benzofurans and Neoplasms

Napabucasin (also known as BBI608) is a natural naphthoquinone originally identified as a cancer cell stemness inhibitor. Accumulated in vitro and in vivo evidence demonstrated that napabucasin showed significant anticancer effects in various types of cancers. Napabucasin inhibits cancer cell proliferation, induces apoptosis and cell cycle arrest, and suppresses metastasis and relapse. Such anticancer activities of napabucasin mainly rely on the inhibition of cancer stemness by targeting signal transducer and activator of transcription 3 (STAT3) and its related gene inhibition. However, several novel molecular targets for napabucasin, such as NAD(P)H:quinone oxidoreductase 1 (NQO1) and thioredoxin reductase 1 (TrxR1), have been reported. Napabucasin represents a promising anticancer lead for multiple cancers. In this mini review, the anticancer potential and the molecular mechanism of napabucasin will be briefly highlighted.

Topics: Apoptosis; Benzofurans; Cell Line, Tumor; Humans; Naphthoquinones; Neoplasms; STAT3 Transcription Factor

Therapy resistance is the principal obstacle to achieving cures in cancer patients and its successful tackling requires a deep understanding of the resistance mediators. Increasing evidence indicates that tumor phosphatases are novel and druggable targets in translational oncology and their modulation may hinder tumor growth and motility and potentiate therapeutic sensitivity in various neoplasms via regulation of various signal transduction pathways. Dual-specificity phosphatases (DUSPs) are key players of cell growth, survival and death and have essential roles in tumor initiation, malignant progression and therapy resistance through regulation of the MAPK signaling pathway. In this review, different aspects of DUSPs are discussed.. A comprehensive literature review was performed using various websites including PubMed.. We provide mechanistic insights into the roles of well-known DUSPs in resistance to a wide range of cancer therapeutic approaches including chemotherapy, radiation and molecular targeted therapy in human malignancies. Moreover, we discuss the development of DUSP modulators, with a focus on DUSP1 and 6 inhibitors. Ultimately, the preclinical investigations of small molecule inhibitors of DUSP1 and 6 are outlined.. Emerging evidence indicates that the DUSP family is aberrantly expressed in human malignancies and plays critical roles in determining sensitivity to a wide range of cancer therapeutic strategies through regulation of the MAPK signaling pathways. Consequently, targeting DUSPs and their downstream molecules can pave the way for more effective cancer therapies.

Topics: Antineoplastic Agents; Benzofurans; Carcinogenesis; Drug Resistance, Neoplasm; Dual Specificity Phosphatase 1; Dual Specificity Phosphatase 6; Gene Expression Regulation, Neoplastic; Humans; Imidazoles; JNK Mitogen-Activated Protein Kinases; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Molecular Targeted Therapy; Neoplasms; p38 Mitogen-Activated Protein Kinases

Cancer is a leading cause of death which imposes a substantial financial burden. Among the several mechanisms involved in cancer progression, imbalance of immune cell-derived factors such as cytokines and chemokines plays a central role. IL-25, as a member of the IL-17 cytokine subfamily, exerts a paradoxical role in cancer, including tumor supportive and tumor suppressive. Hence, we have tried to clarify the role of IL-25 and its receptor in tumor progression and cancer prognosis. It has been confirmed that IL-25 exerts a tumor-suppressive role through inducing infiltration of eosinophils and B cells into the tumor microenvironment and activating the apoptotic pathways. In contrast, the tumor-supportive function has been implemented by activating inflammatory cascades, promoting cell cycle, and inducing type-2 immune responses. Since IL-25 has been dysregulated in tumor tissues and this dysregulation is involved in cancer development, its examination can be used as a tumor diagnostic and prognostic biomarker. Moreover, IL-25-based therapeutic approaches have shown promising results in cancer inhibition. In cancers in which IL-25 has a tumor-suppressive function, employing IL-25-enhancing approaches, such as Virulizin

Topics: Animals; Antineoplastic Agents; Apoptosis; Benzofurans; Bile; Biomarkers, Tumor; Breast Neoplasms; Carcinoma, Hepatocellular; Cell Cycle; Cell Proliferation; Disease Progression; Female; Humans; Immunity, Cellular; Interleukin-17; Liver Neoplasms; Male; Mice; Neoplasms; Prognosis; Prostatic Neoplasms; Receptors, Interleukin-17; Signal Transduction; Tissue Extracts; Tumor Microenvironment

Psoralidin (PSO) is a natural phenolic coumarin that is extracted from the seeds of Psoralea corylifolia L. PSO possesses a variety of pharmacological activities, including anti-oxidative, antibacterial, anti-inflammatory, anti-depressive and estrogenic-like effects. Other studies have indicated that PSO plays a beneficial role in multiple disease, especially cancer and osteoporosis. In this review, we first outline the basic background of PSO. Then we introduced the molecular mechanisms and signaling pathways of PSO in multiple cancers to elucidate its anticancer potential via inducing oxidative stress and apoptosis, inhibiting proliferation, promoting autophagy-dependent cell death, and activating the estrogen receptors (ER)-signaling pathway. Finally, we recommend the direction of future investigations. In general, the information compiled in this paper should serve as a comprehensive repository of information to help design PSO in other research and future efforts.

Topics: Animals; Antineoplastic Agents; Benzofurans; Coumarins; Humans; Neoplasms; Osteoporosis

Napabucasin (BBI608) is an orally administered small molecule that blocks stem cell activity in cancer cells by targeting the signal transducer and activator of transcription 3 pathway. The signal transducer and activator of transcription 3 pathway is over-activated in many types of cancer and has been shown to be an important pathway in cancer stem cell-mediated propagation of cancer. Cancer stem cells are a subpopulation of cancer cells considered to be the primary source of tumor growth, metastasis, and resistance to conventional therapies, and thus, responsible for cancer relapse. This review describes the clinical development program of this first-in-class cancer stemness inhibitor, including preclinical discovery, early clinical trials, current phase III clinical trial evaluation, and future therapeutic combinations. The therapeutic potential of napabucasin was first reported in a preclinical study that demonstrated the potent anti-tumor and anti-metastatic activity of napabucasin in several different cancer types, both in vitro and in vivo. In mouse models, napabucasin was effective both as a monotherapy and in combination with other agents; in particular, synergy was observed with paclitaxel in vivo. Napabucasin clinical trials have demonstrated encouraging anti-tumor activity as monotherapy and in combination with conventional therapeutics, with no significant pharmacokinetic interactions when used in combination therapies. Adverse events attributed to napabucasin have been predominantly mild, although some patients have experienced grade 3 gastrointestinal adverse events. More severe adverse events required reduced or discontinued dosing of napabucasin or medication to reverse or manage symptoms. In conclusion, napabucasin may prove useful in targeting cancer stem cells, with the potential to suppress metastasis and prevent relapse in patients with varying cancer types.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzofurans; Clinical Trials as Topic; Disease Models, Animal; Humans; Naphthoquinones; Neoplasms; Neoplastic Stem Cells; STAT3 Transcription Factor

Resveratrol has been extensively studied to investigate its biological effects, including its chemopreventive potential against cancer. Over the past decade, various resveratrol oligomers, both naturally occurring and synthetic, have been described. These resveratrol oligomers result from the polymerization of two or more resveratrol units to form dimers, trimers, tetramers, or even more complex derivatives. Some oligomers appear to have antitumor activities that are similar or superior to monomeric resveratrol. In this review, we discuss resveratrol oligomers with anticancer potential, with emphasis on well-characterized compounds, such as the dimer gnetin-C and other oligomers from Gnetum gnemon, whose safety, pharmacokinetic, and biological activities have been studied in humans.

Topics: Benzofurans; Chemoprevention; Humans; Neoplasms; Stilbenes

Kinases are known to regulate the majority of human cellular processes such as communication, division, metabolism, survival and apoptosis therefore they can be promising targets in cancer diseases, viral infection and in other disorders. Small molecules acting as selective human protein kinase inhibitors are very attractive pharmacological targets. This review presents a number of examples of biologically active natural and synthetic benzo[b]furans and their derivatives, such as benzo[b]furan-2- and 3-ones, benzo[b]furan-2- and 3-carboxylic acids, as well as benzo[c]furans as potential inhibitors of various human protein kinases. The pathways of function and implication of the inhibitors in cancer and other diseases are discussed.

Topics: Animals; Antineoplastic Agents; Apoptosis; Benzofurans; Drug Design; Humans; Molecular Targeted Therapy; Neoplasms; Protein Kinase Inhibitors; Protein Kinases

Rocaglamides (= flavaglines) are potent natural anti-cancer phytochemicals that inhibit cancer growth at nanomolar concentrations by the following mechanisms: (1) inhibition of translation initiation via inhibition of phosphorylation of the mRNA cap-binding eukaryotic translation initiation factor eIF4E and stabilization of RNA-binding of the translation initiation factor eIF4A in the eIF4F complex; (2) blocking cell cycle progression by activation of the ATM/ATR-Chk1/Chk2 checkpoint pathway; (3) inactivation of the heat shock factor 1 (HSF1) leading to up-regulation of thioredoxin-interacting protein (TXNIP) and consequent reduction of glucose uptake and (4) induction of apoptosis through activation of the MAPK p38 and JNK and inhibition of the Ras-CRaf-MEK-ERK signaling pathway. Besides the anti-cancer activities, rocaglamides are also shown to protect primary cells from chemotherapy-induced cell death and alleviate inflammation- and drug-induced injury in neuronal tissues. This review will focus on the recently discovered molecular mechanisms of the actions of rocaglamides and highlights the benefits of using rocaglamides in cancer treatment.

Topics: Animals; Antineoplastic Agents, Phytogenic; Benzofurans; Cell Cycle Checkpoints; Cell Proliferation; Gene Expression Regulation, Neoplastic; Humans; MAP Kinase Signaling System; Neoplasms; Xenograft Model Antitumor Assays

Both Yucheng and Yusho were events of accidental exposure to highly doses of polychlorinated biphenyls and dibenzofurans in Asian people. Mortality experiences caused by various diseases were reported in both cohorts with similar and dissimilar findings. We thus conducted a meta-analysis of two cohorts to reevaluate the effects of PCBs and PCDFs on major causes of mortalities. Two recently updated Yucheng and Yusho mortality studies were included. For selected diseases, standardized mortality ratios (SMR) and 95% confidence intervals (95% CI) were extracted. Meta-analyses were conducted using a random-effects model only when heterogeneity (I(2)  > 50% and/or p value <0.10 by the Q test) was not found. A total of 1,803 Yucheng subjects (male, N = 830; female, N = 973) with 48,751 person-years of follow-up and 1,664 Yusho subjects (male, N = 860; female, N = 804) with 50,773 person-years are included. An increase in all-cause mortality (pooled SMR=1.2, 95% CI: 1.1-1.3, I(2)  = 0.0%), all cancers (pooled SMR=1.3, 95% CI: 1.1-1.6, I(2)  = 0.0%), lung cancer (pooled SMR=1.7, 95% CI: 1.2-2.3, I(2) =0.0%), heart disease (pooled SMR=1.3, 95% CI: 1.0-1.7, I(2)  = 43.4%) and hepatic disease (pooled SMR=1.9, 95% CI: 1.3-2.8, I(2)  = 0.0%) were found in pooled males. Significant elevation from liver cancer was found in pooled females (pooled SMR=2.0, 95% CI: 1.1-3.6, I(2)  = 0.0%). This meta-analysis of Yucheng and Yusho cohorts showed similar elevation from all cancer, lung cancer, heart disease and hepatic disease mortalities in exposed men. Furthermore, a new finding of elevated liver cancer mortality in exposed women was identified.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Benzofurans; Child; Child, Preschool; Dibenzofurans, Polychlorinated; Environmental Exposure; Female; Food Contamination; Heart Diseases; Humans; Infant; Infant, Newborn; Liver Diseases; Male; Middle Aged; Neoplasms; Poisoning; Polychlorinated Biphenyls; Young Adult

Chronic diseases such as cancer, diabetes, neurodegenerative and cardiovascular diseases are characterized by an enhanced state of oxidative stress, which may result from the overproduction of reactive species and/or a decrease in antioxidant defenses. The search for new chemical entities with antioxidant profile is still thus an emerging field on ongoing interest. Due to the lack of reviews concerning the antioxidant activity of lichen-derived natural compounds, we performed a review of the antioxidant potential and mechanisms of action of natural compounds isolated from lichens. The search terms "lichens", "antioxidants" and "antioxidant response elements" were used to retrieve articles in LILACS, PubMed and Web of Science published until February 2014. From a total of 319 articles surveyed, 32 met the established inclusion and exclusion criteria. It was observed that the most common isolated compound studied was usnic acid, cited in 14 out of the 32 articles. The most often described antioxidant assays for the study of in vitro antioxidant activity were mainly DPPH, LPO and SOD. The most suggested mechanisms of action were scavenging of reactive species, enzymatic activation and inhibition of iNOS. Thus, compounds isolated from lichens are possible candidates for the management of oxidative stress, and may be useful in the treatment of chronic diseases.

