lignans and Pancreatic-Neoplasms

Arctigenin (AR) and its glycoside, arctiin, are two major active ingredients of Arctium lappa L (A lappa), a popular medicinal herb and health supplement frequently used in Asia. In the past several decades, bioactive components from A lappa have attracted the attention of researchers due to their promising therapeutic effects. In the current article, we aimed to provide an overview of the pharmacology of AR and arctiin, focusing on their anti-inflammatory effects, pharmacokinetics properties and clinical efficacies. Compared to acrtiin, AR was reported as the most potent bioactive component of A lappa in the majority of studies. AR exhibits potent anti-inflammatory activities by inhibiting inducible nitric oxide synthase (iNOS) via modulation of several cytokines. Due to its potent anti-inflammatory effects, AR may serve as a potential therapeutic compound against both acute inflammation and various chronic diseases. However, pharmacokinetic studies demonstrated the extensive glucuronidation and hydrolysis of AR in liver, intestine and plasma, which might hinder its in vivo and clinical efficacy after oral administration. Based on the reviewed pharmacological and pharmacokinetic characteristics of AR, further pharmacokinetic and pharmacodynamic studies of AR via alternative administration routes are suggested to promote its ability to serve as a therapeutic agent as well as an ideal bioactive marker for A lappa.

Topics: Animals; Anti-Infective Agents; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Arctium; Cell Line, Tumor; Diabetic Nephropathies; Furans; Glucosides; Humans; Lignans; Neuroprotective Agents; Pancreatic Neoplasms

Arctigenin is evaluated for antitumor efficacy in patients with pancreatic cancer. It has an inhibitory activity on mitochondrial complex I.Therefore, plasma lactate level of patients after arctigenin administration was evaluated for biomarker of clinical response and/or adverse effect. Plasma lactate level in 15 patients enrolled in a Phase I clinical trial of GBS-01 rich in arctigenin was analyzed by colorimetric assay. Statistical analyses for association of plasma lactate and clinical responses, pharmacokinetics of arctigenin, and background factors of each patient by multivariate and univariate analyses.In about half of the patients, transient increase of lactate was observed. Correlation between plasma lactate level and pharmacokinetic parameters of arctigenin and its glucuronide conjugate, and clinical outcome was not detected. Regarding to the determinant of lactate level, only slight association with liver function test was detected. Plasma lactate level is primary determined by reutilization rather than production for antitumor effect and dose not serve as a biomarker. Arctigenin, inhibition of mitochondrial complex I, plasma lactate concentration, phase I clinical trial of GBS-01, Cori cycle.

Topics: Antineoplastic Agents, Phytogenic; Arctium; Area Under Curve; Biomarkers; Carcinoma, Adenosquamous; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Deoxycytidine; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Drugs, Chinese Herbal; Furans; Gemcitabine; Gluconeogenesis; Humans; Kaplan-Meier Estimate; Kidney; Lactic Acid; Lignans; Liver; Mitochondria; Oxidative Phosphorylation; Pancreatic Neoplasms; Plant Extracts

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive types of cancer and exhibits a devastating 5-year survival rate. The most recent procedure for the treatment of PDAC is a combination of several conventional chemotherapeutic agents, termed FOLFIRINOX, that includes irinotecan, leucovorin, oxaliplatin, and 5-fluorouracil (5-FU). However, ongoing treatment using these agents is challenging due to their severe side effects and limitations on the range of patients available for PDAC. Therefore, safer and more innovative anticancer agents must be developed. The anticarcinoma activity of matairesinol that can be extracted from seagrass has been reported in various types of cancer, including prostate, breast, cervical, and pancreatic cancer. However, the molecular mechanism of effective anticancer activity of matairesinol against pancreatic cancer remains unclear. In the present study, we confirmed the inhibition of cell proliferation and progression induced by matairesinol in representative human pancreatic cancer cell lines (MIA PaCa-2 and PANC-1). Additionally, matairesinol triggers apoptosis and causes mitochondrial impairment as evidenced by the depolarization of the mitochondrial membrane, disruption of calcium, and suppression of cell migration and related intracellular signaling pathways. Finally, matairesinol exerts a synergistic effect with 5-FU, a standard anticancer agent for PDAC. These results demonstrate the therapeutic potential of matairesinol in the treatment of PDAC.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Fluorouracil; Furans; Humans; Lignans; Male; Mitochondria; Pancreatic Neoplasms

