; Cell Death; Cell Line, Tumor; Cell Proliferation; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Dioxoles; Down-Regulation; Humans; Lignans; Lung Neoplasms; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction

2019
Honokiol induces endoplasmic reticulum stress-mediated apoptosis in human lung cancer cells.
    Life sciences, 2019, Mar-15, Volume: 221

    Honokiol is a hydroxylated biphenyl natural product and displays potent antitumor activity against several cancers including prostate cancer, melanoma, leukemia, and colorectal cancer. The present study was to investigate the in vitro activity of honokiol against A549 and 95-D human lung cancer cells.. A549 and 95-D cells were used with honokiol treatment. Cell viability was determined by CCK-8 assay. The cell migration and apoptosis were evaluated by wound healing assay and TUNEL staining method respectively. The expressions of ER-related proteins were analyzed by western blot and the CHOP siRNA was used to downregulate the CHOP expression.. The results demonstrated that treatment of A549 and 95-D cells with honokiol significantly reduced cell viability in a dose- and time-dependent manner. Furthermore, honokiol treatment decreased cell migration and enhanced cell apoptosis, which is accompanied by the upregulation of the expressions of ER stress-induced apoptotic signaling molecules such as GRP78, phosphorylated PERK, phosphorylated eIF2α, CHOP, Bcl-2, Bax, and cleaved Caspase 9. Honokiol treatment-induced increase of ER stress-related signaling molecules and apoptotic proteins in A549 and 95-D cells were reversed by CHOP siRNA.. Collectively, we conclude that ER stress may participate in the action of the anticancer activity of honokiol in A549 and 95-D cells and induction of ER stress-related apoptosis may represent a novel therapeutic intervention for human lung cancer.

    Topics: A549 Cells; Apoptosis; Biphenyl Compounds; Cell Line, Tumor; Cell Movement; Cell Survival; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Humans; Lignans; Lung Neoplasms; RNA, Small Interfering; Signal Transduction; Transcription Factor CHOP

2019
Formylated honokiol analogs showed antitumor activity against lung carcinoma.
    Anti-cancer drugs, 2019, Volume: 30, Issue:8

    Honokiol, a biphenolic neolignan with inappreciable toxicity isolated from Magnolia officinalis, has been reported to have antiangiogenic and antitumor properties in several tumor cell lines and tumor xenograft models. In our previous study, structural modification by chemical synthesis has been carried out to develop novel honokiol derivatives to improve antitumor activity and clarify the structure-activity relationship. Honokiol analogs, especially 3,5'-diformylated honokiol HK-(CHO)2, have been found to moderately block the newly grown segmental vessels from the dorsal aorta in the transgenic zebrafish-based assay, show antiangiogenic property, and exert medium cytotoxicity against two lung cell lines (Lewis lung carcinoma LL/2 cells and human non-small-cell lung cancer A549 cells). However, the in-vitro and in-vivo antitumor effects of formylated honokiol derivatives against lung carcinoma remained poorly understood. In the study, two formylated honokiol derivatives also showed potent antitumor effects in the Lewis lung carcinoma cells, K-ras-dirived lung adenocarcinoma mice, and a mouse lung tumor xenograft model, with HK-(CHO)2 being most efficacious. The potential mechanism was inhibiting cell proliferation and inducing apoptosis in lung cancer by the regulation of vascular endothelial growth factor A expression. These results further suggested that HK-(CHO)2 might be potential candidates for the treatment of lung carcinoma.

    Topics: Adenocarcinoma of Lung; Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Biphenyl Compounds; Carcinoma, Lewis Lung; Cell Proliferation; Female; Formates; Humans; Lignans; Lung Neoplasms; Mice; Mice, Inbred C57BL; Mice, Nude; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

2019
Epimagnolin targeting on an active pocket of mammalian target of rapamycin suppressed cell transformation and colony growth of lung cancer cells.
    Molecular carcinogenesis, 2019, Volume: 58, Issue:7

    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

2019
Schizandrin A enhances the efficacy of gefitinib by suppressing IKKβ/NF-κB signaling in non-small cell lung cancer.
    European journal of pharmacology, 2019, Jul-15, Volume: 855

    The emergence of resistance to EGF receptor (EGFR) inhibitor therapy is a significant challenge for patients with non-small cell lung cancer (NSCLC). During the past few years, a correlation between EGFR TKIs resistance and dysregulation of IKKβ/NF-κB signaling has been increasingly suggested. However, few studies have focused on the effects of combining IKK/NF-κB and EGFR inhibitors to overcome EGFR TKIs resistance. In this study, we discovered that Schizandrin A (Sch A), a lignin compound isolated from Schisandra chinesnesis, could synergize with the EGFR receptor inhibitor Gefitinib to inhibit cell growth, induce cell cycle arrest and apoptosis of HCC827/GR cells. Sch A effectively suppressed the phosphorylation of IKKβ and IκBα, as well as the nuclear translocation of NF-κB p65, and showed high and selective affinity for IKKβ in surface plasmon resonance (SPR) experiments, indicating that Sch A was a selective IKKβ inhibitor. Molecular modeling between IKKβ and Sch A suggested that Sch A formed key hydrophobic interactions with IKKβ, which may contribute to its potent IKKβ inhibitory effect. These findings suggest a novel approach to improve poor clinical outcomes in EGFR TKIs therapy, by combining it with Sch A.

    Topics: Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Cycle Checkpoints; Cell Line, Tumor; Cyclooctanes; Drug Synergism; Gefitinib; Humans; I-kappa B Kinase; Lignans; Lung Neoplasms; Molecular Dynamics Simulation; NF-kappa B; Polycyclic Compounds; Protein Conformation; Signal Transduction

2019
Cytological effects of honokiol treatment and its potential mechanism of action in non-small cell lung cancer.
    Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 2019, Volume: 117

    In this study, we aimed to explore key micro(mi)RNAs and their potential regulatory mechanisms induced by honokiol treatment in non-small cell lung cancer (NSCLC) cells.. NSCLC A549 cells were treated with 0 (control) or 45 μM honokiol. Cell proliferation and migration were determined using CCK-8 and transwell assay, respectively, and apoptosis was determined using flow cytometry. RNA-sequencing was performed to detect the transcript expression levels. The differentially expressed miRNAs (DE-miRNAs) between the honokiol group and the control group were screened and analyzed for their functions and pathways. Then, protein-protein interaction (PPI) networks and miRNA-mRNA regulatory networks were constructed. In addition, survival analysis based on the key miRNAs was performed. Finally, the expression of the key miRNAs and their target genes were determined, and their effects on drug sensitivity were validated using their inhibitors.. Cell proliferation and migration were inhibited (P < 0.01), and the apoptosis rate was increased (P < 0.01) after honokiol treatment compared to that in the control group. A total of 26 upregulated and 20 downregulated DE-miRNAs were screened. DE-miRNAs were enriched in 10 pathways and 48 biological processes, such as the PI3K/AKT signaling pathway (involving miR-148a-3p). The miRNA-mRNA regulatory networks involved eight upregulated (including miR-148a-3p and let-7c-5p) and seven downregulated miRNAs (including miR-7-5p) and 190 target mRNAs. Survival analysis revealed that let-7c-5p, miR-148a-3p, and miR-148a-5p levels correlated with NSCLC prognosis. The expression of let-7c-5p, miR-148a-3p, and miR-148a-5p was significantly increased and negatively correlated with the expression of their target genes. The cytological effects of honokiol on A549 cells was partly reversed by treatment with the inhibitors of Let-7c-5p and miR-148a-3p.. Let-7c-5p, miR-148a-3p, miR-148a-5p, and miR-7-5p are favorable indicators of NSCLC patients treated with honokiol.

    Topics: A549 Cells; Apoptosis; Biphenyl Compounds; Carcinoma, Non-Small-Cell Lung; Cell Movement; Cell Proliferation; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Humans; Lignans; Lung Neoplasms; MicroRNAs; Principal Component Analysis; RNA, Messenger

2019
Honokiol inhibits breast cancer cell metastasis by blocking EMT through modulation of Snail/Slug protein translation.
    Acta pharmacologica Sinica, 2019, Volume: 40, Issue:9

    Honokiol (HNK), an active compound isolated from traditional Chinese medicine Magnolia officinalis, has shown potent anticancer activities. In the present study, we investigated the effects of HNK on breast cancer metastasis in vitro and in vivo, as well as the underlying molecular mechanisms. We showed that HNK (10-70 μmol/L) dose-dependently inhibited the viability of human mammary epithelial tumor cell lines MCF7, MDA-MB-231, and mouse mammary tumor cell line 4T1. In the transwell and scratch migration assays, HNK (10, 20, 30 μmol/L) dose-dependently suppressed the invasion and migration of the breast cancer cells. We demonstrated that HNK (10-50 μmol/L) dose-dependently upregulated the epithelial marker E-cadherin and downregulated the mesenchymal markers such as Snail, Slug, and vimentin at the protein level in breast cancer cells. Using a puromycin incorporation assay, we showed that HNK decreased the Snail translation efficiency in the breast cancer cells. In a mouse model of tumor metastasis, administration of HNK (50 mg/kg every day, intraperitoneal (i.p.), 6 times per week for 30 days) significantly decreased the number of metastatic 4T1 cell-derived nodules and ameliorated the histological alterations in the lungs. In addition, HNK-treated mice showed decreased Snail expression and increased E-cadherin expression in metastatic nodules. In conclusion, HNK inhibits EMT in the breast cancer cells by downregulating Snail and Slug protein expression at the mRNA translation level. HNK has potential as an integrative medicine for combating breast cancer by targeting EMT.

    Topics: Animals; Antineoplastic Agents, Phytogenic; Biphenyl Compounds; Breast Neoplasms; Cell Line, Tumor; Cell Movement; Down-Regulation; Epithelial-Mesenchymal Transition; Female; Humans; Lignans; Lung Neoplasms; Mice, Inbred BALB C; Snail Family Transcription Factors

2019
Licarin A induces cell death by activation of autophagy and apoptosis in non-small cell lung cancer cells.
    Apoptosis : an international journal on programmed cell death, 2018, Volume: 23, Issue:3-4

    Lung cancer has a relatively poor prognosis with a low survival rate and drugs that target other cell death mechanism like autophagy may help improving current therapeutic strategy. This study investigated the anti-proliferative effect of Licarin A (LCA) from Myristica fragrans in non-small cell lung cancer cell lines-A549, NCI-H23, NCI-H520 and NCI-H460. LCA inhibited proliferation of all the four cell lines in a dose and time dependent manner with minimum IC50 of 20.03 ± 3.12, 22.19 ± 1.37 µM in NCI-H23 and A549 cells respectively. Hence NCI-H23 and A549 cells were used to assess the ability LCA to induce autophagy and apoptosis. LCA treatment caused G1 arrest, increase in Beclin 1, LC3II levels and degradation of p62 indicating activation of autophagy in both NCI-H23 and A549 cells. In addition, LCA mediated apoptotic cell death was confirmed by MMP loss, increased ROS, cleaved PARP and decreased pro-caspase3. To understand the role of LCA induced autophagy and its association with apoptosis, cells were analysed following treatment with a late autophagy inhibitor-chloroquine and also after Beclin 1 siRNA transfection. Data indicated that inhibition of autophagy resulted in reduced anti-proliferative as well as pro-apoptotic ability of LCA. These findings confirmed that LCA brought about autophagy dependent apoptosis in non-small cell lung cancer cells and hence it may serve as a potential drug candidate for non-small cell lung cancer therapy.