Topics: Antioxidant Response Elements; Antioxidants; Benzofurans; Biphenyl Compounds; Free Radical Scavengers; Humans; Lichens; Neoplasms; Oxidation-Reduction; Oxidative Stress; Picrates

The polychlorinated dibenzo-p-dioxins (PCDD), polychlorinated dibenzofurans (PCDF), and dioxin-like polychlorinated biphenyls (dioxin-like PCB) are ubiquitous in food of animal origin and accumulate in fatty tissues of animals and humans. The most toxic congener is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The toxic responses include dermal toxicity, immunotoxicity, carcinogenicity, and reproductive and developmental toxicity. Toxic equivalency factors have been established for the other PCDD, PCDF and dioxin-like PCB relative to TCDD, and the combined toxicity of a sample can be expressed as toxic equivalent (WHO-TEQ). The EC Scientific Committee for Food evaluated these compounds in 2001. The assessment used the most sensitive adverse toxicological end-points of TCDD in experimental animals. These were developmental and reproductive effects in the male offspring of rats administered TCDD during pregnancy. Because of the large difference between rats and humans in the biological half-life of TCDD, the assessment used a body burden approach to compare across species and derived a tolerable weekly intake of 14 pg TCDD/kg of body weight (bw), which was extended to include all the 2,3,7,8-substituted PCDD and PCDF, and the dioxin-like PCB, and expressed as a group tolerable weekly intake of 14 pg WHO-TEQ/kg bw. The FAO/WHO Joint Expert Committee on Food Additives (JECFA) performed a similar assessment whereas the US Environmental Protection Agency (US EPA) has paid more attention to human data on carcinogenicity.

Topics: Adipose Tissue; Animals; Benzofurans; Body Burden; Dibenzofurans, Polychlorinated; Dioxins; Food Contamination; Humans; Immune System Diseases; Neoplasms; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins; Reproduction; Risk Assessment; Skin Diseases; United States; United States Environmental Protection Agency; World Health Organization

The International Agency for Research on Cancer (IARC) Monographs program reevaluated polychlorinated dibenzo-p-dioxins and evaluated polychlorinated dibenzofurans as possible carcinogenic hazards to humans in February 1997, using the most recent epidemiologic data on exposed human populations, experimental carcinogenicity bioassays in laboratory animals, and supporting evidence on relevant mechanisms of carcinogenesis. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) was evaluated as carcinogenic to humans (IARC group 1 classification) on the basis of limited evidence of carcinogenicity to humans derived from follow-up of workers who had been heavily exposed in industrial accidents and sufficient evidence of carcinogenicity in experimental animals. The evaluation also considered the following supporting evidence: TCDD is a multisite carcinogen in experimental animals and has been shown by several lines of evidence to act through a mechanism involving the aryl hydrocarbon receptor; this receptor is highly conserved in an evolutionary sense and functions the same way in humans as in experimental animals; tissue concentrations of TCDD are similar in heavily exposed human populations in which an increased overall cancer risk was observed and in exposed rats that developed tumors in carcinogenicity tests. Other polychlorinated dibenzo-p-dioxins, the nonchlorinated dibenzo-p-dioxin, and polychlorinated dibenzofurans were evaluated as not classifiable as to their carcinogenicity to humans (group 3).

Topics: Animals; Benzofurans; Carcinogenicity Tests; Carcinogens; Humans; Neoplasms; Occupational Exposure; Polychlorinated Dibenzodioxins; Risk Assessment

Topics: Animals; Benzofurans; Carcinogenicity Tests; Carcinogens; Cohort Studies; Disease Models, Animal; Environmental Exposure; Environmental Pollutants; Humans; Mice; Neoplasms; Rats; Receptors, Aryl Hydrocarbon

There is an increasing need to consider the various routes of exposure to individuals in occupational settings, as well as the exposure of the general public to a broad spectrum of carcinogens. The need to consider indoor environments is increasingly recognized in light of the amount of time spent indoors by a large majority of the population and the recognition that levels of certain toxicants are higher indoors than outdoors. This overview highlights (i) a general comparison of exposure to indoor and outdoor levels of 12 volatile organic compounds and (ii) the exposure of workers and the general public to benzene, 1,3-butadiene, formaldehyde, styrene, tetrachloroethylene, phthalate esters, polychlorinated dibenzofurans, radon, and electromagnetic fields.

Topics: Air Pollution, Indoor; Animals; Benzene; Benzofurans; Butadienes; Carcinogens; Carcinogens, Environmental; Dibenzofurans, Polychlorinated; Dibutyl Phthalate; Diethylhexyl Phthalate; Electromagnetic Fields; Formaldehyde; Humans; Mutagens; Neoplasms; Occupational Diseases; Polychlorinated Dibenzodioxins; Radon; Styrene; Styrenes; Tetrachloroethylene

Chloracne, an acneform eruption resulting from poisoning by halogenated aromatic compounds, has been a considerable problem over the last 40 years. The condition is always a symptom of systemic poisoning and should be familiar to all practitioners, particularly dermatologists. It is difficult to treat and can last for long periods without known additional exposure to chloracnegens. Some chloracnegens are capable of causing a variety of systemic signs and symptoms and may be oncogenic. Although there are probably fewer than 4,000 persons with chloracne worldwide, those found with the disorder should be evaluated medically on a regular basis and followed, if possible, throughout their lives.

Topics: 2,4-Dichlorophenoxyacetic Acid; 2,4,5-Trichlorophenoxyacetic Acid; Acne Vulgaris; Agent Orange; Aniline Compounds; Animals; Azo Compounds; Benzofurans; Biphenyl Compounds; Chemical Phenomena; Chemistry; Dibenzofurans, Polychlorinated; Dioxins; Drug Contamination; Halogens; Humans; Hydrocarbons, Chlorinated; Naphthalenes; Neoplasms; Polychlorinated Dibenzodioxins

This open-label, phase 1/1b study was conducted to evaluate the safety, tolerability, and pharmacokinetics (PK) of fruquintinib in United States (U.S.) patients to confirm the recommended phase 2 dose (RP2D) established in China. Patients with advanced solid tumors who had progressed on approved systemic therapy, were enrolled into 2 successive dose escalation cohorts, fruquintinib 3 mg (n = 7) or 5 mg (n = 7), orally, once daily (QD), 3 weeks on and 1 week off (3/1) with a 3 + 3 design followed by a dose expansion cohort at the RP2D 5 mg dose (n = 6). PK samples were collected on Days 1, 14, and 21 (Cycle 1). One of 6 dose-limiting toxicity (DLT)-evaluable patients in the 3 mg cohort had a DLT of grade 4 hypertension; there were no DLTs in the 5 mg cohort. The RP2D was confirmed to be 5 mg QD 3/1. All 20 patients experienced a treatment-emergent adverse event; grade ≥ 3 in 5 (71.4%; 3 mg dose) and 12 (92.3%; 5 mg dose) patients. Two patients had a confirmed partial response. After single and multiple doses, median peak plasma concentrations occurred at 2 h post-dose. Steady-state was achieved after 14 days of QD dosing with systemic exposure four-fold higher than that after a single dose. Fruquintinib was well tolerated, and the safety and PK profile at the 5 mg RP2D in U.S. patients with advanced solid tumors was consistent with dose-finding studies in China. Preliminary anticancer activity was observed. This study is registered at Clinicaltrials.gov NCT03251378.

Topics: Antineoplastic Agents; Benzofurans; Humans; Maximum Tolerated Dose; Neoplasms; Quinazolines

PF-00337210 is an oral, highly selective vascular endothelial growth factor receptor (VEGFR) inhibitor. We evaluated a composite of biomarkers in real time to identify the recommended phase 2 dose (RP2D) and preliminary anticancer activity of PF-00337210.. Patients (Pts) with advanced cancers were treated once (QD) or twice daily (BID) with escalating doses. Acute effects on tumor perfusion and vascularity were assessed using DCE-MRI, weekly BP readings, soluble VEGFR-2, and hemoglobin levels.. Forty-six pts were treated with 0.67-9 mg QD and 4-6 mg BID of PF-00337210. Nineteen pts (41%) previously received VEGF/VEGFR inhibitors. Two pts had dose-limiting toxicity (DLT) at 9 mg QD (troponin I increase and hypertension). The MTD at QD dose was 8 mg. Common drug-related adverse events were hypertension, fatigue, proteinuria, and nausea. Hypertension incidence and intensity corresponded with dose, but was well controlled with medication. Two confirmed partial responses and minor regressions (>10 to <30% reduction in target lesions) were noted. Complete DCE-MRI was acquired in 21 pts (20 evaluable for vascular response). Ten pts were vascular responders, including 5/6 pts at BID doses. Greatest modulation of soluble VEGFR-2 was at 6 mg BID. The maximum change from baseline in diastolic BP was higher at BID doses. There were no significant differences for systolic BP and hemoglobin levels.. PF-00337210 has profound VEGFR inhibition effects at well-tolerated doses. Antitumor activity and VEGF inhibition effects were observed across BID doses. The RP2D was 6 mg BID.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Benzofurans; Biomarkers, Pharmacological; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Magnetic Resonance Imaging; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Quinolines; Receptors, Vascular Endothelial Growth Factor; Treatment Outcome; Vascular Endothelial Growth Factor Receptor-2; Young Adult

Fruquintinib (HMPL-013) is a novel oral small molecule compound that selectively inhibits vascular endothelial growth factor receptors-1, -2, and -3 with potent inhibitory effects on multiple human tumor xenografts. This first-in-human study was conducted to assess the maximum tolerated dose and dose-limiting toxicities, safety and tolerability, pharmacokinetics, and preliminary anti-tumor activity of fruquintinib.. Patients 18-70 years old with advanced solid tumors refractory to standard therapies were recruited. Fruquintinib was administered orally in 4-week repeating cycles in two regimens, either once daily continuously or once daily for 3-week on/1-week off, until discontinuation due to toxicity or tumor progression. Adverse events were assessed using National Cancer Institute Common Terminology Criteria for Adverse Events v4.0.3. Pharmacokinetic parameters were measured after a single dose and in multiple dosing. Tumor response was assessed by Response Evaluation Criteria in Solid Tumors v1.0.. Forty patients were enrolled into 5 cohorts in continuous regimen and 2 cohorts in 3-week-on/1-week-off regimen. The most common grade 3/4 adverse events were hand-foot skin reaction, hypertension, and thrombocytopenia. PK analysis showed good and rapid absorption followed by slow terminal elimination with a mean half-life of approximately 42 h which was consistent across all dose groups. Thirty-four patients were evaluable for tumor response, including 14 with partial response and 14 with stable disease.. Fruquintinib showed an acceptable safety profile and preliminary evidence of anti-tumor activity in patients with advanced solid tumors. The recommended dose was determined to be either 4 mg QD on a continuous regimen or 5 mg QD on a 3-week-on/1-week-off regimen.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Asian People; Benzofurans; Drug Administration Schedule; Female; Half-Life; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Protein Kinase Inhibitors; Quinazolines; Receptors, Vascular Endothelial Growth Factor; Treatment Outcome; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factor Receptor-3; Young Adult

In the clinical development of oncology drugs, the recommended dose is usually determined using a 3 + 3 dose-escalation study design. However, this phase I design does not always adequately describe dose-toxicity relationships.. 125 patients, with either solid tumours or lymphoma, were included in the study and 1217 platelet counts were available over three treatment cycles. The data was used to build a population pharmacokinetic/pharmacodynamic (PKPD) model using a sequential modeling approach. Model-derived Recommended Doses (MDRD) of abexinostat (a Histone Deacetylase Inhibitor) were determined from simulations of different administration schedules, and the higher bound for the probability of reaching these MDRD with a 3 + 3 design were obtained.. The PKPD model developed adequately described platelet kinetics in both patient populations with the inclusion of two platelet baseline counts and a disease progression component for patients with lymphoma. Simulation results demonstrated that abexinostat administration during the first 4 days of each week in a 3-week cycle led to a higher MDRD compared to the other administration schedules tested, with a maximum probability of 40 % of reaching these MDRDs using a 3 + 3 design.. The PKPD model was able to predict thrombocytopenia following abexinostat administration in both patient populations. A model-based approach to determine the recommended dose in phase I trials is preferable due to the imprecision of the 3 + 3 design.