Topics: Cell Line, Tumor; Cell Proliferation; Humans; Lignans; Matrix Metalloproteinase 3; Pancreatic Neoplasms; Physalis

Six new compounds, wikstronin A (1), wikstronin B (2), wikstresinol (3), acetylwikstresinol (4), bis-5',5'-(+)-matairesinol (5), bis-5,5'-(+)-matairesinol (6), together with 20 known compounds (7-26) were isolated from the CH

Topics: Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Drug Screening Assays, Antitumor; Humans; Lignans; Molecular Structure; Pancreatic Neoplasms; Plant Roots; Wikstroemia

Despite the potential cancer preventive effects of flavonoids and lignans, their ability to reduce pancreatic cancer risk has not been demonstrated in epidemiological studies. Our aim was to examine the association between dietary intakes of flavonoids and lignans and pancreatic cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. A total of 865 exocrine pancreatic cancer cases occurred after 11.3 years of follow-up of 477,309 cohort members. Dietary flavonoid and lignan intake was estimated through validated dietary questionnaires and the US Department of Agriculture (USDA) and Phenol Explorer databases. Hazard ratios (HR) and 95% confidence intervals (CIs) were calculated using age, sex and center-stratified Cox proportional hazards models, adjusted for energy intake, body mass index (BMI), smoking, alcohol and diabetes status. Our results showed that neither overall dietary intake of flavonoids nor of lignans were associated with pancreatic cancer risk (multivariable-adjusted HR for a doubling of intake = 1.03, 95% CI: 0.95-1.11 and 1.02; 95% CI: 0.89-1.17, respectively). Statistically significant associations were also not observed by flavonoid subclasses. An inverse association between intake of flavanones and pancreatic cancer risk was apparent, without reaching statistical significance, in microscopically confirmed cases (HR for a doubling of intake = 0.96, 95% CI: 0.91-1.00). In conclusion, we did not observe an association between intake of flavonoids, flavonoid subclasses or lignans and pancreatic cancer risk in the EPIC cohort.

Topics: Cohort Studies; Diet; Diet Records; Europe; Female; Flavonoids; Humans; Life Style; Lignans; Male; Middle Aged; Pancreatic Neoplasms; Proportional Hazards Models; Prospective Studies

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

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

Over the last twenty years, there is a limited number of effective cytotoxic or biological agents that managed to get approval in advanced pancreatic ductal adenocarcinoma. Despite numerous trials, investments in translational research and generally in health care, the survival of pancreatic cancer patients has improved by a few only months. This disappointing reality necessitates a better understanding of the pathogenesis of this disease and the identification of targetable alterations which might lead to development of more effective drugs or better combinations. At the 2013 Annual Meeting of the American Society of Clinical Oncology, few novel agents and new therapeutic concepts, tested in phase I studies in advanced pancreatic ductal adenocarcinoma, were presented. The first notable phase I study referred to the combination of chemotherapy with local delivery of silencing RNA against the K-ras mutation G12D, in advanced pancreatic ductal adenocarcinoma, which was well tolerated and promising (Abstract #4037). The second one referred to a combination of gemcitabine with pegylated recombinant human hyaluronidase (PEGPH20), an inhibitor of hyaluronan which as a matrix glycosaminoglycan is believed to play role in the reduced drug delivery to cancer (Abstract #4010). The other notable abstract was related to an early phase study which tested the safety and toxicity of arctigenin, a traditional herbal agent found in Arctium lappa Linné, administered as an oral formulation (GMS-01) in pancreatic ductal adenocarcinoma patient resistant to standard chemotherapy (Abstract #2559). The aforementioned early phase studies open new therapeutic approaches which deserve further testing in advanced pancreatic cancer.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase I as Topic; Deoxycytidine; Furans; Gemcitabine; Humans; Hyaluronoglucosaminidase; Lignans; Mutation; Pancreatic Neoplasms; Polyethylene Glycols; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); ras Proteins; Recombinant Proteins; RNA Interference; Treatment Outcome