    Topics: A549 Cells; Antineoplastic Agents, Phytogenic; Apoptosis; Autophagy; Beclin-1; Carcinoma, Non-Small-Cell Lung; Caspase 3; Humans; Lignans; Lung Neoplasms; Myristica; Peroxisome Proliferator-Activated Receptors; Plant Extracts; Reactive Oxygen Species

2018
Discovery and synthesis of novel magnolol derivatives with potent anticancer activity in non-small cell lung cancer.
    European journal of medicinal chemistry, 2018, Aug-05, Volume: 156

    Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Biphenyl Compounds; Carcinoma, Non-Small-Cell Lung; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Female; Human Umbilical Vein Endothelial Cells; Humans; Lignans; Lung Neoplasms; Magnolia; Mice, Inbred BALB C; Mice, Nude; Xenograft Model Antitumor Assays

2018
Functional paclitaxel plus honokiol micelles destroying tumour metastasis in treatment of non-small-cell lung cancer.
    Artificial cells, nanomedicine, and biotechnology, 2018, Volume: 46, Issue:sup2

    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

2018
Honokiol induces apoptosis of lung squamous cell carcinoma by targeting FGF2-FGFR1 autocrine loop.
    Cancer medicine, 2018, Volume: 7, Issue:12

    Lung squamous cell carcinoma (SCC) accounts for a considerable proportion of lung cancer cases, but there is still a lack of effective therapies. FGFR1 amplification is generally considered a promising therapeutic target. Honokiol is a chemical compound that has been proven to be effective against various malignancies and whose analog has been reported to target the mitogen-activated protein kinase family, members of a downstream signaling pathway of FGFR1. This was an explorative study to determine the mechanism of honokiol in lung SCC. We found that honokiol induced apoptosis and cell cycle arrest in lung SCC cell lines in a time- and dose-dependent manner. Honokiol also restricted cell migration in lung SCC cell lines. Moreover, the expression of FGF2 and the activation of FGFR1 were both downregulated by honokiol. Pharmacological inhibition and siRNA knockdown of FGFR1 induced apoptosis in lung SCC cells. Our in vivo study indicated that honokiol could suppress the growth of xenograft tumors, and this effect was associated with the inhibition of the FGF2-FGFR1 signaling pathway. In conclusion, honokiol induced cell apoptosis in lung SCC by targeting the FGF2-FGFR1 autocrine loop.

    Topics: Animals; Antineoplastic Agents; Apoptosis; Biphenyl Compounds; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Movement; Cell Survival; Female; Fibroblast Growth Factor 2; Humans; Lignans; Lung Neoplasms; Mice, Inbred BALB C; Mice, Nude; Receptor, Fibroblast Growth Factor, Type 1

2018
Liposomal honokiol induced lysosomal degradation of Hsp90 client proteins and protective autophagy in both gefitinib-sensitive and gefitinib-resistant NSCLC cells.
    Biomaterials, 2017, Volume: 141

    Honokiol (HK), a natural chemical isolated from Mangnolia officinalis, has shown antitumorigenic activities when used to treat a variety of tumor cell lines. The mechanism of honokiol activity when used to treat gefitinib-sensitive and gefitinib-resistant non-small cell lung cancer (NSCLC) requires elucidation. Here, the presence of liposomal honokiol (LHK) induced apoptotic and antitumor activities in four xenograft models generated using NSCLC cell lines such as HCC827 (gefitinib-sensitive) and H1975 (gefitinib-resistant). Mechanistic studies revealed that LHK inhibited the Akt and Erk1/2, both EGFR signaling cascades effectors, by promoting degradation of HSP90 client proteins (HCP), including wild-type or mutant EGFR, Akt and C-Raf. Molecular biology assays showed that LHK induced HCP degradation through a lysosomal pathway, rather than the canonical proteasome protein degradation pathway. As a result of misfolded protein accumulation, LHK induced endoplasmic reticulum (ER) stress and autophagy. Inhibition of ER stress (with 4-phenylbutyrate) or autophagy (with small interfering RNA) reduced LHK-induced HCP degradations. Additionally, LHK induced autophagy showed a protective role for cancer cell as inhibition of autophagy in vitro and in vivo by autophagosome degradation inhibitors could promote the anticancer activity of LHK. LHK has been approved by the China Food and Drug Administration for first-in-human clinical trials in NSCLC. The current study will guide the design of future LHK clinical trials.

    Topics: Animals; Antineoplastic Agents; Autophagy; Biphenyl Compounds; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Drug Resistance, Neoplasm; Female; Gefitinib; HSP90 Heat-Shock Proteins; Humans; Lignans; Lung Neoplasms; Mice, Inbred BALB C; Mice, Nude; Quinazolines; Signal Transduction

2017
Magnolol Inhibits the Growth of Non-Small Cell Lung Cancer via Inhibiting Microtubule Polymerization.
    Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology, 2017, Volume: 42, Issue:5

    The tubulin/microtubule system, which is an integral component of the cytoskeleton, plays an essential role in mitosis. Targeting mitotic progression by disturbing microtubule dynamics is a rational strategy for cancer treatment.. Microtubule polymerization assay was performed to examine the effect of Magnolol (a novel natural phenolic compound isolated from Magnolia obovata) on cellular microtubule polymerization in human non-small cell lung cancer (NSCLC) cells. Cell cycle analysis, mitotic index assay, cell proliferation assay, colony formation assay, western blotting analysis of cell cycle regulators, Annexin V-FITC/PI staining, and live/dead viability staining were carried out to investigate the Magnolol's inhibitory effect on proliferation and viability of NSCLS cells in vitro. Xenograft model of human A549 NSCLC tumor was used to determine the Magnolol's efficacy in vivo.. Magnolol treatment effectively inhibited cell proliferation and colony formation of NSCLC cells. Further study proved that Magnolol induced the mitotic phase arrest and inhibited G2/M progression in a dose-dependent manner, which were mechanistically associated with expression alteration of a series of cell cycle regulators. Furthermore, Magnolol treatment disrupted the cellular microtubule organization via inhibiting the polymerization of microtubule. We also found treatment with NSCLC cells with Magnolol resulted in apoptosis activation through a p53-independent pathway, and autophgy induction via down-regulation of the Akt/mTOR pathway. Finally, Magnolol treatment significantly suppressed the NSCLC tumor growth in mouse xenograft model in vivo.. These findings identify Magnolol as a promising candidate with anti-microtubule polymerization activity for NSCLC treatment.

    Topics: A549 Cells; Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Biphenyl Compounds; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; G2 Phase Cell Cycle Checkpoints; Humans; Lignans; Lung Neoplasms; M Phase Cell Cycle Checkpoints; Magnolia; Male; Mice, Nude; Microtubules; Proto-Oncogene Proteins c-akt; Signal Transduction; TOR Serine-Threonine Kinases; Transplantation, Heterologous; Tumor Suppressor Protein p53

2017
Arctigenin represses TGF-β-induced epithelial mesenchymal transition in human lung cancer cells.
    Biochemical and biophysical research communications, 2017, 11-18, Volume: 493, Issue:2

    Arctigenin (ARC) is a lignan that is abundant in Asteraceae plants, which show anti-inflammatory and anti-cancer activities. The current study investigated whether ARC affects cancer progression and metastasis, focusing on EMT using invasive human non-small cell lung cancer (NSCLC) cells. No toxicity was observed in the cells treated with different doses of ARC (12-100 μM). The treatment of ARC repressed TGF-β-stimulated changes of metastatic morphology and cell invasion and migration. ARC inhibited TGF-β-induced phosphorylation and transcriptional activity of smad2/3, and expression of snail. ARC also decreased expression of N-cadherin and increased expression of E-cadherin in dose-dependent and time-dependent manners. These changes were accompanied by decreased amount of phospho-smad2/3 in nucleus and nuclear translocation of smad2/3. Moreover, ARC repressed TGF-β-induced phosphorylation of ERK and transcriptional activity of β-catenin. Our data demonstrate anti-metastatic activity of ARC in lung cancer model.

    Topics: Antineoplastic Agents, Phytogenic; Asteraceae; beta Catenin; Cadherins; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Movement; Cell Survival; Epithelial-Mesenchymal Transition; Furans; Humans; Lignans; Lung; Lung Neoplasms; Neoplasm Invasiveness; Phosphorylation; Smad2 Protein; Smad3 Protein; Transforming Growth Factor beta

2017
Tripalmitin nanoparticle formulations significantly enhance paclitaxel antitumor activity against breast and lung cancer cells in vitro.
    Scientific reports, 2017, 10-18, Volume: 7, Issue:1

    Paclitaxel (PTX) is one of the drugs of choice in the treatment of breast and lung cancer. However, its severe side effects, including mielosuppression, cardiotoxicity and neurotoxicity, frequently cause treatment to be discontinued. Solid lipid nanoparticles (NPs) of glyceril tripalmitate (tripalmitin) loaded with PTX (Tripalm-NPs-PTX) including modifications by the addition of hexa(ethylene glycol), β-cyclodextrin and macelignan were developed. All NPs-PTX formulations displayed excellent hemocompatibility and significantly enhanced PTX antitumor activity in human breast (MCF7, MDAMB231, SKBR3 and T47D) and lung (A549, NCI-H520 and NCI-H460) cancer cells. Tripalm-NPs-PTX decreased PTX IC

    Topics: Antineoplastic Agents; beta-Cyclodextrins; Breast Neoplasms; Cell Line; Female; Humans; Lignans; Lung Neoplasms; MCF-7 Cells; Nanoparticles; Neoplastic Stem Cells; Paclitaxel; Polyethylene Glycols; Spheroids, Cellular; Triglycerides; Tumor Cells, Cultured

2017
The antitumour effects of eudesmin on lung cancer by inducing apoptosis via mitochondria-mediated pathway in the tumour cells.
    Pharmaceutical biology, 2017, Volume: 55, Issue:1

    Limonoids possess broad range of biological activities, including antitumour, antimicrobial and antioxidant activities, etc. Eudesmin (EDN) is a type of limonoid which also possesses various activities. However, there is no report on the antitumour lung cancer (LC) activities of this compound.. The present study investigates the antitumour effects of EDN and its potential molecular mechanisms.. The in vitro antitumour effects of EDN on LC A549 cells were evaluated by using MTT assay. The in vivo antitumour effects were investigated on a xenograft athymic nude mouse model. The mice were administered orally with EDN (10, 20 and 40 mg/kg) once daily for 28 days. Effects of EDN on apoptosis-related or signalling proteins (Bcl-2, Bax, caspase-3, caspase-9, P53, Akt and JNK) were assayed by western blot analysis.. Overall, the results indicated that EDN possesses significant antitumour effects on LC and the possible mechanism might be related to induction of mitochondria-mediated apoptosis.