Topics: Antineoplastic Agents; Benzofurans; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Maximum Tolerated Dose; Models, Biological; Neoplasms; Thrombocytopenia

Abexinostat, an oral pan-histone deacetylase inhibitor (HDACi), was evaluated in patients with advanced solid tumours in two single agent phase I studies (PCYC-402 and CL1-78454-002). In PCYC-402 study testing four different administration schedules, the maximum tolerated dose (MTD) was established at 75 mg/m(2) BID (twice daily) and the recommended dose at 60 mg/m(2) BID regardless of the schedule tested. The dose limiting toxicity (DLT), consistently observed across all these schedules, was reversible thrombocytopenia. The CL1-78454-002 study was initially investigating an additional schedule of 14 days on/7 days off. While testing two first cohorts, thrombocytopenia was observed without reaching DLT. To address this issue, a pharmacokinetic/pharmacodynamic (PK/PD) model was used to predict the optimal schedule allowing higher doses with minimal thrombocytopenia. Several administration schedules were simulated using this model. A 4 days on/3 days off schedule was associated with the smallest platelet decrease. Accordingly, the CL1-78454-002 study was amended. After reaching MTD1 (75 mg/m(2) BID) with the initial schedule, subsequent cohorts received abexinostat on a revised schedule of 4 days on/3 days off, starting at one dose level below MTD1 (60 mg/m(2) BID). As expected, the dose-escalation continued for two more dose levels beyond MTD1. The MTD2 reached for this optimised schedule was 105 mg/m(2) BID and the recommended dose 90 mg/m(2) BID. In conclusion, early understanding of toxicities and PK determination allowed us to build a PK/PD model of thrombocytopenia, which predicted the optimal administration schedule. This optimised schedule is currently used in the trials in solid tumours with abexinostat.

Topics: Administration, Intravenous; Administration, Oral; Benzofurans; Computer Simulation; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Dosage Calculations; France; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Maximum Tolerated Dose; Models, Biological; Neoplasms; Platelet Count; Thrombocytopenia

To determine the recommended phase II dose and evaluate the safety and toxicity profile and pharmacokinetic (PK) and pharmacodynamic (PD) effects of BNC105P, an inhibitor of tubulin polymerization that has vascular disrupting and antiproliferative effects.. BNC105P was administered as a 10-minute infusion on days 1 and 8 of a 21-day cycle in a first-in-human phase I study. A dynamic accelerated dose titration method was used for dose escalation. Plasma concentrations of BNC105P (phosphate prodrug) and BNC105 (active agent) were determined. PD assessments were carried out using dynamic contrast enhanced (DCE)-MRI and analysis of a blood-borne biomarker.. Twenty-one subjects with advanced solid tumors were enrolled on 6 dose levels (range: 2.1-18.9 mg/m(2)). The recommended dose level was 16 mg/m(2) and was well tolerated. BNC105P (prodrug) rapidly converted to BNC105 with a half-life of 0.13 hours. Plasma concentrations of BNC105 generally increased in proportion to dose with a half-life of 0.57 hours. Pharmacodymanically active plasma levels were obtained with a dose dependant reduction in the levels of polymerized tubulin (on-target action) being observed in PBMCs. DCE-MRI also indicated blood flow changes in the tumor lesions of a number of subjects.. BNC105P has a favorable toxicity profile at the recommended dose of 16 mg/m(2) and is associated with PD changes consistent with its known mechanism of action. Phase II studies in renal cancer and mesothelioma have commenced.

Topics: Adult; Aged; Aged, 80 and over; Anisoles; Antineoplastic Agents; Benzofurans; Biomarkers; Cardiovascular Agents; Cell Proliferation; Female; Humans; Male; Middle Aged; Neoplasms; Organophosphates; Prodrugs; Tubulin

This study was conducted to assess the feasibility of administering the oral diarylsulfonylurea (DSU) ILX-295501 on a weekly for 3 weeks every 4-week schedule. The study also sought to determine the maximum tolerated dose (MTD) of ILX-295501 on this schedule, characterize its pharmacokinetic behavior, and seek preliminary evidence of anticancer activity.. The initial starting dose of ILX-295501 was 100 mg/m(2), which was equivalent to one-sixth of the highest dose that did not induce irreversible toxicity in dogs, and, using a modified Fibonnaci search scheme to guide dose level selection, the following dose levels were evaluated: 100, 200, 400, 600, 900, 1350, and 1800 mg/m(2). Because severe toxicities were being reported in other trials at doses that encompassed this range and a cumulative toxicity profile was emerging, the study was suspended and then reinitiated to further reevaluate the lower dosing range. In the second part of the study, the following dose levels were selected a priori for evaluation: 400, 800, 1000, 1250, and 1500 mg/m(2); and a modified continual reassessment model was used for dose assignment to determine the MTD, which was defined a priori as the highest dose in which the incidence of dose-limiting toxicity in the first course did not exceed 20%.. Forty-nine patients were treated with 142 courses of ILX-295501 at doses ranging from 100 to 1800 mg/m(2). The incidences of dose-limiting toxicity, principally neutropenia and thrombocytopenia, were unacceptably high at ILX-295501 doses exceeding 1000 mg/m(2), which was determined to be the MTD for both minimally pretreated and heavily pretreated (HP) patients. In contrast to the first generation of DSUs, particularly sulofenur, clinically relevant levels of oxidized hemoglobin (methemoglobin) and secondary hemolytic anemia, were not noted. One HP patient with non-small cell lung carcinoma experienced a partial response. Pharmacokinetic studies revealed that ILX-295501 was absorbed slowly, with peak plasma concentrations (C(max)) achieving 6.02 h, on average, after oral administration. The pharmacokinetic behavior of ILX-295501 was characterized by dose proportionality, a relatively small apparent volume of distribution at steady state (V(ss)/F), averaging 8.02 +/- 14.08 liters, and low apparent total body clearance (CL(t)/F) rate (mean, 0.036 +/- 0.116 liters/h). The initial drug distribution phase was rapid [harmonic mean half-life (t(1/2alpha)), 2.1 +/- 7.0 min], whereas the terminal elimination phase was slow (harmonic mean t(1/2beta,) 150.6 +/- 80.2 h).. The recommended dose for Phase II studies of the oral DSU ILX-295501 administered weekly for 3 weeks every 4 weeks is 1000 mg/m(2)/day for both minimally pretreated and HP patients. The characteristics of the myelosuppressive effects of ILX-295501, the paucity of severe nonhematological toxicities, and preliminary antitumor activity warrant disease-directed evaluations of ILX-295501.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Benzofurans; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Male; Metabolic Clearance Rate; Middle Aged; Neoplasms; Phenylurea Compounds; Sulfonylurea Compounds; Tablets

In a phase II trial, the activity of carzelesin, a cyclopropylpyrroloindole prodrug analog, was assessed.. Carzelesin was used as second- or third-line chemotherapy in patients with breast, ovarian, head and neck cancer and non-Hodgkin's lymphoma, and as first-line chemotherapy in patients with colorectal and gastric cancer and melanoma. The drug was given as a bolus infusion at a 4-weekly dose of 150 microg/m2. A total of 140 patients were entered and a total of 285 courses were administered.. In general, the compound was well tolerated. Myelotoxicity was the most common toxicity. Grade 3 and 4 leukopenia was observed in 18.6% of the courses, neutropenia in 20.3%, thrombocytopenia in 16.2% and anemia in 8.7%. Double nadirs were seen in a total of 41 courses for neutrophils, in 40 for leukocytes and in 3 for platelets. Non-hematological toxicity was very mild. Only one partial response in a patient with melanoma was seen.. At this dose and schedule carzelesin did not yield activity in the types of tumors studied.

Topics: Adult; Aged; Antineoplastic Agents; Benzofurans; Breast Neoplasms; Colorectal Neoplasms; Duocarmycins; Female; Head and Neck Neoplasms; Humans; Indoles; Infusions, Intravenous; Lymphoma, Non-Hodgkin; Male; Melanoma; Middle Aged; Neoplasm Staging; Neoplasms; Ovarian Neoplasms; Prodrugs; Stomach Neoplasms

Carzelesin is a cyclopropylpyrroloindole analogue which acts as a DNA-sequence-specific alkylating agent. In this phase I study, Carzelesin was given as a 4-weekly 10 min i.v. infusion to 51 patients with advanced solid tumours. Patients received a median of two courses (range 1-5) at one of nine dose levels: 24, 48, 96, 130, 150, 170, 210, 250 and 300 microg m(-2). According to NCI-CTC criteria, non-haematological toxicities (grade 1/2) included fever, nausea and vomiting, mucositis and anorexia, none of which was clearly dose related. The dose-limiting toxicity was haematological and consisted mainly of neutropenia and to a lesser extent thrombocytopenia. From the dose level 150 microg m(-2), the haematological toxicity (particularly thrombocytopenia) was delayed in onset, prolonged and cumulative in some patients. In several courses, double WBC nadirs occurred. The maximum tolerated dose for a single course was 300 microg m(-2). From the dose level 170 microg m(-2), the intended dose intensity could not be delivered to most patients receiving > 2 courses owing to cumulative haematological toxicity. The dose level with the best dose intensity for multiple courses was 150 microg m(-2). The pharmacokinetics of Carzelesin and its metabolites (U-76,073; U-76,074) have been established in 31 patients during the first course of treatment using a HPLC method. Carzelesin exhibited linear pharmacokinetics. The concentration of U-76,074 (active metabolite) extended above the lower limit of quantitation (1 ng ml(-1)) for short periods of time and only at the higher dose levels. There was no relationship between neutropenia and the AUC of the prodrug Carzelesin, but the presence of detectable plasma levels of the active metabolite U-76,074 was usually associated with a substantial decrease in ANC values.

Topics: Adult; Aged; Antineoplastic Agents; Benzofurans; Dose-Response Relationship, Drug; Drug Administration Schedule; Duocarmycins; Female; Follow-Up Studies; Humans; Indoles; Infusions, Intravenous; Male; Middle Aged; Neoplasms; Neutropenia; Prodrugs; Thrombocytopenia

Adozelesin, a synthetic analog of the antitumor antibiotic CC-1065, is a novel cytotoxic agent which inhibits DNA synthesis by binding to the minor groove of the DNA helix. Preclinical studies have shown a broad spectrum of activity against a variety of murine and human tumor xenograft models. We conducted a phase I study of adozelesin to (i) determine a recommended dose for phase II testing using a 10 min i.v. infusion, (ii) characterize the toxic effects of the drug using this schedule and (iii) document any antitumor activity observed. Adozelesin was administered as an i.v. infusion every 6 weeks. CBC and biological parameters were performed weekly. The starting dose of 10 microg/m2, corresponding to 1/30 the mouse equivalent lethal dose, was escalated, according to a modified Fibonacci scheme, until dose-limiting toxicity was encountered. Forty-seven adult patients with solid malignancies were entered in the study. Successive dose levels used were 10, 20, 33, 50, 70, 105, 120, 150 and 180 microg/m2. The main toxic effect was myelosuppression, which was dose limiting. The maximally tolerated dose was defined as 180 microg/m2. A minor response with a 4 month duration was reported in one previously treated patient with melanoma. We conclude that the recommended phase II dose of adozelesin given as a 10 min infusion is 150 microg/m2, repeated every 4 weeks.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Benzofurans; Blood; Cyclohexanecarboxylic Acids; Cyclohexenes; Dose-Response Relationship, Drug; Duocarmycins; Female; Humans; Hyperglycemia; Indoles; Infusions, Intravenous; Liver; Male; Middle Aged; Neoplasms; Neutropenia; Treatment Outcome

CC-1065 is a unique alkylating agent that preferentially binds in the minor groove of double-stranded DNA at adenine-thymine-rich sites. Although it has broad antitumor activity in preclinical models its development was discontinued because of deaths observed during preclinical toxicology studies. Adozelesin is a potent synthetic analog that was chosen for clinical development because it had a similar preclinical antitumor spectrum, but did not produce deaths similar to CC-1065 at therapeutic doses. Phase I evaluations using a variety of Adozelesin treatment schedules have been conducted. This report describes our experience using a multiple dose treatment schedule. Endpoints including antitumor response, maximum tolerated dose, dose limiting toxicity as well as other toxicities and the recommended Phase II starting dose were determined. Adozelesin was given as a 10 minute IV infusion for 5 consecutive days every 21 days or upon recovery from toxicity. The dose range evaluated was 6-30 mcg/m2/day. All patients had refractory solid tumors and had received prior cytotoxic treatment. Thirty-three patients (22 men: 11 women) were entered onto the study and 87 courses were initiated. Dose limiting toxicity was cumulative myelosuppression (leucopenia, thrombocytopenia). The maximum tolerated dose was 30 mcg/m2/day. The only other significant toxicity was an anaphylactoid syndrome that occurred in 2 patients. A partial response was observed in a patient with refractory soft tissue sarcoma. The recommended Phase II starting dose of Adozelesin using a 10 minute IV infusion for 5 consecutive days is 25 mcg/m2/day to be repeated every 4-6 weeks to allow recovery from myelotoxicity, based on our experience. Additional Phase I and II studies with Adozelesin are recommended.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Benzofurans; Cyclohexanecarboxylic Acids; Cyclohexenes; Dose-Response Relationship, Drug; Drug Administration Schedule; Duocarmycins; Female; Humans; Indoles; Infusions, Intravenous; Male; Middle Aged; Neoplasms