Survival rates for patients with pancreatic cancer are extremely poor due to its asymptomatic progression to advanced and metastatic stage for which current therapies remain largely ineffective. Therefore, novel therapeutic agents and treatment approaches are desired to improve the clinical outcome. In this study, we determined the effects of honokiol, a biologically active constituent of oriental medicinal herb Magnolia officinalis/grandiflora, on two pancreatic cancer cell lines, MiaPaCa and Panc1, alone and in combination with the standard chemotherapeutic drug, gemcitabine. Honokiol exerted growth inhibitory effects on both the pancreatic cancer cell lines by causing cell cycle arrest at G₁ phase and induction of apoptosis. At the molecular level, honokiol markedly decreased the expression of cyclins (D1 and E) and cyclin-dependent kinases (Cdk2 and Cdk4), and caused an increase in Cdk inhibitors, p21 and p27. Furthermore, honokiol treatment led to augmentation of Bax/Bcl-2 and Bax/Bcl-xL ratios to favor apoptosis in pancreatic cancer cells. These changes were accompanied by enhanced cytoplasmic accumulation of NF-κB with a concomitant decrease in nuclear fraction and reduced transcriptional activity of NF-κB responsive promoter. This was associated with decreased phosphorylation of inhibitor of kappa B alpha (IκB-α) causing its stabilization and thus increased cellular levels. Importantly, honokiol also potentiated the cytotoxic effects of gemcitabine, in part, by restricting the gemcitabine-induced nuclear accumulation of NF-κB in the treated pancreatic cancer cell lines. Altogether, these findings demonstrate, for the first time, the growth inhibitory effects of honokiol in pancreatic cancer and indicate its potential usefulness as a novel natural agent in prevention and therapy.

Topics: Apoptosis; bcl-2-Associated X Protein; bcl-X Protein; Biphenyl Compounds; Cell Cycle; Cell Cycle Proteins; Cell Line, Tumor; Cell Nucleus; Cell Proliferation; Cell Survival; Deoxycytidine; Drug Screening Assays, Antitumor; Drug Synergism; G1 Phase; Gemcitabine; Humans; Lignans; NF-kappa B; Pancreatic Neoplasms; Protein Transport

Twelve phenolic compounds, including three stilbenes, two flavonoids, two coumarins, one neolignan, and four lignans, isolated from Euphorbia and Pycnanthus species or obtained by derivatization, were assayed for their potential antineoplastic efficacy in three human cancer cell lines: gastric (EPG85-257), pancreatic (EPP85-181), and colon (HT-29) carcinomas as well as derived multidrug-resistant sublines. In each case, two different multidrug-resistant variants, i.e., cell lines with classical and atypical MDR phenotype, were used. The majority of the MDR cancer sublines showed increased sensitivities to the studied compounds when compared to the parental sublines. The most active compound was the flavonoid naringenin, found to be 15-fold more effective against the atypical MDR subline of gastric carcinoma than in parental drug-sensitive cells. Furthermore, the stilbene trans-3,5,3',4'-tetramethoxypiceatannol and the lignans 4'-hydroxy-3,3',4-trimethoxylignan and heliobuphthalmin also exhibited high antineoplasic activities against the classical MDR subline derived from gastric carcinoma. The results of this study suggest that some phenolic compounds might be valuable for the treatment of multidrug-resistant cancer cells.