    Topics: A549 Cells; Administration, Oral; Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Blotting, Western; Dose-Response Relationship, Drug; Down-Regulation; Furans; Gene Expression Regulation, Neoplastic; Humans; Inhibitory Concentration 50; Lignans; Lung Neoplasms; Male; Mice; Mice, Nude; Mitochondria; Up-Regulation; Xenograft Model Antitumor Assays

2017
The action and mechanism of myrislignan on A549 cells in vitro and in vivo.
    Journal of natural medicines, 2017, Volume: 71, Issue:1

    Myrislignan is a natural compound with little pharmacological study. In our investigation, we investigated the effect of myrislignan in the induction of apoptosis in A549 cells in vitro and in vivo. Myrislignan inhibited the proliferation of A549 cells in a dose- and time-dependent manner assayed by MTT. In addition, Hoechst flow cytometry showed that myrislignan significantly induced apoptosis and cell cycle arrest in A549 cells. The apoptosis and anti-cell proliferation was mediated by the activation of mitogen-activated protein kinase and the inhibition of epidermal growth factor receptor signal pathway, change of mitochondrial membrane potential, the releasing of c-Myc, the downregulation of the level of the anti-apoptotic protein Bcl-2, and the upregulation of the level of the pro-apoptotic protein Bax. In conclusion, those results reveal a potential mechanism for the anti-cancer effect of myrislignan on human lung cancer, while suggesting that myrislignan may be a promising compound for the treatment of lung cancer.

    Topics: A549 Cells; Apoptosis; Biological Products; Cell Line, Tumor; Cell Proliferation; Humans; Immunohistochemistry; Lignans; Lung Neoplasms; Signal Transduction; Xenograft Model Antitumor Assays

2017
Honokiol Decreases Lung Cancer Metastasis through Inhibition of the STAT3 Signaling Pathway.
    Cancer prevention research (Philadelphia, Pa.), 2017, Volume: 10, Issue:2

    Lung cancer is the leading cause of cancer death in the United States. Metastasis to lymph nodes and distal organs, especially brain, leads to severe complications and death. Preventing lung cancer development and metastases is an important strategy to reduce lung cancer mortality. Honokiol (HNK), a natural compound present in the extracts of magnolia bark, has a favorable bioavailability profile and recently has been shown to readily cross the blood-brain barrier. In the current study, we evaluated the antimetastatic effects of HNK in both the lymph node and brain mouse models of lung tumor metastasis. We tested the efficacy of HNK in preventing 18 H2030-BrM3 cell (brain-seeking human lung tumor cells) migration to lymph node or brain. In an orthotopic mouse model, HNK significantly decreased lung tumor growth compared with the vehicle control group. HNK also significantly reduced the incidence of lymph node metastasis and the weight of mediastinal lymph nodes. In a brain metastasis model, HNK inhibits metastasis of lung cancer cells to the brain to approximately one third of that observed in control mice. We analyzed HNK's mechanism of action, which indicated that its effect is mediated primarily by inhibiting the STAT3 pathway. HNK specifically inhibits STAT3 phosphorylation irrespective of the mutation status of EGFR, and knockdown of STAT3 abrogated both the antiproliferative and the antimetastatic effects of HNK. These observations suggest that HNK could provide novel chemopreventive or therapeutic options for preventing both lung tumor progression and lung cancer metastasis. Cancer Prev Res; 10(2); 133-41. ©2016 AACR.

    Topics: Animals; Antineoplastic Agents, Phytogenic; Biphenyl Compounds; Brain Neoplasms; Cell Line, Tumor; Cell Movement; Cell Proliferation; Female; Humans; Lignans; Lung Neoplasms; Lymphatic Metastasis; Mice; Mice, Inbred NOD; Mice, SCID; Signal Transduction; STAT3 Transcription Factor; Xenograft Model Antitumor Assays

2017
Enterolactone alters FAK-Src signaling and suppresses migration and invasion of lung cancer cell lines.
    BMC complementary and alternative medicine, 2017, Jan-09, Volume: 17, Issue:1

    Systemic toxicity of chemotherapeutic agents and the challenges associated with targeting metastatic tumors are limiting factors for current lung cancer therapeutic approaches. To address these issues, plant-derived bioactive components have been investigated for their anti-cancer properties because many of these agents are non-toxic to healthy tissues. Enterolactone (EL) is a flaxseed-derived mammalian lignan that has demonstrated anti-migratory properties for various cancers, but EL has not been investigated in the context of lung cancer, and its anticancer mechanisms are ill-defined. We hypothesized that EL could inhibit lung cancer cell motility by affecting the FAK-Src signaling pathway.. Non-toxic concentrations of EL were identified for A549 and H460 human lung cancer cells by conducting 3-(4, 5-Dimethylthiazol-2-yl)-2, 5-Dephenyltetrazolium Bromide (MTT) assays. The anti-migratory and anti-invasive potential of EL for lung cancer cell lines was determined by scratch wound healing and Matrigel® invasion assays. Changes in filamentous actin (F-actin) fiber density and length in EL-treated cells were determined using phalloidin-conjugated rhodamine dye and fluorescent microscopy. Vinculin expression in focal adhesions upon EL treatment was determined by immunocytochemistry. Gene and protein expression levels of FAK-Src signaling molecules in EL-treated lung cancer cells were determined using PCR arrays, qRT-PCR, and western blotting.. Non-toxic concentrations of EL inhibited lung cancer cell migration and invasion in a concentration- and time-dependent manner. EL treatment reduced the density and number of F-actin fibers in lung cancer cell lines, and reduced the number and size of focal adhesions. EL decreased phosphorylation of FAK and its downstream targets, Src, paxillin, and decreased mRNA expression of cell motility-related genes, RhoA, Rac1, and Cdc42 in lung cancer cells.. Our data suggest that EL suppresses lung cancer cell motility and invasion by altering FAK activity and subsequent activation of downstream proteins needed for focal adhesion formation and cytoskeletal rearrangement. Therefore, administration of EL may serve as a safe and complementary approach for inhibiting lung tumor cell motility, invasion, and metastasis.

    Topics: 4-Butyrolactone; Cell Adhesion; Cell Line, Tumor; Cell Movement; Cytoskeleton; Flax; Focal Adhesion Kinase 1; Humans; Lignans; Lung Neoplasms; Phosphorylation; Plant Extracts; Signal Transduction; src-Family Kinases

2017
Boehmenan, a lignan from the Chinese medicinal plant Clematis armandii, induces apoptosis in lung cancer cells through modulation of EGF-dependent pathways.
    Phytomedicine : international journal of phytotherapy and phytopharmacology, 2016, May-15, Volume: 23, Issue:5

    Epidermal growth factor receptor (EGFR) is an effective molecular target for cancer treatment. Boehmenan, a lignan from the dried stems of Clematis armandii, exhibited the potent cytotoxic effects against many cancer cell lines in previous studies. However, the effects and underlying mechanism of boehmenan on non-small cell lung cancer (NSCLC) remains unclear.. The present study was designed to determine the in vitro anti-cancer properties and underlying molecular mechanisms of boehmenan on A549 NSCLC cells.. Cellular viability and chemoattractive properties of macrophages were investigated by using MTT and transwell migration assay, respectively. Mitochondrial membrane potential (ΔΨm), apoptotic ratio, and cell cycle were measured by flow cytometry. Protein expression was visualized by Western blot using specific antibodies.. Boehmenan concentration-dependently suppressed proliferation and induced G1 phase arrest in A549 NSCLC cells, which were accompanied by reduction of migration, colony formation and increase of apoptosis in A549 cells. In addition, boehmenan treatment markedly modulated apoptosis-related protein (p53, p21, cleaved caspase 3, and cleaved PARP) and cyclin D1 expression and induced ΔΨm collapse in a concentration dependent manner. Furthermore, boehmenan concentration-dependently inhibited EGF-induced activation of EGFR and its downstream signaling molecules, including MEK, Akt, ERK1/2, and STAT3.. Taken together, our results suggested that boehmenan-mediated anti-tumor property was mediated by modulation of mitochondria and EGFR signaling pathway in A549 NSCLC cells.

    Topics: Apoptosis; Carcinoma, Non-Small-Cell Lung; Caspase 3; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Clematis; Epidermal Growth Factor; ErbB Receptors; Humans; Lignans; Lung Neoplasms; Membrane Potential, Mitochondrial; Mitochondria; Molecular Structure; Plants, Medicinal; Signal Transduction

2016
Novel histone deacetylase inhibitors derived from Magnolia officinalis significantly enhance TRAIL-induced apoptosis in non-small cell lung cancer.
    Pharmacological research, 2016, Volume: 111

    Histone modifications play critical roles in the progression of non-small cell lung cancer (NSCLC), which accounts for almost 85% of all diagnosed lung cancers. Magnolol and polyphenol mixture (PM) derived from Magnolia officinalis exhibited remarkable antitumor activities in lung cancer. However, the epigenetic effects and molecular mechanisms of magnolol and PM in NSCLC have yet to be reported. In this study, the epigenetic effects of magnolol and PM in NSCLC were examined in vitro and in vivo. Results revealed that magnolol and PM significantly suppressed the expression levels and function of class I histone deacetylases (HDACs). In A549 and H1299 cells, magnolol and PM remarkably induced cell apoptosis by arresting the cell cycle in the G0/G1 phase while simultaneously activating various pro-apoptotic signals, including TRAIL-R2 (DR5), Bax, caspase 3, cleaved caspase 3, and cleaved PARP. However, these apoptosis-promoting effects could be attenuated by TSA, which is a specific class I HDACs inhibitor. ChIP assays also demonstrated that magnolol and PM significantly enriched the histone acetyl mark (H3K27ac) in the promoter region of DR5. In A549 xenograft model, magnolol and PM notably reduced tumor growth by 44.40% and 35.40%, respectively. Therefore, magnolol and PM, as potential inhibitors of class I HDACs, induced tumor cell apoptosis and suppressed tumor growth partially by epigenetically activating DR5, which is a key protein in death receptor signaling pathway.

    Topics: A549 Cells; Acetylation; Animals; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Apoptosis Regulatory Proteins; Biphenyl Compounds; Carcinoma, Non-Small-Cell Lung; Cell Cycle Checkpoints; Cell Proliferation; Dose-Response Relationship, Drug; Epigenesis, Genetic; Female; Histone Deacetylase 1; Histone Deacetylase Inhibitors; Histones; Humans; Lignans; Lung Neoplasms; Magnolia; Mice, Inbred BALB C; Mice, Nude; Phytotherapy; Plant Extracts; Plants, Medicinal; Polyphenols; Promoter Regions, Genetic; Receptors, TNF-Related Apoptosis-Inducing Ligand; Signal Transduction; Time Factors; TNF-Related Apoptosis-Inducing Ligand; Tumor Burden; Xenograft Model Antitumor Assays

2016
Honokiol suppresses lung tumorigenesis by targeting EGFR and its downstream effectors.
    Oncotarget, 2016, Sep-06, Volume: 7, Issue:36

    Since epidermal growth factor receptor (EGFR) is commonly deregulated in pre-malignant lung epithelium, targeting EGFR may arrest the development of lung cancer. Here, we showed that honokiol (2.5-7.5 μM), a bioactive compound of Magnolia officinalis, differentially suppressed proliferation (up to 93%) and induced apoptosis (up to 61%) of EGFR overexpressing tumorigenic bronchial cells and these effects were paralleled by downregulation of phospho-EGFR, phospho-Akt, phospho-STAT3 and cell cycle-related proteins as early as 6-12 h post-treatment. Autocrine secretion of EGF sensitized 1170 cells to the effects of honokiol. Molecular docking studies indicated that honokiol binds to the tyrosine kinase domain of EGFR although it was less efficient than erlotinib. However, the anti-proliferative and pro-apoptotic activities of honokiol were stronger than those of erlotinib. Upon combinatory treatment, honokiol sensitized bronchial cells and erlotinib resistant H1650 and H1975 cells to erlotinib. Furthermore, in a mouse lung tumor bioassay, intranasal instillation of liposomal honokiol (5 mg/kg) for 14 weeks reduced the size and multiplicity (49%) of lung tumors and the level of total- and phospho-EGFR, phospho-Akt and phospho-STAT3. Overall, our results indicate that honokiol is a promising candidate to suppress the development and even progression of lung tumors driven by EGFR deregulation.

    Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Biological Assay; Biphenyl Compounds; Bronchi; Carcinogenesis; Cell Cycle; Cell Proliferation; Cell Survival; Disease Progression; ErbB Receptors; Erlotinib Hydrochloride; Female; Lignans; Lung Neoplasms; Magnolia; Mice; Molecular Docking Simulation; Nitrosamines; Plant Extracts; RNA, Small Interfering

2016
Honokiol inhibits EMT-mediated motility and migration of human non-small cell lung cancer cells in vitro by targeting c-FLIP.
    Acta pharmacologica Sinica, 2016, Volume: 37, Issue:12

    Honokiol (HNK) is a natural compound isolated from the magnolia plant with numerous pharmacological activities, including inhibiting epithelial-mesenchymal transition (EMT), which has been proposed as an attractive target for anti-tumor drugs to prevent tumor migration. In this study we investigated the effects of HNK on EMT in human NSCLC cells in vitro and the related signaling mechanisms.. TNF-α (25 ng/mL) in combination with TGF-β1 (5 ng/mL) was used to stimulate EMT of human NSCLC A549 and H460 cells. Cell proliferation was analyzed using a sulforhodamine B assay. A wound-healing assay and a transwell assay were performed to examine cell motility. Western blotting was used to detect the expression levels of relevant proteins. siRNAs were used to knock down the gene expression of c-FLIP and N-cadherin. Stable overexpression of c-FLIP L (H157-FLIP L) or Lac Z (H157-Lac Z) was also performed.. Treatment with TNF-α+TGF-β1 significantly enhanced the migration of A549 and H460 cells, increased c-FLIP, N-cadherin (a mesenchymal marker), snail (a transcriptional modulator) and p-Smad2/3 expression, and decreased IκB levels in the cells; these changes were abrogated by co-treatment with HNK (30 μmol/L). Further studies demonstrated that expression level of c-FLIP was highly correlated with the movement and migration of NSCLC cells, and the downstream effectors of c-FLIP signaling were NF-κB signaling and N-cadherin/snail signaling, while Smad signaling might lie upstream of c-FLIP.. HNK inhibits EMT-mediated motility and migration of human NSCLC cells in vitro by targeting c-FLIP, which can be utilized as a promising target for cancer therapy, while HNK may become a potential anti-metastasis drug or lead compound.

    Topics: Animals; Antineoplastic Agents; Apoptosis; Autophagy; Biphenyl Compounds; Carcinoma, Non-Small-Cell Lung; CASP8 and FADD-Like Apoptosis Regulating Protein; Cell Line, Tumor; Cell Movement; Epithelial-Mesenchymal Transition; Humans; Lignans; Lung Neoplasms

2016
Honokiol suppresses pancreatic tumor growth, metastasis and desmoplasia by interfering with tumor-stromal cross-talk.
    Carcinogenesis, 2016, 11-01, Volume: 37, Issue:11

    The poor clinical outcome of pancreatic cancer (PC) is largely attributed to its aggressive nature and refractoriness to currently available therapeutic modalities. We previously reported antitumor efficacy of honokiol (HNK), a phytochemical isolated from various parts of Magnolia plant, against PC cells in short-term in vitro growth assays. Here, we report that HNK reduces plating efficiency and anchorage-independent growth of PC cells and suppresses their migration and invasiveness. Furthermore, significant inhibition of pancreatic tumor growth by HNK is observed in orthotopic mouse model along with complete-blockage of distant metastases. Histological examination suggests reduced desmoplasia in tumors from HNK-treated mice, later confirmed by immunohistochemical analyses of myofibroblast and extracellular matrix marker proteins (α-SMA and collagen I, respectively). At the molecular level, HNK treatment leads to decreased expression of sonic hedgehog (SHH) and CXCR4, two established mediators of bidirectional tumor-stromal cross-talk, both in vitro and in vivo . We also show that the conditioned media (CM) from HNK-treated PC cells have little growth-inducing effect on pancreatic stellate cells (PSCs) that could be regained by the addition of exogenous recombinant SHH. Moreover, pretreatment of CM of vehicle-treated PC cells with SHH-neutralizing antibody abolishes their growth-inducing potential on PSCs. Likewise, HNK-treated PC cells respond poorly to CM from PSCs due to decreased CXCR4 expression. Lastly, we show that the transfection of PC cells with constitutively active IKKβ mutant reverses the suppressive effect of HNK on nuclear factor-kappaB activation and partially restores CXCR4 and SHH expression. Taken together, these findings suggest that HNK interferes with tumor-stromal cross-talk via downregulation of CXCR4 and SHH and decreases pancreatic tumor growth and metastasis.

    Topics: Animals; Antineoplastic Agents, Phytogenic; Biphenyl Compounds; Cell Communication; Cell Line, Tumor; Down-Regulation; Female; Gene Expression; Hedgehog Proteins; Humans; Lignans; Liver Neoplasms, Experimental; Lung Neoplasms; Mice; Pancreatic Neoplasms; Receptors, CXCR4; Tumor Microenvironment; Xenograft Model Antitumor Assays

2016
Arctigenin Inhibits Lung Metastasis of Colorectal Cancer by Regulating Cell Viability and Metastatic Phenotypes.
    Molecules (Basel, Switzerland), 2016, Aug-27, Volume: 21, Issue:9

    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

2016
The Topoisomerase 1 Inhibitor Austrobailignan-1 Isolated from Koelreuteria henryi Induces a G2/M-Phase Arrest and Cell Death Independently of p53 in Non-Small Cell Lung Cancer Cells.
    PloS one, 2015, Volume: 10, Issue:7

    Koelreuteria henryi Dummer, an endemic plant of Taiwan, has been used as a folk medicine for the treatment of hepatitis, enteritis, cough, pharyngitis, allergy, hypertension, hyperlipidemia, and cancer. Austrobailignan-1, a natural lignan derivative isolated from Koelreuteria henryi Dummer, has anti-oxidative and anti-cancer properties. However, the effects of austrobailignan-1 on human cancer cells have not been studied yet. Here, we showed that austrobailignan-1 inhibited cell growth of human non-small cell lung cancer A549 and H1299 cell lines in both dose- and time-dependent manners, the IC50 value (48 h) of austrobailignan-1 were 41 and 22 nM, respectively. Data from flow cytometric analysis indicated that treatment with austrobailignan-1 for 24 h retarded the cell cycle at the G2/M phase. The molecular event of austrobailignan-1-mediated G2/M phase arrest was associated with the increase of p21Waf1/Cip1 and p27Kip1 expression, and decrease of Cdc25C expression. Moreover, treatment with 100 nM austrobailignan-1 for 48 h resulted in a pronounced release of cytochrome c followed by the activation of caspase-2, -3, and -9, and consequently induced apoptosis. These events were accompanied by the increase of PUMA and Bax, and the decrease of Mcl-1 and Bcl-2. Furthermore, our study also showed that austrobailignan-1 was a topoisomerase 1 inhibitor, as evidenced by a relaxation assay and induction of a DNA damage response signaling pathway, including ATM, and Chk1, Chk2, γH2AX phosphorylated activation. Overall, our results suggest that austrobailignan-1 is a novel DNA damaging agent and displays a topoisomerase I inhibitory activity, causes DNA strand breaks, and consequently induces DNA damage response signaling for cell cycle G2/M arrest and apoptosis in a p53 independent manner.

    Topics: Carcinoma, Non-Small-Cell Lung; Cell Death; Cell Line, Tumor; DNA Topoisomerases, Type I; G2 Phase Cell Cycle Checkpoints; Humans; Lignans; Lung Neoplasms; M Phase Cell Cycle Checkpoints; Plants, Medicinal; Topoisomerase I Inhibitors; Tumor Suppressor Protein p53

2015
Arctigenin enhances chemosensitivity to cisplatin in human nonsmall lung cancer H460 cells through downregulation of survivin expression.
    Journal of biochemical and molecular toxicology, 2014, Volume: 28, Issue:1

    Arctigenin, a dibenzylbutyrolactone lignan, enhances cisplatin-mediated cell apoptosis in cancer cells. Here, we sought to investigate the effects of arctigenin on cisplatin-treated non-small-cell lung cancer (NSCLC) H460 cells. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and annexin-V/propidium iodide staining were performed to analyze the proliferation and apoptosis of H460 cells. Arctigenin dose-dependently suppressed cell proliferation and potentiated cell apoptosis, coupled with increased cleavage of caspase-3 and poly(ADP-ribose) polymerase. Moreover, arctigenin sensitized H460 cells to cisplatin-induced proliferation inhibition and apoptosis. Arctigenin alone or in combination with cisplatin had a significantly lower amount of survivin. Ectopic expression of survivin decreased cell apoptosis induced by arctigenin (P < 0.05) or in combination with cisplatin (P < 0.01). Moreover, arctigenin (P < 0.05) or in combination with cisplatin (P < 0.01) induced G1/G0 cell-cycle arrest. Our data provide evidence that arctigenin has a therapeutic potential in combina-tion with chemotherapeutic agents for NSLC.

    Topics: Antineoplastic Agents; Base Sequence; Carcinoma, Non-Small-Cell Lung; Cell Cycle; Cell Line, Tumor; Cisplatin; DNA Primers; Down-Regulation; Drug Resistance, Neoplasm; Drug Synergism; Furans; Humans; Inhibitor of Apoptosis Proteins; Lignans; Lung Neoplasms; Polymerase Chain Reaction; Survivin

2014
Bioactive Lignans from Zanthoxylum alatum Roxb. stem bark with cytotoxic potential.
    Journal of ethnopharmacology, 2014, Feb-27, Volume: 152, Issue:1

    Zanthoxylum alatum is used in traditional medicinal systems for number of disorders like cholera, diabetes, cough, diarrhea, fever, headache, microbial infections, toothache, inflammation and cancer. The aim of the present study was to evaluate Zanthoxylum alatum stem bark for its cytotoxic potential and to isolate the bioactive constituents.. Cytotoxicity of the different extracts and isolated compounds was studied on lung carcinoma cell line (A549) and pancreatic carcinoma cell line (MIA-PaCa) using MTT assay. Isolation of compounds from most active extract (petroleum ether) was done on silica gel column. Structure elucidation was done by using various spectrophotometric techniques like UV, IR, (1)H NMR, (13)C NMR and mass spectroscopy. The type of cell death caused by most active compound C was explored by fluorescence microscopy using the acridine orange/ethidium bromide method.. Petroleum ether extract of plant has shown significant cytotoxic potential. Three lignans sesamin (A), kobusin (B), and 4'O demethyl magnolin (C) has been isolated. All lignans showed cytotoxic activities in different ranges. Compound C was the novel bioactive compound from a plant source and found to be most active. In apoptosis study, treatment caused typical apoptotic morphological changes. It enhances the apoptosis at IC50 dose (21.72 µg/mL) however showing necrotic cell death at higher dose after 24h on MIA-PaCa cell lines.. Petroleum ether extract (60-80 °C) of Zanthoxylum alatum has cytotoxic potential. The lignans isolated from the petroleum ether extract were responsible for the cytotoxic potential of the extract. 4'O demethyl magnolin was novel compound from Zanthoxylum alatum. Hence the Zanthoxylum alatum can be further explored for the development of anticancer drug.

    Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Cell Line, Tumor; Dose-Response Relationship, Drug; Humans; Inhibitory Concentration 50; Lignans; Lung Neoplasms; Pancreatic Neoplasms; Plant Bark; Plant Extracts; Plant Stems; Time Factors; Zanthoxylum

2014
Taiwanin A targets non-steroidal anti-inflammatory drug-activated gene-1 in human lung carcinoma.
    Fitoterapia, 2014, Volume: 99

    Taiwanin A (α,β-bis(piperonylidene)-γ-butyrolactone) is extracted from Taiwania cryptomerioides. Taiwanin A is extracted from tree bark and exhibits antitumor activity in breast, liver, and lung cancer cell lines. The objective of this study was to demonstrate the cytotoxicity of Taiwanin A against tumor cells by increasing the expression of non-steroidal anti-inflammatory drug-activated gene-1 (NAG-1). NAG-1 has been reported to exhibit antitumor and proapoptotic activities, suggesting potential use in cancer therapy. Inhibiting NAG-1 mRNA expression in A549 reduced the cytotoxicity caused by Taiwanin A. Furthermore, the c-Jun-N-terminal kinase/Ste20-related protein proline/alanine-rich kinase (JNK/SPAK) pathway played a key role in the influence of NAG-1 on cell viability, whereas the addition of the JNK pathway inhibitor SP600125 resulted in an inhibitory effect on NAG-1 and recovery of Taiwanin-A-treated cells. A xenograft tumor model demonstrated that Taiwanin A dose-dependently significantly decreases tumor-mediated growth in nude mice by increasing the NAG-1 expression accompanying tumor apoptosis. These data supported the hypothesis that Taiwanin A inhibits lung carcinoma growth by increasing NAG-1 expression through the JNK pathway both in vivo and in vitro. This result can contribute to a compound design for increasing cytotoxicity activity in the future.

    Topics: Animals; Anthracenes; Antineoplastic Agents, Phytogenic; Apoptosis; Cell Line, Tumor; Furans; Growth Differentiation Factor 15; Humans; JNK Mitogen-Activated Protein Kinases; Lignans; Lung Neoplasms; MAP Kinase Signaling System; Mice, Inbred BALB C; Mice, Nude; Protein Serine-Threonine Kinases; Xenograft Model Antitumor Assays

2014
Honokiol inhibits lung tumorigenesis through inhibition of mitochondrial function.
    Cancer prevention research (Philadelphia, Pa.), 2014, Volume: 7, Issue:11

    Honokiol is an important bioactive compound found in the bark of Magnolia tree. It is a nonadipogenic PPARγ agonist and capable of inhibiting the growth of a variety of tumor types both in vitro and in xenograft models. However, to fully appreciate the potential chemopreventive activity of honokiol, a less artificial model system is required. To that end, this study examined the chemopreventive efficacy of honokiol in an initiation model of lung squamous cell carcinoma (SCC). This model system uses the carcinogen N-nitroso-trischloroethylurea (NTCU), which is applied topically, reliably triggering the development of SCC within 24 to 26 weeks. Administration of honokiol significantly reduced the percentage of bronchial that exhibit abnormal lung SCC histology from 24.4% bronchial in control to 11.0% bronchial in honokiol-treated group (P = 0.01) while protecting normal bronchial histology (present in 20.5% of bronchial in control group and 38.5% of bronchial in honokiol-treated group. P = 0.004). P63 staining at the SCC site confirmed the lung SCCs phenotype. In vitro studies revealed that honokiol inhibited lung SCC cells proliferation, arrested cells at the G1-S cell-cycle checkpoint, while also leading to increased apoptosis. Our study showed that interfering with mitochondrial respiration is a novel mechanism by which honokiol changed redox status in the mitochondria, triggered apoptosis, and finally leads to the inhibition of lung SCC. This novel mechanism of targeting mitochondrial suggests honokiol as a potential lung SCC chemopreventive agent.

    Topics: Adenosine Triphosphate; Animals; Anticarcinogenic Agents; Apoptosis; Biphenyl Compounds; Bronchi; Carcinogens; Carcinoma, Squamous Cell; Carmustine; Caspase 3; Caspase 7; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Female; Gene Expression Regulation, Neoplastic; Green Fluorescent Proteins; Humans; Lignans; Lung Neoplasms; Mice; Mitochondria; Neoplasm Transplantation; Oxidation-Reduction; Reactive Oxygen Species

2014
Honokiol inhibits non-small cell lung cancer cell migration by targeting PGE₂-mediated activation of β-catenin signaling.
    PloS one, 2013, Volume: 8, Issue:4

    Lung cancer remains a leading cause of death due to its metastasis to distant organs. We have examined the effect of honokiol, a bioactive constituent from the Magnolia plant, on human non-small cell lung cancer (NSCLC) cell migration and the molecular mechanisms underlying this effect. Using an in vitro cell migration assay, we found that treatment of A549, H1299, H460 and H226 NSCLC cells with honokiol resulted in inhibition of migration of these cells in a dose-dependent manner, which was associated with a reduction in the levels of cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2). Celecoxib, a COX-2 inhibitor, also inhibited cell migration. Honokiol inhibited PGE2-enhanced migration of NSCLC cells, inhibited the activation of NF-κB/p65, an upstream regulator of COX-2, in A549 and H1299 cells, and treatment of cells with caffeic acid phenethyl ester, an inhibitor of NF-κB, also inhibited migration of NSCLC cells. PGE2 has been shown to activate β-catenin signaling, which contributes to cancer cell migration. Therefore, we checked the effect of honokiol on β-catenin signaling. It was observed that treatment of NSCLC cells with honokiol degraded cytosolic β-catenin, reduced nuclear accumulation of β-catenin and down-regulated matrix metalloproteinase (MMP)-2 and MMP-9, which are the down-stream targets of β-catenin and play a crucial role in cancer cell metastasis. Honokiol enhanced: (i) the levels of casein kinase-1α, glycogen synthase kinase-3β, and (ii) phosphorylation of β-catenin on critical residues Ser(45), Ser(33/37) and Thr(41). These events play important roles in degradation or inactivation of β-catenin. Treatment of celecoxib also reduced nuclear accumulation of β-catenin in NSCLC cells. FH535, an inhibitor of Wnt/β-catenin pathway, inhibited PGE2-enhanced cell migration of A549 and H1299 cells. These results indicate that honokiol inhibits non-small cell lung cancer cells migration by targeting PGE2-mediated activation of β-catenin signaling.

    Topics: beta Catenin; Biphenyl Compounds; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Movement; Cell Nucleus; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Dinoprostone; Drugs, Chinese Herbal; Gene Knockdown Techniques; Humans; Lignans; Lung Neoplasms; Neoplasm Invasiveness; RNA Interference; Signal Transduction; Sulfonamides; Transcription Factor RelA

2013
Mechanism of arctigenin-mediated specific cytotoxicity against human lung adenocarcinoma cell lines.
    Phytomedicine : international journal of phytotherapy and phytopharmacology, 2013, Dec-15, Volume: 21, Issue:1

    The lignan arctigenin (ARG) from the herb Arctium lappa L. possesses anti-cancer activity, however the mechanism of action of ARG has been found to vary among tissues and types of cancer cells. The current study aims to gain insight into the ARG mediated mechanism of action involved in inhibiting proliferation and inducing apoptosis in lung adenocarcinoma cells. This study also delineates the cancer cell specificity of ARG by comparison with its effects on various normal cell lines. ARG selectively arrested the proliferation of cancer cells at the G0/G1 phase through the down-regulation of NPAT protein expression. This down-regulation occurred via the suppression of either cyclin E/CDK2 or cyclin H/CDK7, while apoptosis was induced through the modulation of the Akt-1-related signaling pathway. Furthermore, a GSH synthase inhibitor specifically enhanced the cytotoxicity of ARG against cancer cells, suggesting that the intracellular GSH content was another factor influencing the susceptibility of cancer cells to ARG. These findings suggest that specific cytotoxicity of ARG against lung cancer cells was explained by its selective modulation of the expression of NPAT, which is involved in histone biosynthesis. The cytotoxicity of ARG appeared to be dependent on the intracellular GSH level.

    Topics: Adenocarcinoma; Adenocarcinoma of Lung; Antineoplastic Agents, Phytogenic; Apoptosis; Arctium; Cell Cycle Proteins; Cell Line; Cyclin E; Cyclin-Dependent Kinase 2; Cyclins; Down-Regulation; Furans; Glutathione; Humans; Lignans; Lung Neoplasms; Nuclear Proteins; Oncogene Proteins; Phytotherapy; Plant Extracts; Proto-Oncogene Proteins c-akt; Signal Transduction

2013
Antimetastatic activity of honokiol in osteosarcoma.
    Cancer, 2012, Apr-15, Volume: 118, Issue:8

    Metastasizing osteosarcoma has a mean 5-year survival rate of only 20% to 30%. Therefore, novel chemotherapeutics for more effective treatment of this disease are required.. The antineoplastic activity of honokiol, which was demonstrated previously in numerous malignancies, was studied in vivo in C3H mice subcutaneously injected with syngeneic β-galactosidase bacterial gene (lacZ)-expressing LM8 osteosarcoma (LM8-lacZ) cells. In vitro cytotoxic effects of honokiol were investigated in 8 human and 2 murine osteosarcoma cell lines with different in vivo metastatic potential.. Seven days after subcutaneous flank injection of LM8-lacZ cells, daily intraperitoneal treatment of mice with 150 mg/kg honokiol reduced the number of micrometastases in the lung by 41% and reduced the number of macrometastases in the lung and liver by 69% and 80%, respectively, compared with control. Primary tumor growth was not inhibited. In osteosarcoma cell lines, honokiol inhibited the metabolic activity with a half-maximal concentration (IC(50) ) between 8.0 μg/mL and 16 μg/mL. Cyclosporin A partially reversed the inhibition of metabolic activity in LM8-lacZ cells. Cell proliferation and wound healing migration of LM8-lacZ cells were inhibited by honokiol with an IC(50) between 5.0 μg/mL and 10 μg/mL. Higher concentrations caused rapid cell death, which was distinct from necrosis, apoptosis, or autophagy but was associated with swelling of the endoplasmic reticulum, cytoplasmic vacuolation, and morphologically altered mitochondria.. Honokiol exhibited prominent antimetastatic activity in experimental osteosarcoma and caused rapid cell death in vitro that was unrelated to necrosis, apoptosis, or autophagy. The authors concluded that honokiol has considerable potential for the treatment of metastasizing osteosarcoma.

    Topics: Animals; Antineoplastic Agents; Apoptosis; Biphenyl Compounds; Bone Neoplasms; Cell Death; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; Female; Humans; Lignans; Liver Neoplasms; Lung Neoplasms; Mice; Mice, Inbred C3H; Osteosarcoma

2012
In vitro growth inhibition of human cancer cells by novel honokiol analogs.
    Bioorganic & medicinal chemistry, 2012, May-15, Volume: 20, Issue:10

    Honokiol possesses many pharmacological activities including anti-cancer properties. Here in, we designed and synthesized honokiol analogs that block major honokiol metabolic pathway which may enhance their effectiveness. We studied their cytotoxicity in human cancer cells and evaluated possible mechanism of cell cycle arrest. Two analogs, namely 2 and 4, showed much higher growth inhibitory activity in A549 human lung cancer cells and significant increase of cell population in the G0-G1 phase. Further elucidation of the inhibition mechanism on cell cycle showed that analogs 2 and 4 inhibit both CDK1 and cyclin B1 protien levels in A549 cells.