Carzelesin (U-80244), one of the synthetic DNA minor groove binding cyclopropylpyrroloindole analogues, was selected for clinical development because of its high potency, promising antitumor activity in murine solid tumors and leukemia, and significant therapeutic efficacy against colon and rhabdomyosarcoma xenografts. In this Phase I study, carzelesin was given daily for 5 consecutive days to (a) determine the maximum tolerable dose (MTD) and the pattern of toxicity of this schedule; (b) define the pharmacokinetic profile of the parent, as was done for the intermediate compound U-76073 and the DNA-reactive agent U-76074; and (c) document any antitumor activity observed. Carzelesin was given as a 10-min infusion with a constant-rate infusion pump. Treatment was repeated every 4 weeks or when blood counts had recovered to normal values. The starting dose of 12 microgram/m2/day was escalated by 20-30% increments until the MTD (defined as the dose leading to grade 4 hematological or grade 3 nonhematological toxicity in at least two of six patients) was reached. Pharmacokinetic studies were planned on days 1 and 5 of the first cycle in at least two patients per dose level. Plasma levels of carzelesin, U-76073, and U-76074 were determined by high-performance liquid chromatography with UV detection and a detection limit of 0.5 ng/ml. Twenty-five patients were entered in the study, and 56 cycles were evaluable for hematological toxicity. Subsequent dose levels evaluated were 24, 30, 35, and 40 microgram/m2. Both neutropenia and thrombocytopenia were dose limiting and cumulative, with a high interpatient variability. Neutropenia occurred earlier (median time to neutrophil nadir and recovery, 15 and 29 days, respectively) than thrombocytopenia (median time to platelet nadir and recovery, 25 and >/=26 days, respectively); there were delays of treatment because of persisting thrombocytopenia in all patients treated at the MTD. At the MTD, the peak plasma concentrations of carzelesin were achieved at the end of the infusion and were higher than those found cytotoxic in vitro against tumor cell lines. Carzelesin was detectable up to a maximum of 1 h after the infusion. Smaller amounts of U-76073 were detectable for a maximum of 30 min only at the MTD, whereas U-76074 was never found. An 8-month partial remission was reported in one previously untreated patient with hepatocellular carcinoma at 40 microgram/m2. The MTD was fixed at 40 microgram/m2 daily; 35 and 30 micro

Topics: Adult; Aged; Antineoplastic Agents; Area Under Curve; Benzofurans; Bronchial Spasm; Drug Administration Schedule; Duocarmycins; Female; Flushing; Humans; Hypersensitivity; Indoles; Male; Middle Aged; Nausea; Neoplasms; Neutropenia; Tachycardia; Thrombocytopenia; Treatment Outcome

During a phase I clinical and pharmacologic trial, 26 patients with refractory solid tumors were treated with increasing doses of adozelesin by brief intravenous infusion every 3 weeks. Overall, adozelesin was well tolerated. The dose-limiting toxicity was myelosuppression, mainly thrombocytopenia and leukopenia. Nonhematologic toxicity was generally mild, with fatigue (36%), local reaction at the infusion site (24%), nausea or vomiting (20%) and hypersensitivity reaction (16%) being the most common adverse effects. There were no objective clinical responses. The maximally tolerated dose on this schedule was 188 micrograms/m2 with the recommended phase II starting dose being 150 micrograms/m2 on an every 3 week schedule. Adozelesin merits broad investigation at the phase II level.

Topics: Adult; Aged; Antineoplastic Agents; Benzofurans; Cyclohexanecarboxylic Acids; Cyclohexenes; Drug Resistance; Duocarmycins; Female; Humans; Indoles; Infusions, Intravenous; Male; Middle Aged; Neoplasms

Adozelesin, a synthetic analogue of the antitumor antibiotic CC-1065, is the first of a class of potent sequence-specific alkylating agents to be brought to clinical trial. In preclinical in vitro testing, it has demonstrated antitumor activity at picomolar concentrations.. We conducted a phase I study of adozelesin to (a) determine a recommended dose for phase II testing using a 24-hour intravenous infusion, (b) characterize the toxic effects of the drug using this schedule, and (c) document any antitumor activity observed.. Adozelesin was given as a 24-hour continuous intravenous infusion. Treatments were initially scheduled every 3 weeks, but the prolonged myelosuppression observed necessitated a final dosing interval of every 6 weeks. The starting dose of 30 micrograms/m2 was escalated using a modified Fibonacci scheme until dose-limiting toxicity was encountered.. Twenty-nine patients were entered in the study. Successive dose levels used were 30, 60, 100, 150, 120, and 100 micrograms/m2. Prolonged thrombocytopenia and granulocytopenia were dose limiting. No antitumor responses were observed.. We recommend that the phase II dose of adozelesin given as a continuous 24-hour intravenous infusion be 100 micrograms/m2, repeated every 6 weeks. Other potentially less myelosuppressive schedules could be pursued.

Topics: Adult; Aged; Antineoplastic Agents; Benzofurans; Cyclohexanecarboxylic Acids; Cyclohexenes; Drug Administration Schedule; Duocarmycins; Female; Hematologic Diseases; Humans; Indoles; Infusions, Intravenous; Male; Middle Aged; Neoplasms; Treatment Outcome

RG 12915 is a potent, selective 5-HT3 receptor antagonist with a biologic half-life of 11-20 hours. RG 12915 prevents cisplatin-induced emesis in ferrets at doses of 0.03 mg/kg. Animal toxicology studies permitted safe testing in humans at doses of up to 2.0 mg/kg. This dose-ranging trial of intravenous RG 12915 was performed to determine the optimal dosage and adverse effects and to observe for antiemetic effects in patients receiving anticancer chemotherapy.. Twenty-six patients receiving chemotherapy likely to cause vomiting received a single intravenous dose of RG 12915 at a rate of 3 ml/minute beginning 60 minutes before chemotherapy. Four dose levels were explored: 0.25, 0.50, 1.0, and 2.0 mg/kg.. No dose-limiting toxicities were observed. All adverse effects were mild and transient and included discomfort at the infusion site, hyperglycemia, headache, serum aspartate transaminase (AST) and alanine transaminase (ALT) elevations, and sedation. Antiemetic efficacy was seen in patients receiving cisplatin at doses of greater than or equal to 100 mg/m2.. RG 12915 can be administered safely at the dose levels explored. Single intravenous doses of RG 12915 prevented or lessened emesis caused by chemotherapy, including cisplatin given at doses of greater than or equal to 100 mg/m2. RG 12915 warrants further testing. Of the doses tested, the 2.0 mg/kg dose is the most appropriate for further exploration.

Topics: Adolescent; Adult; Antiemetics; Antineoplastic Agents; Benzofurans; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cisplatin; Dose-Response Relationship, Drug; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Nausea; Neoplasms; Serotonin Antagonists; Vomiting

Natural products continue to be an inspiration for new drugs to treat debilitating diseases such as cancer. Usnic acid is a secondary metabolite isolated predominately from lichen species and has been shown to exhibit antiproliferative properties, however its application is limited by poor drug-like properties and low specificity. We report our work on investigating the reactivity of usnic acid for incorporating heterocyclic rings and the divergent reactivity that can be obtained by simply altering the reaction solvent and temperature. The synthesised derivatives were then tested against HeLa cancer cells for their antiproliferative properties. A number of promising compounds were obtained including 4, 5 and 9 that showed an IC

Topics: Benzofurans; HeLa Cells; Humans; Lichens; Neoplasms

Topics: Animals; B7-H1 Antigen; Benzofurans; Carboxylic Acids; Immunotherapy; Mice; Neoplasms; Organic Chemicals; Programmed Cell Death 1 Receptor; Protein Tyrosine Phosphatases; Receptors, Antigen, T-Cell; Tyrosine

Ultrasound- and microwave-assisted green synthetic strategies were applied to furnish benzofuran-oxadiazole

Topics: A549 Cells; Antineoplastic Agents; Benzofurans; Cell Survival; Chemistry Techniques, Synthetic; Hemolysis; Humans; Microwaves; Molecular Docking Simulation; Neoplasms; Oxadiazoles; Triazoles

Single-modality tumor therapy confronts many challenges, such as incomplete tumor ablation, tumor metastasis, and limited tumor tissue penetration. Combination therapy simultaneously achieves deep drug delivery to fully exert synergistic effects and has received increasing attention. Herein, based on the excellent efficacy of anti-angiogenesis therapy combined with chemotherapy and the specific size of the poly-amidoamine dendrimer (PAMAM), we developed a pH-triggered size-converted nano-drug delivery system to co-deliver fruquintinib (FRU) and doxorubicin (DOX). This study used cyclic Arg-Gly-Asp (cRGD) as the target, pH-responsive liposomes (PRLs), and PAMAM as the drug carrier. The FRU and DOX-loaded small-particle-size complex polyamide-amine-doxorubicin (PD) was encapsulated into PRLs with the target to construct a size-converted nano-drug delivery system, PRL-PD/FRU-cRGD. This nanoparticle (∼120 nm) actively targeted tumor tissues and used the acidic microenvironment outside tumor cells to release FRU and small-particle-size complex PD (∼15 nm), enabling the conversion of large-size nanoparticles to small-size nanoparticles and resulting in efficient tumor accumulation. In addition, the released PD could realize the deep delivery of DOX, showing efficient deep tumor penetration and further enhancing the tumor-suppressing effect. The results of in vivo and in vitro experiments showed that PRL-PD/FRU-cRGD exhibited the excellent synergistic effects of anti-angiogenesis therapy combined with chemotherapy and effectively inhibited tumor cell proliferation and metastasis, thereby achieving efficient tumor therapy. Thus, PRL-PD/FRU-cRGD shows great potential for combined tumor therapy.

Topics: Benzofurans; Doxorubicin; Drug Carriers; Humans; Liposomes; Nanoparticles; Neoplasms; Quinazolines; Tumor Microenvironment

As the key stromal cells that mediate the desmoplastic reaction, tumor-associated fibroblasts (TAFs) play a critical role in the limited nanoparticle penetration and suppressive immune tumor microenvironment. Herein, we found that salvianolic acid B-loaded PEGylated liposomes (PEG-SAB-Lip) can interfere with the activation of TAFs by inhibiting the secretion of TGF-β1. After inhibiting the activation of TAFs, collagen deposition in tumors was reduced, and the penetration of nanoparticles in tumors was enhanced. The results of RT-qPCR and immunofluorescence staining showed the high expression of Th1 cytokines and chemokines (CXCL9 and CXCL10) and the recruitment of CD4

Topics: Benzofurans; Cancer-Associated Fibroblasts; CD8-Positive T-Lymphocytes; Fibroblasts; Humans; Immunologic Factors; Immunotherapy; Liposomes; Neoplasms; Smad Proteins; Transforming Growth Factor beta1; Tumor Microenvironment

Tumor vasculature is characterized by aberrant structure and function, resulting in immune suppressive profiles of tumor microenvironment (TME) through limiting immune cell infiltration into tumors. The defective vascular perfusion in tumors also impairs the delivery and efficacy of chemotherapeutic agents. Targeting abnormal tumor blood vessels has emerged as an effective therapeutic strategy to improve the outcome of chemotherapy and immunotherapy. In this study, we demonstrated that Salvianolic acid B (SalB), one of the major ingredients of Salvia miltiorriza elicited vascular normalization in the mouse models of breast cancer, contributing to improved delivery and response of chemotherapeutic agent cisplatin as well as attenuated metastasis. Moreover, SalB in combination with anti-PD-L1 blockade retarded tumor growth, which was mainly due to elevated infiltration of immune effector cells and boosted delivery of anti-PD-L1 into tumors. Mechanistically, tumor cell enhancer of zeste homolog 2 (Ezh2)-driven cytokines disrupted the endothelial junctions with diminished VE-cadherin expression, which could be rescued in the presence of SalB. The restored vascular integrity by SalB via modulating the interactions between tumor cells and endothelial cells (ECs) offered a principal route for achieving vascular normalization. Taken together, our data elucidated that SalB enhanced sensitivity of tumor cells to chemotherapy and immunotherapy through triggering tumor vascular normalization, providing a potential therapeutic strategy of combining SalB and chemotherapy or immunotherapy for patients with breast cancer.