Topics: Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Colonic Neoplasms; Drug Resistance, Multiple; Euphorbia; Flavanones; Humans; Lignans; Magnoliopsida; Myristicaceae; Neoplasms; Pancreatic Neoplasms; Phenols; Phytotherapy; Plant Extracts; Stilbenes; Stomach Neoplasms

Tumor cells generally proliferate rapidly and the demand for essential nutrients as well as oxygen always exceeds the supply due to the unregulated growth and the insufficient and inappropriate vascular supply. However, cancer cells show an inherent ability to tolerate extreme conditions, such as that characterized by low nutrient and oxygen supply, by modulating their energy metabolism. Thus, targeting nutrient-deprived cancer cells may be a novel strategy in anticancer drug development. Based on that, we established a novel screening method to discover anticancer agents that preferentially inhibit cancer cell viability under the nutrient-deprived condition. After screening 500 medicinal plant extracts used in Japanese Kampo medicine, we found that a CH(2)Cl(2)-soluble extract of Arctium lappa exhibited 100% preferential cytotoxicity under the nutrient-deprived condition at a concentration of 50 microg/mL with virtually no cytotoxicity under nutrient-rich condition. Further bioassay-guided fractionation and isolation led to the isolation of arctigenin as the primary compound responsible for such preferential cytotoxicity; the compound exhibited 100% preferential cytotoxicity against nutrient-deprived cells at a concentration of 0.01 microg/mL. Furthermore, arctigenin was also found to strongly suppress the PANC-1 tumor growth in nude mice, as well as the growth of several of the tested pancreatic cancer cell lines, suggesting the feasibility of this novel antiausterity approach in cancer therapy. Further investigation of the mechanism of action of arctigenin revealed that the compound blocked the activation of Akt induced by glucose starvation, which is a key process in the tolerance exhibited by cancer cells to glucose starvation.

Topics: Animals; Antineoplastic Agents, Phytogenic; Arctium; Carcinoma, Hepatocellular; Cell Line, Tumor; Drug Screening Assays, Antitumor; Female; Furans; Glucose; Humans; Lignans; Liver Neoplasms; Mice; Mice, Inbred BALB C; Mice, Nude; Pancreatic Neoplasms; Phosphorylation; Proto-Oncogene Proteins c-akt; Xenograft Model Antitumor Assays

The effects of a cholesterol-free diet, a cholesterol-free diet supplemented with sesamin, and a diet supplemented with sesamin on pancreatic carcinogenesis of N-nitrosobis(2-oxopropyl)amine (BOP) were investigated in 140 female Syrian golden hamsters. BOP (70 and 20 mg/kg body wt) was injected s.c. twice at an interval of 2 weeks at the beginning of the experiment. Starting 3 weeks thereafter, the animals were maintained on basal diet, cholesterol-free diet, basal diet plus sesamin, or cholesterol-free diet plus sesamin for a further 15 weeks. All surviving hamsters were killed at week 18, and the pancreatic tissues examined histologically. The incidences of pancreatic neoplastic and preneoplastic lesions in each group did not show any statistically significant variation. The cholesterol-free diet significantly decreased the cholesterol contents of the serum, pancreas and liver, and sesamin supplement significantly decreased the cholesterol contents of the serum and liver. Both the cholesterol-free diet and sesamin decreased the serum lipoperoxide levels. The results thus indicated that low cholesterol per se and sesamin exert no significant influence on BOP-initiated pancreatic carcinogenesis in hamsters, at least within the 4 month period after carcinogen treatment.

Topics: Animals; Carcinogens; Cholesterol; Cholestyramine Resin; Cricetinae; Dioxoles; Female; Lignans; Lipid Peroxides; Mesocricetus; Nitrosamines; Pancreas; Pancreatic Neoplasms