    Topics: Antineoplastic Agents, Phytogenic; Biphenyl Compounds; Blotting, Western; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Humans; Inhibitory Concentration 50; Lignans; Lung Neoplasms; Molecular Structure; Structure-Activity Relationship

2012
Anti-proliferative neolignans from Saururus chinensis against human cancer cell lines.
    Biological & pharmaceutical bulletin, 2012, Volume: 35, Issue:8

    Activity-guided fractionation of an 80% EtOH extract from the aerial parts of Saururus chinensis led to isolation of three anti-proliferative neolignans (1-3) along with four flavonoids (4-7) and four aristolactams (8-11). Their chemical structures were identified by analysis of spectroscopic data. All compounds 1-11 were evaluated for their activities against 28 human cancer cell lines using an in vitro cell proliferation assay. Compounds 1-3 showed potent anti-proliferative activities against cervical (C33a, IC50=0.01 µM for 1; 0.28 µM for 2; 2.80 µM for 3) and lung (NCI-H460, IC50=0.05 µM for 1; 1.37 µM for 2; 6.46 µM for 3) cancer cells without any remarkable cytotoxic effects on human normal lung cells as a control. Taken together, these data demonstrated the identification of anti-proliferative neolignans which are active components of S. chinensis.

    Topics: Animals; Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Female; Humans; Lignans; Lung Neoplasms; Male; Mice; Mice, Inbred BALB C; Molecular Structure; Phytotherapy; Plant Components, Aerial; Plant Extracts; Saururaceae; Uterine Cervical Neoplasms

2012
Anticancer potential of magnolol for lung cancer treatment.
    Archives of pharmacal research, 2011, Volume: 34, Issue:4

    Lung malignancy is a major cause of human mortality. As such, safe pharmacological agents that can detect lung cancer are urgently required. Magnolol has been reported to have anticancer property. However, it is still unclear whether magnolol induces apoptosis of lung carcinoma cells. In this study, magnolol inhibited cell growth, increased lactate dehydrogenase release, and modulated cell cycle in human lung carcinoma A549 cells. Magnolol induced the activation of caspase-3 and cleavage of Poly-(ADP)-ribose polymerase, and decreased the expression level of nuclear factor-κB/Rel A in the nucleus. In addition, magnolol inhibited basic fibroblast growth factor-induced proliferation and capillary tube formation of human umbilical vein endothelial cells. These data indicate that magnolol is a potential candidate for treating of human lung carcinoma.

    Topics: Antineoplastic Agents; Apoptosis; Biphenyl Compounds; Blotting, Western; Carcinoma, Non-Small-Cell Lung; Caspase 3; Cell Culture Techniques; Cell Cycle; Cell Line, Tumor; Cell Nucleus; Cell Proliferation; Cell Survival; Endothelial Cells; Endothelium, Vascular; Flow Cytometry; Humans; Lignans; Lung Neoplasms; Neovascularization, Pathologic; NF-kappa B; Poly(ADP-ribose) Polymerases

2011
Antitumor-promoting activity of lignans: inhibition of human cytomegalovirus IE gene expression.
    Anticancer research, 2010, Volume: 30, Issue:2

    Chemoprevention is a promising new approach to cancer prevention. Since the beginning of chemoprevention studies, short-term in vitro models used in the study of carcinogenesis have been applied in the identification of antitumor-promoting agents.. The lignans threo-4,4'-dihydroxy-3-methoxylignan, (-)-dihydroguaiaretic acid, 4'-hydroxy-3,3',4-trimethoxylignan, 3,3',4,4'-tetramethoxylignan, 4,4'-diacetyl-3,3'-dimethoxylignan, talaumidin, heliobuphthalmin, (-)-dihydro-cubebin, and hinokinin were evaluated for their ability to inhibit human cytomegalovirus (HCMV) IE-antigen expression in lung cancer cells (A549).. Most of the evaluated compounds reduced IE-antigen expression of HCMV, the best result being obtained with 4,4'-dihydroxy-3-methoxylignan. However, a dose-dependent significant increase of IE-antigen expression was found for the derivative (-)-dihydrocubebin.. The results of this study suggest that some of these lignans might be valuable as potential cancer chemopreventive agents.

    Topics: Adenocarcinoma; Antineoplastic Agents; Cell Survival; Cytomegalovirus; Cytomegalovirus Infections; Gene Expression Regulation, Viral; Humans; Immediate-Early Proteins; Immunoenzyme Techniques; Lignans; Lung Neoplasms; Myristicaceae; Plant Extracts; Tumor Cells, Cultured

2010
Lignans from Santalum album and their cytotoxic activities.
    Chemical & pharmaceutical bulletin, 2010, Volume: 58, Issue:4

    A new neolignan, (7R,8R)-5-O-demethylbilagrewin (1), together with four known lignans (2-5), were isolated from the heartwood of Santalum album (Santalaceae). The structure of 1 was determined by analysis of extensive spectroscopic data. The isolated compounds and derivatives were evaluated for their cytotoxic activities against HL-60 human promyelocytic leukemia cells and A549 human lung adenocarcinoma cells. Compounds 1 and 2 exhibited cytotoxicity against HL-60 cells with IC(50) values of 1.5+/-0.02 and 4.3+/-0.13 microM, and against A549 cells with IC(50) values of 13.6+/-0.32 and 19.9+/-1.27 microM, respectively. The aldehyde group of 1 and 2 was revealed to be a structural requirement for the appearance of cytotoxicity in this type of lignans. These tumor cell deaths were shown to be mediated through induction of apoptosis.

    Topics: Adenocarcinoma; Antineoplastic Agents, Phytogenic; Apoptosis; Cell Line, Tumor; Cytotoxins; DNA Fragmentation; Humans; Leukemia; Lignans; Lung Neoplasms; Molecular Structure; Neoplasms; Santalum

2010
Biodegradable self-assembled PEG-PCL-PEG micelles for hydrophobic honokiol delivery: I. Preparation and characterization.
    Nanotechnology, 2010, May-28, Volume: 21, Issue:21

    This study aims to develop self-assembled poly(ethylene glycol)-poly(epsilon-caprolactone)-poly(ethylene glycol) (PEG-PCL-PEG, PECE) micelles to encapsulate hydrophobic honokiol (HK) in order to overcome its poor water solubility and to meet the requirement of intravenous administration. Honokiol loaded micelles (HK-micelles) were prepared by self-assembly of PECE copolymer in aqueous solution, triggered by its amphiphilic characteristic assisted by ultrasonication without any organic solvents, surfactants and vigorous stirring. The particle size of the prepared HK-micelles measured by Malvern laser particle size analyzer were 58 nm, which is small enough to be a candidate for an intravenous drug delivery system. Furthermore, the HK-micelles could be lyophilized into powder without any adjuvant, and the re-dissolved HK-micelles are stable and homogeneous with particle size about 61 nm. Furthermore, the in vitro release profile showed a significant difference between the rapid release of free HK and the much slower and sustained release of HK-micelles. Moreover, the cytotoxicity results of blank micelles and HK-micelles showed that the PECE micelle was a safe carrier and the encapsulated HK retained its potent antitumor effect. In short, the HK-micelles were successfully prepared by an improved method and might be promising carriers for intravenous delivery of HK in cancer chemotherapy, being effective, stable, safe (organic solvent and surfactant free), and easy to produce and scale up.

    Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Biphenyl Compounds; Cell Growth Processes; Cell Line, Tumor; Colonic Neoplasms; Drug Delivery Systems; Drug Screening Assays, Antitumor; Drug Stability; Drugs, Chinese Herbal; Humans; Lignans; Lung Neoplasms; Mice; Micelles; Microscopy, Electron, Transmission; Particle Size; Polyesters; Polyethylene Glycols; Solubility; Sonication; X-Ray Diffraction

2010
Obtusilactone A and (-)-sesamin induce apoptosis in human lung cancer cells by inhibiting mitochondrial Lon protease and activating DNA damage checkpoints.
    Cancer science, 2010, Volume: 101, Issue:12

    Several compounds from Cinnamomum kotoense show anticancer activities. However, the detailed mechanisms of most compounds from C. kotoense remain unknown. In this study, we investigated the anticancer activity of obtusilactone A (OA) and (-)-sesamin in lung cancer. Our results show that human Lon is upregulated in non-small-cell lung cancer (NSCLC) cell lines, and downregulation of Lon triggers caspase-3 mediated apoptosis. Through enzyme-based screening, we identified two small-molecule compounds, obtusilactone A (OA) and (-)-sesamin from C. kotoense, as potent Lon protease inhibitors. Obtusilactone A and (-)-sesamin interact with Ser855 and Lys898 residues in the active site of the Lon protease according to molecular docking analysis. Thus, we suggest that cancer cytotoxicity of the compounds is partly due to the inhibitory effects on Lon protease. In addition, the compounds are able to cause DNA double-strand breaks and activate checkpoints. Treatment with OA and (-)-sesamin induced p53-independent DNA damage responses in NSCLC cells, including G(1) /S checkpoint activation and apoptosis, as evidenced by phosphorylation of checkpoint proteins (H2AX, Nbs1, and Chk2), caspase-3 cleavage, and sub-G(1) accumulation. In conclusion, OA and (-)-sesamin act as both inhibitors of human mitochondrial Lon protease and DNA damage agents to activate the DNA damage checkpoints as well induce apoptosis in NSCLC cells. These dual functions open a bright avenue to develop more selective chemotherapy agents to overcome chemoresistance and sensitize cancer cells to other chemotherapeutics.

    Topics: Amino Acid Sequence; Antineoplastic Agents; Apoptosis; Blotting, Western; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Separation; Comet Assay; Dioxoles; DNA Damage; Flow Cytometry; Humans; Lignans; Lung Neoplasms; Mitochondria; Molecular Sequence Data; Protease La; Protein Structure, Quaternary; Signal Transduction

2010
Self-assembled honokiol-loaded micelles based on poly(epsilon-caprolactone)-poly(ethylene glycol)-poly(epsilon-caprolactone) copolymer.
    International journal of pharmaceutics, 2009, Mar-18, Volume: 369, Issue:1-2

    Self-assembled polymeric micelles are widely applied in drug delivery system (DDS). In this study, honokiol (HK) loaded micelles were prepared from biodegradable poly(epsilon-caprolactone)-poly(ethylene glycol)-poly(epsilon-caprolactone) (PCEC) copolymers. Micelles were prepared by self-assembly of triblock copolymer PCEC in distilled water triggered by its amphiphilic character without any organic solvent. Drug loading and encapsulation efficiency were determined by adjusting the weight ratio of HK and PCEC. The particle size and zeta potential distribution of obtained micelles were determined using Malvern laser particle sizer, and spherical geometry were observed on atomic force microscope (AFM). Otherwise, the thermo-sensitivity of honokiol-loaded micelles was monitored. And the cytotoxicity results of drug loaded micelles showed that the encapsulated honokiol remained potent antitumor effect. Moreover, in vitro release profile demonstrated a significant difference between rapid release of free honokiol and much slower and sustained release of HK-loaded micelles. These results suggested that we have successfully prepared honokiol-loaded micelles in an improved method which is safer and more efficient. The prepared micelles might be potential carriers for honokiol delivery in cancer chemotherapy.