Topics: Animals; Antineoplastic Agents; Benzofurans; Cisplatin; Endothelial Cells; Enhancer of Zeste Homolog 2 Protein; Immunologic Factors; Immunotherapy; Mice; Neoplasms; T-Lymphocytes; Tumor Microenvironment

Rocaglates are natural compounds that have been extensively studied for their ability to inhibit translation initiation. Rocaglates represent promising drug candidates for tumor treatment due to their growth-inhibitory effects on neoplastic cells. In contrast to natural rocaglates, synthetic analogues of rocaglates have been less comprehensively characterized, but were also shown to have similar effects on the process of protein translation. Here, we demonstrate an enhanced growth-inhibitory effect of synthetic rocaglates when combined with glucose anti-metabolite 2-deoxy-D-glucose (2DG) in different cancer cell lines. Moreover, we unravel a new aspect in the mechanism of action of synthetic rocaglates involving reduction of glucose uptake mediated by downregulation or abrogation of glucose transporter GLUT-1 expression. Importantly, cells with genetically induced resistance to synthetic rocaglates showed substantially less pronounced treatment effect on glucose metabolism and did not demonstrate GLUT-1 downregulation, pointing at the crucial role of this mechanism for the anti-tumor activity of the synthetic rocaglates. Transcriptome profiling revealed glycolysis as one of the major pathways differentially regulated in sensitive and resistant cells. Analysis of synthetic rocaglate efficacy in a 3D tissue context with a co-culture of tumor and normal cells demonstrated a selective effect on tumor cells and substantiated the mechanistic observations obtained in cancer cell lines. Increased glucose uptake and metabolism is a universal feature across different tumor types. Therefore, targeting this feature by synthetic rocaglates could represent a promising direction for exploitation of rocaglates in novel anti-tumor therapies.

Topics: Benzofurans; Cell Proliferation; Glucose; Glucose Transporter Type 1; Humans; Neoplasms

Mitochondria are crucial regulators of the intrinsic pathway of apoptosis. Herein, we report a photosensitizer-conjugated camptothecin (CPT)-based prodrug for combinative chemo-photodynamic treatment of solid tumors with cascade activations. Upon light irradiation, our prodrug can effectively target the mitochondria of cancer cells, generate singlet oxygen to increase the level of reactive oxygen species (ROS) and trigger ROS-responsive release of CPT, which synergistically induce mitochondrial damage and cause the apoptosis of cancer cells, therefore achieving high therapeutic efficacy for solid tumors and minimized adverse effects to normal tissues. Our prodrug holds great promise as a potent and inspiring means for cancer treatment.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Benzofurans; Camptothecin; Cell Line, Tumor; Drug Therapy, Combination; Humans; Mitochondria; Neoplasms; Photochemotherapy; Photosensitizing Agents; Prodrugs; Reactive Oxygen Species

Guangsangon E (GSE) is a novel Diels-Alder adduct isolated from leaves of Morus alba L, a traditional Chinese medicine widely applied in respiratory diseases. It is reported that GSE has cytotoxic effect on cancer cells. In our research, we investigated its anticancer effect on respiratory cancer and revealed that GSE induces autophagy and apoptosis in lung and nasopharyngeal cancer cells. We first observed that GSE inhibits cell proliferation and induces apoptosis in A549 and CNE1 cells. Meanwhile, the upregulation of autophagosome marker LC3 and increased formation of GFP-LC3 puncta demonstrates the induction of autophagy in GSE-treated cells. Moreover, GSE increases the autophagy flux by enhancing lysosomal activity and the fusion of autophagosomes and lysosomes. Next, we investigated that endoplasmic reticulum (ER) stress is involved in autophagy induction by GSE. GSE activates the ER stress through reactive oxygen species (ROS) accumulation, which can be blocked by ROS scavenger NAC. Finally, inhibition of autophagy attenuates GSE-caused cell death, termed as "autophagy-mediated cell death." Taken together, we revealed the molecular mechanism of GSE against respiratory cancer, which demonstrates great potential of GSE in the treatment of representative cancer.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Autophagy; Benzofurans; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; Endoplasmic Reticulum Stress; Female; Humans; Mice, Inbred BALB C; Mice, Nude; Morus; Neoplasms; Plant Leaves; Reactive Oxygen Species; Resorcinols; Xenograft Model Antitumor Assays

Five new compounds, eupatodibenzofuran A (

Topics: Acetophenones; Antineoplastic Agents, Phytogenic; Apoptosis; Benzofurans; Cell Proliferation; Chromones; Eupatorium; Humans; Molecular Structure; Neoplasms; Phytochemicals; Plant Extracts; Structure-Activity Relationship; Tumor Cells, Cultured

A large number of secondary metabolites have been isolated from the filamentous fungus

Topics: Benzofurans; Casein Kinase II; Cell Line, Tumor; Cell Proliferation; Cell Survival; Humans; Neoplasms; Protein Kinase Inhibitors; Spiro Compounds; Stachybotrys

The PI3K/Akt/mTOR kinase pathway is extensively deregulated in human cancers. One critical node under regulation of this signaling axis is eukaryotic initiation factor (eIF) 4F, a complex involved in the control of translation initiation rates. eIF4F-dependent addictions arise during tumor initiation and maintenance due to increased eIF4F activity-generally in response to elevated PI3K/Akt/mTOR signaling flux. There is thus much interest in exploring eIF4F as a small molecule target for the development of new anticancer drugs. The DEAD-box RNA helicase, eIF4A, is an essential subunit of eIF4F, and several potent small molecules (rocaglates, hippuristanol, pateamine A) affecting its activity have been identified and shown to demonstrate anticancer activity in vitro and in vivo in preclinical models. Recently, a number of new small molecules have been reported as having the capacity to target and inhibit eIF4A. Here, we undertook a comparative analysis of their biological activity and specificity relative to the eIF4A inhibitor, hippuristanol.

Topics: Antineoplastic Agents; Benzofurans; Cell Proliferation; Cell Survival; Epoxy Compounds; Eukaryotic Initiation Factor-4A; Eukaryotic Initiation Factor-4F; Humans; Macrolides; Neoplasms; Phosphatidylinositol 3-Kinases; Protein Biosynthesis; Proto-Oncogene Proteins c-akt; Small Molecule Libraries; Sterols; Thiazoles; TOR Serine-Threonine Kinases

Topics: Animals; Antineoplastic Agents; Apoptosis; Benzofurans; Cell Line, Tumor; Drug Design; Female; Humans; Mice, Inbred BALB C; Molecular Docking Simulation; Molecular Structure; Naphthoquinones; Neoplasms; Protein Binding; S Phase Cell Cycle Checkpoints; STAT3 Transcription Factor; Structure-Activity Relationship; Xenograft Model Antitumor Assays

Cancer stem cells (CSCs), a subpopulation of cancer cells endowed with self-renewal, tumorigenicity, pluripotency, chemoresistance, differentiation, invasive ability, and plasticity, reside in specialized tumor niches and are responsible for tumor maintenance, metastasis, therapy resistance, and tumor relapse. The new-age "hierarchical or CSC" model of tumor heterogeneity is based on the concept of eradicating CSCs to prevent tumor relapse and therapy resistance. Small-molecular entities and biologics acting on various stemness signaling pathways, surface markers, efflux transporters, or components of complex tumor microenvironment are under intense investigation as potential anti-CSC agents. In addition, smart nanotherapeutic tools have proved their utility in achieving CSC targeting. Several CSC inhibitors in clinical development have shown promise, either as mono- or combination therapy, in refractory and difficult-to-treat cancers. Clinical investigations with CSC marker follow-up as a measure of clinical efficacy are needed to turn the "hype" into the "hope" these new-age oncology therapeutics have to offer.

Topics: Antineoplastic Agents; Autophagy; Benzofurans; Cell Cycle Proteins; Dasatinib; Drug Repositioning; Epigenomics; Humans; Nanotechnology; Naphthoquinones; Neoplasms; Neoplastic Stem Cells; Protein Kinase Inhibitors; Resveratrol; Signal Transduction; Terpenes

Combination of photodynamic therapy (PDT) and photothermal therapy (PTT) generally requires different components to build a composite irradiated with different excitation lights. One component photoactive agent for enhanced combination of PDT and PTT under the excitation of a single wavelength light source is more urgent in tumor phototherapy via adjusting spatial arrangement of photoactive units. Herein, porphyrin-based covalent organic framework nanoparticles (COF-366 NPs) were synthesized to control the orderly spatial arrangement of the photoactive building units and firstly used for antitumor therapy in vivo. COF-366 NPs provide the simultaneous therapy of PDT and PTT under a single wavelength light source with the monitoring of photoacoustic (PA) imaging, which makes the operation simpler and more convenient. COF-366 NPs had achieved good phototherapy effect even in the face of large tumors. The prepared multifunctional COF-366 NPs open up a new avenue to phototherapeutic materials and expand the application range of covalent organic framework.

Topics: Animals; Benzofurans; Cell Line, Tumor; Combined Modality Therapy; Female; Hemolysis; Magnetic Resonance Spectroscopy; Mice; Mice, Inbred BALB C; Mice, Nude; Nanoparticles; Neoplasm Transplantation; Neoplasms; Neoplasms, Experimental; Organic Chemicals; Photoacoustic Techniques; Phototherapy; Porphyrins; Rabbits; Reactive Oxygen Species

The transcription factor STAT3 is an attractive target for a variety of cancers therapy. Napabucasin, applied in phase III clinical trials for the treatment of a variety of cancers, was regarded as one of the most promising anticancer drug by targeting STAT3. Herein, a novel series of napabucasin derivatives were designed and synthesized, which presented a potent inhibitory activity on a variety of cancers cells. Among the derivatives compound 8q exhibited potent inhibitory activity on U251, HepG2, HT29 and CT26 cells with the IC

Topics: Administration, Oral; Animals; Antineoplastic Agents; Benzofurans; Cell Line; Cell Line, Tumor; Drug Screening Assays, Antitumor; Humans; Inhibitory Concentration 50; Mice; Naphthoquinones; Neoplasms; Protein Binding; Solubility; STAT3 Transcription Factor; Structure-Activity Relationship

A novel series of benzodihydrofuran derivatives was developed as potent MEK inhibitors through scaffold hopping based on known clinical compounds. Further SAR exploration and optimization led to another benzofuran series with good oral bioavailability in rats. One of the compounds EBI-1051 (28d) demonstrated excellent in vivo efficacy in colo-205 tumor xenograft models in mouse and is suitable for pre-clinical development studies for the treatment of melanoma and MEK associated cancers. Compared to AZD6244, EBI-1051 showed superior potency in some cancer cell lines such as colon-205, A549 and MDA-MB-231.

Topics: Administration, Oral; Animals; Benzofurans; Cell Line, Tumor; Cell Survival; Drug Evaluation, Preclinical; Enzyme Activation; Humans; Mice; Mice, Nude; Mitogen-Activated Protein Kinase Kinases; Neoplasms; Protein Kinase Inhibitors; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; Transplantation, Heterologous

STAT3 plays a vital role in maintaining the self-renewal of tumor stem cells. BBI608, a small molecule identified by its ability to inhibit gene transcription driven by STAT3 and cancer stemness properties, can inhibit stemness gene expression and kill stemness-high cancer cells isolated from a variety of cancer types. In order to improve the pharmacokinetic properties of BBI608 and the antitumor activity, a series of BBI608 derivatives were designed and synthesized here. Most of these compounds were more potent than BBI608 on HepG2 cells, compound LD-8 had the most potent inhibitory activity among them and was 5.4-fold more potent than BBI608 (IC

Topics: Antineoplastic Agents; Benzofurans; Cell Proliferation; Drug Design; Drug Screening Assays, Antitumor; Hep G2 Cells; Humans; Molecular Docking Simulation; Naphthoquinones; Neoplasms; Neoplastic Stem Cells; STAT3 Transcription Factor

The concentrations of POPs (persistent organic pollutants) including 16 compounds of OCPs, 12 dioxin-like PCBs congeners, and 17 PCDDs/Fs congeners were determined in 46 human adipose tissue samples gathered from Jordanian citizens. Thirteen adipose tissue samples of healthy people were collected from Jordan University Hospital and 33 adipose tissue samples of cancer-affected patients were collected from King Hussein Cancer Center. All samples were extracted, cleaned-up, and analyzed using GC/MS. In the healthy person's samples, among the OCP compounds, the highest concentration was found for heptachlor-oxo-epoxide (5696.71 μg/kg), while among the PCB congeners, the non-ortho PCB 126 shows the highest TEQ concentrations (5554.5 μg TEQ/kg) and among the PCDDs/Fs congeners, the highest TEQ value was found for the congener 2,3,4,7,8-PeCDFs (5.93 μg TEQ/kg). For the cancer-affected patient's samples, the highest concentration among the OCP compounds was found for o,p-DDT (638.7 μg/kg), while among the PCBs congeners, the highest TEQ value was found for the non-ortho-PCB 126 (3366.24 μg TEQ/kg) and among the PCDDs/Fs congeners, the highest TEQ value was found for the congener 1,2,3,7,8-PeCDDs (20.64 μg TEQ/kg). OCP concentration level in adipose tissue samples for healthy people was 32 times higher than for cancer patient persons, while the TEQ values for dioxin-like PCB concentrations in adipose tissue samples of healthy people was 2.2 times higher than in the samples of cancer-affected patient and the TEQ values for PCDDs/Fs in adipose tissue samples of cancer-affected patient was 3 times higher than in the samples of healthy people.

Topics: Benzofurans; DDT; Dibenzofurans, Polychlorinated; Dioxins; Environmental Exposure; Environmental Monitoring; Environmental Pollutants; Female; Furans; Gas Chromatography-Mass Spectrometry; Humans; Jordan; Male; Neoplasms; Pesticides; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins

Dictamnus dasycarpus is a traditional Chinese medicine thathas been commonly used in the treatment of cancer. Fraxinellone is a natural product isolated from the D. dasycarpus plant, which has been shown to exhibit neuroprotective and anti-inflammatory activities. However, whether fraxinellone exerts anticancer effects and the mechanisms by which it may inhibit tumor growth remain unknown. Here, we found that fraxinellone, in a dose-dependented manner, inhibited the expression of programmed cell death ligand-1 (PD-L1), which plays a pivotal role in tumorigenesis. It was subsequently shown that fraxinellone reduced HIF-1α protein synthesis via the mTOR/p70S6K/eIF4E and MAPK pathways. It also inhibited activation of STAT3 via the JAK1, JAK2, and Src pathways. Immunoprecipitation and western blotting assays showed that fraxinellone inhibited PD-L1 expression by reducing STAT3 and HIF-1α cooperatively. Flow cytometry, colony formation, and EdU incorporation assays demonstrated that fraxinellone inhibited cell proliferation through suppression of PD-L1. Tube formation, migration, and invasion assays showed that fraxinellone inhibits angiogenesis by suppressing PD-L1. In vivo studies further supported anticancer role for fraxinellone, demonstrating that fraxinellone treatment inhibited the growth of tumor xenografts. We concluded that fraxinellone inhibits PD-L1 expression by downregulating the STAT3 and HIF-1α signaling pathways, subsequently inhibiting proliferation and angiogenesis in cancer cells. These studies reveal previously unknown characteristics of fraxinellone and provide new perspectives into the mechanism of cancer inhibition of the compound.

Topics: Animals; Antineoplastic Agents; B7-H1 Antigen; Benzofurans; Cell Line, Tumor; Cell Movement; Female; Human Umbilical Vein Endothelial Cells; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Mice, Inbred BALB C; Mice, Nude; Molecular Docking Simulation; Neoplasms; STAT3 Transcription Factor

Members of the tropomyosin receptor kinase (TRK) family are expressed in their constitutively activated forms as a result of a gene fusion that occurs across a wide variety of cancer types. We have identified CH7057288 as a potent and selective TRK inhibitor that belongs to a novel chemical class. CH7057288 showed selective inhibitory activity against TRKA, TRKB, and TRKC in cell-free kinase assays and suppressed proliferation of TRK fusion-positive cell lines, but not that of TRK-negative cell lines. Strong

Topics: Animals; Benzofurans; Cell Line, Tumor; Drug Resistance, Neoplasm; Female; Humans; Mice, Inbred BALB C; Mice, Nude; Mutation; Neoplasms; Oncogene Proteins, Fusion; Protein Kinase Inhibitors; Protein Kinases; Signal Transduction; Xenograft Model Antitumor Assays

Topics: Antineoplastic Agents; Benzofurans; Cell Cycle; Cell Proliferation; Cell Survival; HeLa Cells; Humans; Models, Molecular; Neoplasms

A new series of 2-chloropheny-substituted benzofuro[3,2-b]pyridines were designed, synthesized, and evaluated for topoisomerase I and II inhibition and antiproliferative activity. Compounds 17-19, 23, 24, 26, and 27 exhibited excellent topo II inhibitory activity. A systematic structure-activity relationship study revealed the important role of chlorine substitution in the strong topoisomerase inhibitory activity.

Topics: Antineoplastic Agents; Benzofurans; Cell Line, Tumor; Cell Proliferation; DNA Topoisomerases, Type I; DNA Topoisomerases, Type II; Halogenation; Humans; Neoplasms; Pyridines; Topoisomerase Inhibitors

Treatment of cancer patients with chemotherapeutic drugs is often associated with the occurrence of tumors with a multidrug resistance (MDR). Furthermore, the relation between overexpression of P-glycoprotein (P-gp) and resistant cancers has been well established. In this study, novel 2-aminobenzofuran derivatives were synthesized and tested for their ability to modulate P-gp mediated multidrug resistance (MDR) in vitro. The most potent compound, 43, increased P-gp inhibitory activity at 5 μM by 11.12-fold and was 3.6-fold stronger than verapamil. Furthermore, 43 can sensitize Flp-In™-293/MDR cells toward vincristine, paclitaxel and doxorubicin by 17.95-fold, 13.68-fold and 26.43-fold at 2.5 μM, respectively. 43 also can sensitize the resistant cancer cell line KBvin toward vincristine, paclitaxel and doxorubicin by 246.43-fold, 38.72-fold and 5.16-fold at 2.5 μM, respectively. In conclusion, important aspects for developing potent P-gp inhibitors have been emphasized in this study, providing a starting point for the further structural optimization of P-gp inhibitors.

Topics: Amination; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B; Benzofurans; Cell Line, Tumor; Doxorubicin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Molecular Docking Simulation; Neoplasms; Paclitaxel; Structure-Activity Relationship; Vincristine

The molecular mechanism by which Profilin acts as a tumor suppressor is still unclear. Several chemotherapeutic agents, used till date either have unfavorable side effects or acquired resistance in tumor cells. Our findings show that Profilin enhances cell death mediated by several chemotherapeutic-agents. The activation of NF-κB and its dependent genes, mediated by paclitaxel and vinblastine, was completely inhibited in Profilin overexpressing cells. This inhibition was due to the Profilin mediated attenuation of IκBα degradation, thereby preventing p65 nuclear translocation and low NF-κB DNA binding activity.Moreover, Profilin increases level of p53 in the presence of known inducers, such as doxorubicin, vinblastine, and benzofuran. This increased p53 level leads to enhanced cell death as indicated by activation of caspases 3, 8, 9, which results in cleavage of PARP.Furthermore, knocking down of p53 in Profilin overexpressing cells leads to decreased cell death. Ectopic expression of Profilin in HCT116 p53 knock out cells showed lesser cell death as compared to the HCT116 p53 wild type cells. For the first time, we provide evidences, which suggest that Profilin synergizes with chemotherapeutic drugs to induce tumor cell death by regulating NF-κB and p53. Thus, modulation of Profilin may be a useful strategy for effective combination therapy.

Topics: Antineoplastic Agents; Apoptosis; Benzofurans; Caspase 3; Caspase 8; Caspase 9; Cell Line, Tumor; Doxorubicin; Enzyme Activation; HCT116 Cells; Humans; Neoplasms; NF-KappaB Inhibitor alpha; Paclitaxel; Poly(ADP-ribose) Polymerases; Profilins; Proto-Oncogene Proteins c-mdm2; RNA Interference; RNA, Small Interfering; Transcription Factor RelA; Transcriptional Activation; Tumor Suppressor Protein p53; Tumor Suppressor Proteins; Up-Regulation; Vinblastine

p53-independent malignant cancer is still severe health problem of human beings. HIF-1 pathway is believed to play an important role in the survival and developing progress of such cancers. In the present study, with the aim to inhibit the proliferation of p53-independent malignant cells, we disclose the optimization of 6a, the starting compound which is discovered in the screening of in-house compound collection. The structure-activity relationship (SAR) is summarized. The most potent derivative 8d, inhibits the proliferation of both p53-null and p53-mutated cells through inhibition of HIF-1 pathway. Our findings here provide a new chemotype in designing potent anticancer agent especially against those p53-independent malignant tumors.

Topics: Antineoplastic Agents; Benzofurans; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Discovery; Drug Screening Assays, Antitumor; HCT116 Cells; Humans; Hypoxia-Inducible Factor 1; MCF-7 Cells; Molecular Structure; Neoplasms; Structure-Activity Relationship; Tumor Suppressor Protein p53

The discovery of the TRAIL protein and its death receptors DR4/5 changed the horizon of cancer research because TRAIL specifically kills cancer cells. However, the validity of TRAIL-based cancer therapies has yet to be established, as most cancer cells are TRAIL-resistant. In this report, we demonstrate that TRAIL-resistance of many cancer cell lines can be overcome after siRNA- or rocaglamide-mediated downregulation of c-FLIP expression and simultaneous inhibition of IAPs activity using AT406, a pan-antagonist of IAPs. Combined triple actions of the TRAIL, the IAPs inhibitor, AT406, and the c-FLIP expression inhibitor, rocaglamide (ART), markedly improve TRAIL-induced apoptotic effects in most solid cancer cell lines through the activation of an extrinsic apoptosis pathway. Furthermore, this ART combination does not harm normal cells. Among the 18 TRAIL-resistant cancer cell lines used, 15 cell lines become sensitive or highly sensitive to ART, and two out of three glioma cell lines exhibit high resistance to ART treatment due to very low levels of procaspase-8. This study provides a rationale for the development of TRAIL-induced apoptosis-based cancer therapies.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Azocines; Benzhydryl Compounds; Benzofurans; CASP8 and FADD-Like Apoptosis Regulating Protein; Cell Line, Tumor; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Neoplasms; RNA, Small Interfering; Signal Transduction; TNF-Related Apoptosis-Inducing Ligand; X-Linked Inhibitor of Apoptosis Protein

In 1968, rice oil contaminated with polychlorinated biphenyls and polychlorinated dibenzofurans caused a severe outbreak of food poisoning in Japan and was termed locally as "Yusho" (oil disease). In our previous study, we found that area-based standardized mortality ratios (SMRs) of some diseases were elevated shortly after the incident. This previous study, however, was unable to determine whether these elevated SMRs were a result of other area-specific factors. To overcome this limitation, we obtained mortality data from the 5 years before the incident and conducted an area-based study using vital statistics records dating from 1963 to 2002.. The population of Nagasaki Prefecture was set as the reference population for calculating SMRs. We also included data on cause-specific mortality attributable to cancer and expanded the population to encompass two severely exposed areas where contaminated rice oil was distributed (namely Tamanoura and Naru). We also calculated SMRs in the remainder of the Shimo-Goto region, excluding the exposed area, which was used as a comparison area.. Even after considering the time trends in mortality before the incident, mortality due to diabetes mellitus and heart disease, as well as all-cause mortality, was found to be elevated shortly afterward. Additionally, mortalities due to uterine cancer in Tamanoura and leukemia were also elevated at 30-34 and 10-59 years after the event in both exposed areas, respectively. SMRs for leukemia in Tamanoura were as high as 3.0 (95% confidence interval 1.4-6.2) and 2.4 (1.2-4.8) 10-19 years later. In this period, SMRs for leukemia in the comparison area were not elevated.. Further epidemiological studies are needed regarding this rice-oil, "Yusho" outbreak, especially with regard to cancer and non-cancer mortality.