    Topics: Antineoplastic Agents, Phytogenic; Biphenyl Compounds; Cell Line, Tumor; Delayed-Action Preparations; Drug Carriers; Drug Delivery Systems; Humans; Lasers; Lignans; Lung Neoplasms; Micelles; Microscopy, Atomic Force; Particle Size; Polyesters; Polyethylene Glycols; Temperature

2009
Dibenzocyclooctadiene lignans overcome drug resistance in lung cancer cells--study of structure-activity relationship.
    Toxicology in vitro : an international journal published in association with BIBRA, 2009, Volume: 23, Issue:6

    A panel of nine dibenzo[a,c]cyclooctadiene lignans, schizandrin, gomisin A, gomisin N, gomisin J, angeloylgomisin H, tigloylgomisin P, deoxyschizandrin, gamma-schizandrin and wuweizisu C was examined for their effect on multidrug resistance, as well as their anti-proliferative activities. COR-L23/R, a multidrug resistant sub-line, which has been reported to over-express multidrug resistance-associated protein (MRP1), was used for the experiments together with its parent cell line COR-L23 (human lung cell carcinoma). We found that lignans deoxyschizandrin and gamma-schizandrin at relatively non-toxic concentrations restored the cytotoxic action of doxorubicin to COR-L23/R cells. Deoxyschizandrin and gamma-schizandrin also significantly enhanced the accumulation of doxorubicin in drug resistant cells. Both lignans alone had no effect on the cell cycle; however, when combined with sub-toxic doses of doxorubicin, they induced cell cycle arrest in the G2/M phase, which is typical for toxic doses of doxorubicin. Our results suggest that deoxyschizandrin and gamma-schizandrin potentiate the cytotoxic effect of doxorubicin in doxorubicin resistant lung cancer cells COR-L23/R by increasing the accumulation of doxorubicin inside the cells. The common structural feature of both active lignans is the R-biaryl configuration and the absence of a hydroxy group at C-8. Unlike the reversal effect, the cytotoxicity of lignans with the R-biaryl configuration was similar to that observed for lignans with the S-biaryl configuration.

    Topics: Antibiotics, Antineoplastic; Carcinoma, Large Cell; Cell Division; Cell Line, Tumor; Cyclooctanes; Dose-Response Relationship, Drug; Doxorubicin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; G2 Phase; Humans; Lignans; Lung Neoplasms; Structure-Activity Relationship

2009
The natural product honokiol preferentially inhibits cellular FLICE-inhibitory protein and augments death receptor-induced apoptosis.
    Molecular cancer therapeutics, 2008, Volume: 7, Issue:7

    Targeting death receptor-mediated apoptosis has emerged as an effective strategy for cancer therapy. However, certain types of cancer cells are intrinsically resistant to death receptor-mediated apoptosis. In an effort to identify agents that can sensitize cancer cells to death receptor-induced apoptosis, we have identified honokiol, a natural product with anticancer activity, as shown in various preclinical studies, as an effective sensitizer of death receptor-mediated apoptosis. Honokiol alone moderately inhibited the growth of human lung cancer cells; however, when combined with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), greater effects on decreasing cell survival and inducing apoptosis than TRAIL alone were observed, indicating that honokiol cooperates with TRAIL to enhance apoptosis. This was also true to Fas-induced apoptosis when combined with Fas ligand or an agonistic anti-Fas antibody. Among several apoptosis-associated proteins tested, cellular FLICE-inhibitory protein (c-FLIP) was the only one that was rapidly down-regulated by honokiol in all of the tested cell lines. The down-regulation of c-FLIP by honokiol could be prevented by the proteasome inhibitor MG132. Moreover, honokiol increased c-FLIP ubiquitination. These results indicate that honokiol down-regulates c-FLIP by facilitating its degradation through a ubiquitin/proteasome-mediated mechanism. Enforced expression of ectopic c-FLIP abolished the ability of honokiol to enhance TRAIL-induced apoptosis. Several honokiol derivatives, which exhibited more potent effects on down-regulation of c-FLIP than honokiol, showed better efficacy than honokiol in inhibiting the growth and enhancing TRAIL-induced apoptosis as well. Collectively, we conclude that c-FLIP down-regulation is a key event for honokiol to modulate the death receptor-induced apoptosis.

    Topics: Apoptosis; Biphenyl Compounds; Carcinoma, Non-Small-Cell Lung; CASP8 and FADD-Like Apoptosis Regulating Protein; Cell Line, Tumor; Cell Proliferation; Cell Survival; Down-Regulation; Humans; JNK Mitogen-Activated Protein Kinases; Lignans; Lung Neoplasms; Proteasome Endopeptidase Complex; Protein Processing, Post-Translational; Receptors, Death Domain; TNF-Related Apoptosis-Inducing Ligand; Ubiquitin

2008
Improved therapeutic effectiveness by combining liposomal honokiol with cisplatin in lung cancer model.
    BMC cancer, 2008, Aug-16, Volume: 8

    Honokiol is a major bioactive compound extracted from Magnolia. The present study was designed to determine whether liposomal honokiol has the antitumor activity against human lung cancer as well as potentiates the antitumor activity of cisplatin in A549 lung cancer xenograft model, if so, to examine the possible mechanism in the phenomenon.. human A549 lung cancer-bearing nude mice were treated with liposomal honokiol, liposomal honokiol plus DDP or with control groups. Apoptotic cells and vessels were evaluated by fluorescent in situ TUNEL assay and by immunohistochemistry with an antibody reactive to CD31 respectively.. The present study showed that liposomal honokiol alone resulted in effective suppression of the tumor growth, and that the combined treatment with honokiol plus DDP had the enhanced inhibition of the tumor growth and resulted in a significant increase in life span. The more apparent apoptotic cells in the tumors treated with honokiol plus DDP was found in fluorescent in situ TUNEL assay, compared with the treatment with control groups. In addition, the combination of honokiol and DDP apparently reduced the number of vessels by immunolabeling of CD31 in the tissue sections, compared with control groups.. In summary, our data suggest that honokiol alone had the antitumor activity against human lung cancer in A549 lung cancer xenograft model, and that the combination of honokiol with DDP can enhance the antitumor activity, and that the enhanced antitumor efficacy in vivo may in part result from the increased induction of the apoptosis and the enhanced inhibition of angiogenesis in the combined treatment. The present findings may be of importance to the further exploration of the potential application of the honokiol alone or the combined approach in the treatment of lung carcinoma.

    Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Biphenyl Compounds; Cell Line, Tumor; Cisplatin; Humans; In Situ Nick-End Labeling; Lignans; Liposomes; Lung Neoplasms; Mice; Neoplasm Transplantation; Neovascularization, Pathologic; Plant Extracts; Platelet Endothelial Cell Adhesion Molecule-1

2008
Liposomal honokiol, a potent anti-angiogenesis agent, in combination with radiotherapy produces a synergistic antitumor efficacy without increasing toxicity.
    Experimental & molecular medicine, 2008, Dec-31, Volume: 40, Issue:6

    Honokiol is an active compound purified from magnolia that has been shown to induce cell differentiation, apoptosis, and anti-angiogenesis effects, as well as an enhancement in tumor growth delay in combination with chemotherapeutic agents in several mouse xenograft models. Our goal was to investigate the radiosensitization effect of honokiol on lung carcinoma. The radiosensitization effect of liposomal honokiol in Lewis lung carcinoma cells (LL/2) was analyzed using an in vitro clonogenic survival assay. For an in vivo study, Lewis lung carcinoma-bearing C57BL/6 mice were treated with either liposomal honokiol at 25 mg/kg or 5 Gy of single tumor radiation, or a combination of both over 12 days of treatment. The tumor growth delay and the survival time were evaluated. In addition, histological analysis of tumor sections was performed to examine changes by detecting the microvessel density and apoptosis in tumor tissues. In the clonogenic survival assay, LL/2 cells treated with IC(50) Lipo-HNK for 24 h showed a radiation enhancement ratio of 1.9. After 12 days of combination treatment, the tumor volume decreased 78% and produced an anti-tumor activity 1.3-fold greater than a predicted additive effect of honokiol and radiation alone. This combination treatment also caused an 8.7 day delay in tumor growth. The cell cycle distribution and histological analysis demonstrated that liposomal honokiol has an anti-tumor effect via inducing apoptosis and inhibiting angiogenesis. Liposomal honokiol can enhance tumor cell radiosensitivity in vitro and in vivo, indicating that radiotherapy combined with liposomal honokiol can lead to greater anti-tumor efficacy.

    Topics: Angiogenesis Inhibitors; Animals; Apoptosis; Biphenyl Compounds; Carcinoma, Lewis Lung; Cell Cycle; Cell Line, Tumor; Combined Modality Therapy; Humans; Lignans; Liposomes; Lung Neoplasms; Magnolia; Mice; Neoplasm Transplantation; Neovascularization, Pathologic; Radiation Tolerance; Transplantation, Heterologous

2008
Magnolol-induced H460 cells death via autophagy but not apoptosis.
    Archives of pharmacal research, 2007, Volume: 30, Issue:12

    We have reported that the protective effect of Magnolol on TBHP-induced injury in human nonsmall lung cancer H460 cells is partially via a p53 dependent mechanism. In this study, we found that Magnolol displayed a stimulatory effect at low concentrations (< or = 20 microM) whilst inhibitory effect at high concentrations (> or = 40 microM) in H460 cells. To investigate the mechanism of inducing the biphasic effect in H460 cells with Magnolol, we showed that Magnolol stimulated DNA synthesis at low concentrations and displayed an inhibition effect at high concentrations in H460 cells. More importantly, the inhibition of DNA synthesis was accompanied by the S phase cell cycle arrest and the appearance of intense intracytoplasmic vacuoles. These vacuoles can be labeled by autophagic marker monodansylcadaverin (MDC), 3-methyladenine (3-MA), an inhibitor of autophagy, was able to inhibit the occurrence of autophagy. The results of the LDH activity assay and TUNEL assay also showed that Magnolol at high concentrations inhibiting H460 cell growth was not via apoptotic pathway. Furthermore, accompanied by the occurrence of autophagy, the expression of phospho-Akt was down-regulated but PTEN significantly was up-regulated. In conclusion, Magnolol induces H460 cells death by autophagy but not apoptotic pathway. Blockade of PI3K/PTEN/Akt pathway is maybe related to Magnolol-induced autophagy. Autophagic cells death induction by Magnolol underlines the potential utility of its induction as a new cancer treatment modality.