Topics: Adolescent; Adult; Aged; Benzofurans; Cause of Death; Child; Child, Preschool; Dibenzofurans, Polychlorinated; Environmental Exposure; Environmental Pollutants; Humans; Infant; Japan; Middle Aged; Neoplasms; Oryza; Plant Oils; Polychlorinated Biphenyls; Vital Statistics

In a continuation of our efforts to identify bioactive compounds from Red Sea Verongid sponges, the organic extract of the sponge Suberea species afforded seven compounds including two new dibrominated alkaloids, subereamollines C and D (1 and 2), together with the known compounds aerothionin (3), homoaerothionin (4), aeroplysinin-1 (5), aeroplysinin-2 (6) and a revised subereaphenol C (7) as ethyl 2-(2,4-dibromo-3,6-dihydroxyphenyl)acetate. The structures of the isolated compounds were assigned by different spectral data including optical rotations, 1D (1H and 13C) and 2D (COSY, multiplicity-edited HSQC, and HMBC) NMR and high-resolution mass spectroscopy. Aerothionin (3) and subereaphenol C (7) displayed potent cytotoxic activity against HeLa cell line with IC50 values of 29 and 13.3 µM, respectively. In addition, aeroplysinin-2 (6) showed potent antimigratory activity against the human breast cancer cell line MDA-MB-231 with IC50 of 18 µM. Subereamollines C and D are new congeners of the previously reported compounds subereamollines A and B with methyl ester functionalities on the side chain. These findings provide further insight into the biosynthetic capabilities of members of the genus Suberea and the chemical diversity as well as the biological activity of these compounds.

Topics: Alkaloids; Animals; Antineoplastic Agents; Benzofurans; Bromobenzenes; Cell Line, Tumor; Cell Movement; Cell Proliferation; Drug Discovery; Egypt; Humans; Hydrocarbons, Brominated; Hydroquinones; Isoxazoles; Magnetic Resonance Spectroscopy; Molecular Structure; Neoplasms; Oceans and Seas; Porifera; Saudi Arabia; Secondary Metabolism; Spectrometry, Mass, Electrospray Ionization; Spiro Compounds; Stereoisomerism

An asymmetric synthesis of diheteroarylalkanals through one-pot dienamine and Friedel-Crafts reaction is presented. The reaction tolerates a large variety of substituents at different positions of the starting aldehyde and also in the indole nucleophile, and a range of diheterocyclic alkanals can be achieved. Furthermore, we have studied the antiproliferative activity of these new compounds in representative cancer tumor cell lines.

Topics: Aldehydes; Antineoplastic Agents; Benzofurans; Cell Line, Tumor; Cell Proliferation; Combinatorial Chemistry Techniques; Humans; Indoles; Models, Molecular; Neoplasms

A series of (E,Z)-1-(dihydrobenzofuran-5-yl)-3-phenyl-2-(1,2,4-triazol-1-yl)-2-propen-1-ones (C1-C35) were designed and synthesized, and the structures of compounds (Z)-C27 and (Z)-C29 were confirmed by single-crystal X-ray diffraction. The antitumor activities of these novel compounds against cervical cancer (HeLa), lung cancer (A549), and breast cancer (MCF-7) cell lines were evaluated in vitro. Majority of the title compounds exhibited strong antitumor activities and were much more promising than the positive control Taxol, which were also accompanied by lower cytotoxicity to normal cells. In particular, compounds (E,Z)-C24 exhibited the most consistent potent activities against three neoplastic cells with IC50 values ranging from 3.2 to 7.1 μm. Further researches demonstrated that compounds (E,Z)-C24 could induce cell apoptosis and arrest cell cycle at the G2/M and S phases. Meanwhile, the structure-activity relationship between the configurations and cytotoxicity of the compounds was also investigated.

Topics: Antineoplastic Agents; Apoptosis; Benzofurans; Breast Neoplasms; Cell Cycle; Cell Line, Tumor; Crystallography, X-Ray; Drug Design; Drug Screening Assays, Antitumor; Female; HEK293 Cells; HeLa Cells; Humans; Lung Neoplasms; MCF-7 Cells; Neoplasms; Structure-Activity Relationship; Uterine Cervical Neoplasms

In an effort to search for new cancer-fighting therapeutics, we identified a novel anticancer constituent, Lappaol F, from plant Arctium Lappa L. Lappaol F suppressed cancer cell growth in a time- and dose-dependent manner in human cancer cell lines of various tissue types. We found that Lappaol F induced G(1) and G(2) cell-cycle arrest, which was associated with strong induction of p21 and p27 and reduction of cyclin B1 and cyclin-dependent kinase 1 (CDK1). Depletion of p21 via genetic knockout or short hairpin RNA (shRNA) approaches significantly abrogated Lappaol F-mediated G(2) arrest and CDK1 and cyclin B1 suppression. These results suggest that p21 seems to play a crucial role in Lappaol F-mediated regulation of CDK1 and cyclin B1 and G(2) arrest. Lappaol F-mediated p21 induction was found to occur at the mRNA level and involved p21 promoter activation. Lappaol F was also found to induce cell death in several cancer cell lines and to activate caspases. In contrast with its strong growth inhibitory effects on tumor cells, Lappaol F had minimal cytotoxic effects on nontumorigenic epithelial cells tested. Importantly, our data also demonstrate that Lappaol F exhibited strong growth inhibition of xenograft tumors in nude mice. Lappaol F was well tolerated in treated animals without significant toxicity. Taken together, our results, for the first time, demonstrate that Lappaol F exhibits antitumor activity in vitro and in vivo and has strong potential to be developed as an anticancer therapeutic.

Topics: 4-Butyrolactone; Animals; Antineoplastic Agents; Apoptosis; Arctium; Benzofurans; Cell Cycle Checkpoints; Cell Line, Tumor; Humans; Mice; Neoplasms; Plant Extracts; Xenograft Model Antitumor Assays

One of the main obstacles of conventional anticancer therapy is the toxicity of chemotherapeutics to normal tissues. So far, clinical approaches that aim to specifically reduce chemotherapy-mediated toxicities are rare. Recently, a number of studies have demonstrated that herbal extracts derived from traditional Chinese medicine (TCM) may reduce chemotherapy-induced side effects. Thus, we screened a panel of published cancer-inhibiting TCM compounds for their chemoprotective potential and identified the phytochemical Rocaglamide (Roc-A) as a candidate. We show that Roc-A significantly reduces apoptotic cell death induced by DNA-damaging anticancer drugs in primary human and murine cells. Investigation of the molecular mechanism of Roc-A-mediated protection revealed that Roc-A specifically blocks DNA damage-induced upregulation of the transcription factor p53 by inhibiting its protein synthesis. The essential role of p53 in Roc-A-mediated protection was confirmed by siRNA knockdown of p53 and by comparison of the effects of Roc-A on chemoprotection of splenocytes isolated from wild-type and p53-deficient mice. Importantly, Roc-A did not protect p53-deficient or -mutated cancer cells. Our data suggest that Roc-A may be used as an adjuvant to reduce the side effects of chemotherapy in patients with p53-deficient or -mutated tumors.

Topics: Animals; Antineoplastic Agents; Apoptosis; Benzofurans; Cell Line, Tumor; DNA Damage; Down-Regulation; Drug Interactions; Drugs, Chinese Herbal; Humans; Mice; Mice, Inbred C57BL; Mice, Knockout; Neoplasms; Protective Agents; Tumor Suppressor Protein p53

Topics: Animals; Antineoplastic Agents; Benzofurans; DNA Damage; Drugs, Chinese Herbal; Humans; Neoplasms; Protective Agents; Tumor Suppressor Protein p53

A commercial laccase, Suberase® from Novozymes, was used to catalyse the synthesis of 5,6-dihydroxylated benzo[b]furans and catechol derivatives. The yields were, in some cases, similar to or better than that obtained by other enzymatic, chemical or electrochemical syntheses. The synthesised derivatives were screened against renal (TK10), melanoma (UACC62), breast (MCF7) and cervical (HeLa) cancer cell lines. GI50, TGI and LC50 are reported for the first time. Anticancer screening showed that the cytostatic effects of the 5,6-dihydroxylated benzo[b]furans were most effective against the melanoma (UACC62) cancer cell line with several compounds exhibiting potent growth inhibitory activities (GI50=0.77-9.76 µM), of which two compounds had better activity than the anticancer agent etoposide (GI50  0.89 µM). One compound exhibited potent activity (GI50=9.73 µM) against the renal (TK10) cancer cell line and two exhibited potent activity (GI50=8.79 and 9.30 µM) against the breast (MCF7) cancer cell line. These results encourage further studies of the 5,6-dihydroxylated benzo[b]furans for their potential application in anticancer therapy.

Topics: Antineoplastic Agents; Benzofurans; Catechols; Cell Line, Tumor; Etoposide; HeLa Cells; Humans; Laccase; Lethal Dose 50; MCF-7 Cells; Neoplasms

(Z)-2-((1H-Indazol-3-yl)methylene)-6-methoxy-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one is a potent and selective proviral integration site in moloney murine leukemia virus kinase 1 (PIM1) inhibitor with an IC₅₀ value of 3 nM. (Z)-2-((1H-Indazol-3-yl)methylene)-6-[(11)C]methoxy-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one, a new potential PET probe for imaging of the enzyme PIM1, was first designed and synthesized in 20-30% decay corrected radiochemical yield and 370-740 GBq/μmol specific activity at end of bombardment (EOB). The synthetic strategy was to prepare a carbon-11-labeled Boc-protected intermediate followed by a quick acidic de-protection.

Topics: Animals; Benzofurans; Carbon Isotopes; Fungal Proteins; Humans; Indazoles; Mice; Mitogen-Activated Protein Kinases; Neoplasms; Piperazines; Positron-Emission Tomography; Protein Kinase Inhibitors; Radiopharmaceuticals

The ribosome is centrally situated to sense metabolic states, but whether its activity, in turn, coherently rewires transcriptional responses is unknown. Here, through integrated chemical-genetic analyses, we found that a dominant transcriptional effect of blocking protein translation in cancer cells was inactivation of heat shock factor 1 (HSF1), a multifaceted transcriptional regulator of the heat-shock response and many other cellular processes essential for anabolic metabolism, cellular proliferation, and tumorigenesis. These analyses linked translational flux to the regulation of HSF1 transcriptional activity and to the modulation of energy metabolism. Targeting this link with translation initiation inhibitors such as rocaglates deprived cancer cells of their energy and chaperone armamentarium and selectively impaired the proliferation of both malignant and premalignant cells with early-stage oncogenic lesions.

Topics: Animals; Antineoplastic Agents; Benzofurans; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic; DNA-Binding Proteins; Energy Metabolism; Gene Expression Regulation, Neoplastic; Heat Shock Transcription Factors; High-Throughput Screening Assays; Humans; Mice; Neoplasm Transplantation; Neoplasms; NIH 3T3 Cells; Protein Biosynthesis; Ribosomes; Transcription Factors

Eight new dihydrobenzofuran neolignans, pinnatifidanin C I-VIII (1-8), together with two known analogs (9-10) were isolated from the seeds of Crataegus pinnatifida. Their structures were elucidated by spectroscopic analyses, especially 1D, 2D NMR and CD spectra. The cytotoxic activities of all isolates against human cancer cell lines were assayed, and most interestingly, compound 10 revealed preferred cytotoxicity on the HT-1080 cell line and displayed much stronger inhibitory activity (IC50=8.86 μM) compared with positive control 5-fluorouracil (IC50=35.62 μM). Meanwhile, antioxidant activities of all the isolates were evaluated using 2,2-diphenyl-1-pikrylhydrazyl (DPPH) and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) assays, and the results showed that most of the isolates exhibited potent antioxidant activity.

Topics: Antineoplastic Agents, Phytogenic; Antioxidants; Benzofurans; Benzothiazoles; Biphenyl Compounds; Cell Line, Tumor; Crataegus; Humans; Inhibitory Concentration 50; Lignans; Molecular Structure; Neoplasms; Phytotherapy; Picrates; Plant Extracts; Seeds; Sulfonic Acids

Regulation of hypoxia inducible factor (HIF)-1α stabilization, which in turn contributes to adaptation of tumor cells to hypoxia has been highlighted as a promising therapeutic target in angiogenesis-related diseases. We have identified a new small molecule, G0811, as a potent angiogenesis inhibitor that targets HIF-1α signal transduction. G0811 suppressed HIF-1α stability in cancer cells and inhibited in vitro and in vivo angiogenesis, as validated by tube formation, chemoinvasion, and chorioallantoic membrane (CAM) assays. In addition, G0811 effectively decreased the expression of vascular endothelial growth factor (VEGF), which is one of target genes of HIF-1α. However, G0811 did not exhibit anti-proliferative activities or toxicity in human umbilical vein endothelial cells (HUVECs) at effective doses. These results demonstrate that G0811 could be a new angiogenesis inhibitor that acts by targeting HIF-1α signal transduction pathway.