    Topics: Antineoplastic Agents; Apoptosis; Autophagy; Biphenyl Compounds; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; DNA; Humans; Lignans; Lung Neoplasms; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase

2007
Phytoestrogens and risk of lung cancer.
    JAMA, 2006, Feb-15, Volume: 295, Issue:7

    Topics: Diet; Humans; Lignans; Lung Neoplasms; Phytoestrogens; Risk

2006
Dietary phytoestrogens and lung cancer risk.
    JAMA, 2005, Sep-28, Volume: 294, Issue:12

    Despite lung-specific in vitro and in vivo studies that support a chemopreventive role for phytoestrogens, there has been little epidemiologic research focused on dietary intake of phytoestrogens and risk of lung cancer.. To examine the relationship between dietary intake of phytoestrogens and risk of lung cancer.. Ongoing US case-control study of 1674 patients with lung cancer (cases) and 1735 matched healthy controls. From July 1995 through October 2003, participants were personally interviewed with epidemiologic and food frequency questionnaires to collect demographic information and to quantify dietary intake of 12 individual phytoestrogens.. Risk of lung cancer, estimated using unconditional multivariable logistic regression analyses stratified by sex and smoking status and adjusted for established and putative lung cancer risk factors.. Reductions in risk of lung cancer tended to increase with each increasing quartile of phytoestrogen intake. The highest quartiles of total phytosterols, isoflavones, lignans, and phytoestrogens were each associated with reductions in risk of lung cancer ranging from 21% for phytosterols (odds ratio [OR], 0.79; 95% confidence interval [CI], 0.64-0.97; P = .03 for trend) to 46% for total phytoestrogens from food sources only (OR, 0.54; 95% CI, 0.42-0.70; P<.001 for trend). Sex-specific effects were also apparent. For men, statistically significant trends for decreasing risk with increasing intake were noted for each phytoestrogen group, with protective effects for the highest quartile of intake ranging from 24% for phytosterols (OR, 0.76; 95% CI, 0.56-1.02; P = .04 for trend) to 44% for isoflavones (OR, 0.56; 95% CI, 0.41-0.76; P<.001 for trend), while in women, significant trends were only present for intake of total phytoestrogens from food sources only, with a 34% (OR, 0.66; 95% CI, 0.46-0.96; P = .01 for trend) protective effect for the highest quartile of intake. The apparent benefits of high phytoestrogen intake were evident in both never and current smokers but less apparent in former smokers. In women, statistically significant joint effects were evident between hormone therapy use and phytoestrogen intake. Specifically, high intake of the lignans enterolactone and enterodiol and use of hormone therapy were associated with a 50% (OR, 0.50; 95% CI, 0.31-0.68; P = .04 for interaction) reduction in risk of lung cancer.. While there are limitations and concerns regarding case-control studies of diet and cancer, these data provide further support for the limited but growing epidemiologic evidence that phytoestrogens are associated with a decrease in risk of lung cancer. Confirmation of these findings is still required in large-scale, hypothesis-driven, prospective studies.

    Topics: Aged; Case-Control Studies; Diet; Diet Surveys; Female; Food; Humans; Isoflavones; Lignans; Logistic Models; Lung Neoplasms; Male; Middle Aged; Phytoestrogens; Phytosterols; Risk Factors; Smoking; United States

2005
Effector mechanism of magnolol-induced apoptosis in human lung squamous carcinoma CH27 cells.
    British journal of pharmacology, 2003, Volume: 138, Issue:1

    1 Magnolol, an active component isolated from the root and stem bark of Magnolia officinalis, has been reported to exhibit antitumour effects, but little is known about its molecular mechanisms of action. 2 Magnolol inhibited proliferation of human lung squamous carcinoma CH27 cells at low concentrations (10-40 microM), and induced apoptosis at high concentrations (80-100 microM). 3 Treatment with 80 microM magnolol significantly increased the expression of Bad and Bcl-X(S) proteins, whereas it decreased the expression of Bcl-X(L). Overexpression of Bcl-2 protected CH27 cells against magnolol-triggered apoptosis. 4 Magnolol treatment resulted in accumulation of cytosolic cytochrome c and activation of caspase-9 and downstream caspases (caspase-3 and -6). Pretreatment with z-VAD-fmk markedly inhibited magnolol-induced cell death, but did not prevent cytosolic cytochrome c accumulation. 5 Magnolol induced a modest and persistent JNK activation and ERK inactivation in CH27 cells without evident changes in the protein levels. The responsiveness of JNK and ERK to magnolol suggests the involvement of these kinases in the initiation of the apoptosis process. 6 These results indicate that regulation of the Bcl-2 family, accumulation of cytosolic cytochrome c, and activation of caspase-9 and caspase-3 may be the effector mechanisms of magnolol-induced apoptosis.

    Topics: Apoptosis; Biphenyl Compounds; Carcinoma, Squamous Cell; Cell Line; Cell Survival; Gene Expression Regulation; Humans; Lignans; Lung Neoplasms; Magnolia; MAP Kinase Signaling System; Plant Bark; Plant Extracts; Tumor Cells, Cultured

2003
Down-modulation of Bcl-XL, release of cytochrome c and sequential activation of caspases during honokiol-induced apoptosis in human squamous lung cancer CH27 cells.
    Biochemical pharmacology, 2002, May-01, Volume: 63, Issue:9

    Honokiol is a phenolic compound purified from Magnolia officinalis, which induced the apoptotic cell death in several types of human cancer cells. In the present study, the molecular mechanism of honokiol-mediated apoptotic process was examined in human squamous lung cancer CH27 cells. Here, we found that honokiol-induced apoptotic cell death was accompanied by upregulation of Bad and downregulation of Bcl-XL, while honokiol had no effect on the levels of Bcl-2, Bcl-XS, Bag-1, Bax and Bak proteins. Moreover, honokiol treatment caused the release of mitochondrial cytochrome c to cytosol and sequential activation of caspases. Proteolytic activation of caspase-3 and cleavage of PARP, an in vivo substrate for caspase-3, were observed in honokiol-treated CH27 cells. Furthermore, treatment with caspase inhibitors z-DEVD-fmk and z-VAD-fmk markedly blocked honokiol-induced apoptosis. These results demonstrated that modulation of Bcl-XL and Bad proteins, release of mitochondrial cytochrome c and activation of caspase-3, participated in honokiol-triggered apoptotic process in human squamous lung cancer CH27 cells.

    Topics: Antineoplastic Agents, Phytogenic; Apoptosis; bcl-X Protein; Biphenyl Compounds; Caspases; Cytochrome c Group; Enzyme Activation; Humans; Lignans; Lung Neoplasms; Proto-Oncogene Proteins c-bcl-2; Tumor Cells, Cultured

2002
Anti-tumor-promoting activity of lignans from the aerial part of Saussurea medusa.
    Cancer letters, 2000, Sep-29, Volume: 158, Issue:1

    In the course of our continuing search for novel cancer chemopreventive agents from natural sources, several kinds of Compositae plants were screened. Consequently, the lignans, arctiin (ARC) and arctigenin (ARC-G), were obtained from the aerial part of Saussurea medusaas active constituents. These compounds exhibited the remarkable anti-tumor-promoting effect on two-stage carcinogenesis test of mouse skin tumors induced by 7, 12-dimethylbenz[a]anthracene as an initiator and 12-O-tetradecanoyl phorbol-13-acetate as a promoter by both topical application and oral administration. Furthermore, ARC-G exhibited potent anti-tumor-promoting activity on two-stage carcinogenesis test of mouse pulmonary tumors induced by 4-nitroquinoline-N-oxide as an initiator and glycerol as a promoter.

    Topics: 4-Nitroquinoline-1-oxide; 9,10-Dimethyl-1,2-benzanthracene; Administration, Oral; Administration, Topical; Animals; Antineoplastic Agents, Phytogenic; Asteraceae; Cells, Cultured; Disease Models, Animal; Female; Glycerol; Lignans; Lung Neoplasms; Mice; Mice, Inbred ICR; Mice, Inbred SENCAR; Neoplasm Transplantation; Phytotherapy; Skin Neoplasms; Tetradecanoylphorbol Acetate

2000
Effects of n-tritriacontane-16,18-dione, curcumin, chlorphyllin, dihydroguaiaretic acid, tannic acid and phytic acid on the initiation stage in a rat multi-organ carcinogenesis model.
    Cancer letters, 1997, Feb-26, Volume: 113, Issue:1-2

    The modifying effects of the naturally occurring antioxidants n-tritriacontane-16,18-dione (TTAD), curcumin, dihydroguaiaretic acid (DHGA), chlorophyllin, tannic acid and phytic acid on the initiation stage in a rat multi-organ carcinogenesis model were examined in male F344 rats. Animals were initiated with two i.p. injections of 2,2'-dihydroxy-di-n-propylnitrosamine (DHPN), followed by two i.g. administrations of N-ethyl-N-hydroxyethylnitrosamine (EHEN), and then three s.c. injections of 3,2'-methyl-4-aminobiphenyl (DMAB) during the first 3 weeks. Starting 1 day before the first carcinogen application, groups of rats received diet containing one of the antioxidants (0.2% TTAD, the others at 1% each) until 1 week after the last carcinogen exposure. Surviving animals were killed and complete autopsies were performed at the end of week 36. Histological examination revealed no inhibitory effects in terms of the multiplicities and/or incidences of neoplastic lesions in any of the organs examined, other than a significant increase in seminal vesicle atypical hyperplasia observed in rats treated with tannic acid. Thus, the antioxidants, with the exception of tannic acid, did not show any modifying effects on the initiation stage in the present multi-organ carcinogenesis model and at the present dose levels applied.

    Topics: Aminobiphenyl Compounds; Animals; Antimutagenic Agents; Antineoplastic Agents; Antioxidants; Carcinogens; Chlorophyllides; Curcumin; Diethylnitrosamine; Guaiacol; Hydrolyzable Tannins; Lignans; Liver Neoplasms; Lung Neoplasms; Male; Neoplasms, Experimental; Nitrosamines; Paraffin; Phytic Acid; Precancerous Conditions; Rats; Rats, Inbred F344

1997
Inhibitory effects of shouseiryu-to on two-stage carcinogenesis. II. Anti-tumor-promoting activities of lignans from Asiasarum heterotropoides var. mandshuricum.
    Biological & pharmaceutical bulletin, 1997, Volume: 20, Issue:7

    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

1997
Synthesis and cytotoxicity of novel lignans.
    Journal of medicinal chemistry, 1995, Jun-09, Volume: 38, Issue:12

    In this study the syntheses of 11 novel lignans are described. Their cytotoxicities are studied in GLC4, a human small cell lung carcinoma cell line, using the microculture tetrazolium (MTT) assay. Ten of these compounds were substituted with a menthyloxy group on the 5-position of the lactone. These compounds can easily be prepared in (novel) 'one-pot', three- or four-step syntheses. In addition, methods for controlling the stereogenic centers are described. Furthermore, five naturally occurring podophyllotoxin-related compounds were tested. The cytotoxicities of all lignan compounds, and of three non-lignan intermediates originating from the syntheses, were compared with the clinically applied anticancer agents etoposide, teniposide, and cisplatin. Most compounds showed moderate to high activities against GLC4, and two of the compounds containing a menthyloxy group showed activities comparable to the reference cytotoxic agents.

    Topics: Antineoplastic Agents; Carcinoma, Small Cell; Humans; Lignans; Lung Neoplasms; Tumor Cells, Cultured

1995
Synthesis and evaluation of pyrazolignans. A new class of cytotoxic agents.
    Bioorganic & medicinal chemistry, 1995, Volume: 3, Issue:9

    A series of fused pyrazole derivatives of cyclolignans have been prepared through simple chemical routes and evaluated for their cytotoxic activities in culture cells of P-388 murine leukemia, A-549 lung carcinoma and HT-29 colon carcinoma. Despite the lack of the lactone moiety in their structures, they show IC50 values at microM levels.

    Topics: Animals; Antineoplastic Agents, Phytogenic; Drug Screening Assays, Antitumor; HT29 Cells; Humans; Leukemia P388; Lignans; Lung Neoplasms; Magnetic Resonance Spectroscopy; Mice; Pyrazoles; Structure-Activity Relationship

1995