Topics: Androgen Antagonists; Benzofurans; Cell Line, Tumor; Culture Media, Conditioned; Drug Screening Assays, Antitumor; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Neoplasms; Neovascularization, Pathologic; Neovascularization, Physiologic; Protein Stability; Signal Transduction; Sulfonamides; Vascular Endothelial Growth Factor A

Polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) have been reported as possible carcinogenic hazards to humans. However, epidemiological studies on their carcinogenic roles are limited. The current study was designed to determine the concentrations and characteristics of PCDD/Fs and evaluate their association with cancer mortality in exposed workers in one automobile foundry factory. PCDD/F levels in factory and surrounding environment were analyzed through air and settling dust sampling. The cancer mortalities among workers in this foundry factory were calculated using data from a cohort study. The results showed that the PCDD/F concentrations of air in workplace ranged 0.36-2.25 pg World Health Organization-Toxic Equivalent (WHO-TEQ) Nm(-3) (average 1.01 pg WHO-TEQ Nm(-3)), which were 1.16-7.26 times higher than those outside the factory. The PCDD/F concentrations of settling dust in the workplace ranged 3.34-18.64 pg WHO-TEQ g(-1) (average 8.25 pg WHO-TEQ g(-1)), which were lower than those just outside the factory (average 16.13 pg WHO-TEQ g(-1)). Furthermore, a cohort study of workers in this factory with average follow-up of 24.52 years showed that cancer was the leading cause of death, with significant elevated mortality (standardized mortality ratio (SMR)=1.70, 95% confidence interval (CI): 1.35-2.13) among workers, when compared with Chinese national mortality. The cancer mortality among front-line workers was increased significantly (adjusted relative risk (RR)=1.73, 95% CI: 1.14-2.60), particularly among melting and casting workers, when compared with that among assistant workers. Our results indicated that there was a dose-response relationship between PCDD/F exposure and cancer mortality among foundry workers.

Topics: Automobiles; Benzofurans; Cohort Studies; Dibenzofurans, Polychlorinated; Gas Chromatography-Mass Spectrometry; Humans; Industry; Neoplasms; Occupational Exposure; Polychlorinated Dibenzodioxins

Sulfuretin (3',4',6'-trihydroxyaurone), one of the key flavonoids isolated from Rhus verniciflua, is known to suppress inflammation and oxidative stress. However, the anti-cancer properties of sulfuretin as well as its mechanism of action remain poorly understood. Here, we show that the expression of miR-30C is markedly enhanced in sulfuretin-stimulated cells, consequently promoting apoptosis and cell cycle arrest in human cancer cell lines. The transient transfection of pre-miR-30C resulted in greater than 70% growth inhibition in PC-3 cells and provided strong evidence that miR-30C selectively suppresses the expression of cyclin D1 and D2, but not cyclin D3. Target validation analysis revealed that 3'-UTR of cyclin D2 is a direct target of miR-30C, whereas suppression by miR-30C of cyclin D1 may occur through indirect mRNA regulation. In addition, silencing miR-30C expression partially reversed sulfuretin-induced cell death. Taken together, our data suggest that miR-30C, a tumor suppressor miRNA, contributes to anti-cancer properties of sulfuretin by negatively regulating cyclin D1 and D2, providing important implications of sulfuretin and miR-30C for the therapeutic intervention of human cancers.

Topics: Antineoplastic Agents; Apoptosis; Benzofurans; Cell Line, Tumor; Cyclin D1; Cyclin D2; Down-Regulation; Flavonoids; Humans; MicroRNAs; Neoplasms

We have previously isolated dieckol, a nutrient polyphenol compound, from the brown alga, Ecklonia cava (Lee et al.,2010a). Dieckol shows both antitumor and antioxidant activity and thus is of special interest for the development of chemopreventive and chemotherapeutic agents against cancer. However, the mechanism by which dieckol exerts its antitumor activity is poorly understood. Here, we show that dieckol, derived from E. cava, inhibits migration and invasion of HT1080 cells by scavenging intracellular reactive oxygen species (ROS). H2O2 or integrin signal-mediated ROS generation increases migration and invasion of HT1080 cells, which correlates with Rac1 activation and increased expression and phosphorylation of focal adhesion kinase (FAK). Rac1 activation is required for ROS generation. Depletion of FAK by siRNA suppresses Rac1-ROS-induced cell migration and invasion. Dieckol treatment attenuated intracellular ROS levels and activation of Rac1 as well as expression and phosphorylation of FAK. Dieckol treatment also decreases complex formation of FAK-Src-p130C as and expression of MMP2, 9, and 13. These results suggest that the Rac1-ROS-linked cascade enhances migration and invasion of HT1080 cells by inducing expression of MMPs through activation of the FAK signaling pathway, whereas dieckol downregulates FAK signaling through scavenging intracellular ROS. This finding provides new insights into the mechanisms by which dieckol is able to suppress human cancer progresssion and metastasis. Therefore, we suggest that dieckol is a potential therapeutic agent for cancer treatment.

Topics: Antineoplastic Agents; Benzofurans; Cell Line, Tumor; Cell Movement; Focal Adhesion Protein-Tyrosine Kinases; Free Radical Scavengers; Humans; Neoplasm Invasiveness; Neoplasms; Phaeophyceae; rac1 GTP-Binding Protein; Reactive Oxygen Species; RNA, Small Interfering; Signal Transduction; Transcriptional Activation

Health risk assessment due to the atmospheric emissions of carcinogenic pollutants (PCDD/Fs and Cd) from a waste gasification plant is performed by means of a probabilistic approach based on probability density functions for the description of the input data of the model parameters involved in the assessment. These functions incorporate both the epistemic and stochastic uncertainty of the input data (namely, the emission rate of the pollutants) and of all the parameters used for individual exposure assessment through the pathways of inhalation, soil ingestion and dermal contact, and diet. The uncertainty is propagated throughout the evaluation by Monte Carlo technique, resulting in the probability distribution of the individual risk. The median risk levels nearby the plant are in the 10(-8)-10(-10) range, ten-fold lower than the deterministic estimate based on precautionary values for the input data; however, the very upper percentiles (>95th) of the risk distribution can exceed the conventional 10(-6) reference value. The estimated risk is almost entirely determined by the Cd exposure through the diet; the pathways arising from PCDD/Fs exposure are without any practical significance, suggesting that the emission control should focus on Cd in order to reduce the carcinogenic risk. Risk variance decomposition shows the prevailing influence on the estimated risk of the Cd concentration at the emission stack: thus, for a more accurate risk assessment the efforts should focus primarily on the definition of its probability density function.

Topics: Air Pollutants; Air Pollution; Benzofurans; Cadmium; Carcinogens; Dibenzofurans, Polychlorinated; Environmental Exposure; Humans; Models, Chemical; Monte Carlo Method; Neoplasms; Polychlorinated Dibenzodioxins; Refuse Disposal; Risk Assessment

Little is known about the mortality risk associated with chronic dioxin exposure in the general U.S. populations.. To explore the association between dioxin-like chemicals and mortality risk in a large population-based cohort study.. The analysis included 2361 subjects aged 40 years or older from the 1999-2004 National Health and Nutrition Examination Survey (NHANES). Exposure to a mixture of dioxin-like chemicals, including dibenzo-p-dioxins, dibenzofurans, and polychlorinated biphenyls was estimated using toxic equivalency values (TEQs) calculated with 2005 World Health Organization toxic equivalency factors. All-cause and cause-specific mortalities were obtained from the NHANES-linked follow-up data through December 31, 2006. Cox proportional-hazards models were applied to assess the associations of interest.. A total of 242 deaths occurred during the follow-up period, including 75 from cardiovascular disease and 72 from cancer. There was an increased mortality risk associated with logarithmically expressed dioxin TEQs for all-cause deaths (hazard ratio=1.19, 95% confidence interval=1.02-1.39, p=0.02). Similar graded dose-response trends were found for cardiovascular and cancer mortality which did not reach statistical significance.. In general, higher dioxin exposure is associated with an increased mortality risk among subjects aged 40 and above. The cause-specific analyses and responsible mechanisms will require further investigation.

Topics: Adult; Aged; Aged, 80 and over; Benzofurans; Cardiovascular Diseases; Dibenzofurans, Polychlorinated; Dioxins; Environmental Exposure; Female; Humans; Male; Middle Aged; Mortality; Neoplasms; Nutrition Surveys; Polychlorinated Biphenyls; United States

Flavaglines represent a family of plant natural products that display potent anticancer, cardioprotective, and neuroprotective activities. Novel flavagline derivatives were synthesized and examined for their cytotoxicity on a panel of human cancer cell lines, their cardioprotection against doxorubicin-induced apoptosis in cardiomyocytes, and their neuroprotection in culture models of Parkinson's disease and cisplatin-induced neurotoxicity. The structural requirements of flavaglines for cardio- and neuroprotection were for the first time unraveled and appeared to be slightly different from those for cytotoxicity on cancer cells. We provide also the first evidence that flavaglines may alleviate cisplatin-induced neurotoxicity, suggesting a prophylactic potential of these compounds to prevent this frequently encountered adverse effect of cancer chemotherapies.

Topics: Animals; Antibiotics, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Apoptosis; Benzofurans; Biological Products; Cardiotonic Agents; Cells, Cultured; Cisplatin; Cytoprotection; Disease Models, Animal; Dopaminergic Neurons; Doxorubicin; Humans; Mice; Models, Molecular; Molecular Structure; Myocytes, Cardiac; Neoplasms; Parkinson Disease; Rats; Structure-Activity Relationship

Atmospheric concentrations of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs), polybrominated dibenzo-p-dioxins and dibenzofurans (PBDD/Fs), and polybrominated diphenyl ethers (PBDEs) were measured in Taizhou, a large electronic equipment waste (e-waste) recycling area in East China. The mean concentrations (in summer and winter) of PCDD/Fs (0.45 and 0.39 pg WHO-TEQ m⁻³, where WHO-TEQ is the toxic equivalent set by the World Health Organisation), PBDD/Fs (0.22 and 0.18 pg WHO-TEQ m⁻³), and PBDEs (270 and 225 pg m⁻³) in this region have declined compared with those in 2005, due to regulations on primitive e-waste recycling activities. However, these concentrations remain higher than the historically highest levels in Europe and North America. The congener profiles of 2,3,7,8-substituted PCDD/Fs were similar, with OCDD, 1,2,3,4,6,7,8-HpCDF, OCDF, and 1,2,3,4,6,7,8-HpCDD being the most abundant congeners at all sites. The PCDD/F homologue profiles in the present study were different from those typically observed at non-e-waste locations, indicating a distinct source in this region. Seasonal differences were found in the lower brominated PBDE profiles. These differences indicate that the PBDE emission sources in summer (e.g., strong evaporation sources) differed from those in winter. However, the relatively steady congener profiles of the highly brominated PBDEs suggest that these PBDEs were controlled primarily by similar emission mechanisms. The lifetime excess cancer risks from exposure to PCDD/Fs and PBDD/Fs via inhalation ranged from 0.7 × 10⁻⁵ to 5.4 × 10⁻⁵, or approximately 80 cancer cases in the Taizhou population.

Topics: Air Pollutants; Air Pollution; Benzofurans; Bromine Compounds; China; Dioxins; Electronic Waste; Environmental Exposure; Environmental Monitoring; Halogenated Diphenyl Ethers; Humans; Neoplasms; Polychlorinated Dibenzodioxins; Polymers; Risk Assessment

The lichen compound usnic acid (UA) is a lipophilic weak acid that acts as a proton shuttle and causes loss of mitochondrial inner membrane potential. In the current study we show that UA treatment induced the formation of autophagosomes in human cancer cells, but had minimal effects on normal human fibroblasts. However, autophagic flux was incomplete, degradation of autophagosomal content did not occur and acidification was defective. UA-treated cells showed reduced ATP levels and activation of AMP kinase as well as signs of cellular stress. UA is thus likely to trigger autophagosome formation both by energy depletion and stress conditions. Our findings indicate that the H(+)-shuttling effect of UA operates not only in mitochondria as previously shown, but also in lysosomes, and have implications for therapeutic manipulation of autophagy and pH-determined drug distribution.

Topics: Adenosine Triphosphate; Adenylate Kinase; Benzofurans; Drug Screening Assays, Antitumor; Enzyme Activation; Humans; Lichens; Lysosomes; Microtubule-Associated Proteins; Mitochondria; Neoplasms; Phagosomes; Protons; Signal Transduction; Vacuoles

Since 2008, sewage sludge is being used as alternative fuel in a cement plant placed in Vallcarca (Catalonia, Spain). To evaluate the temporal trend of the environmental levels of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) and a number of metals (As, Cd, Co, Cr, Cu, Hg, Mn, Ni, Pb, Sn, Tl, V, and Zn), as well as the potentially associated human health risks, samples of soil, herbage, and air were collected around the facility, after approximately one year of the permanent partial substitution of fuel. The temporal evolution of the pollutant levels was assessed by comparing the measured concentrations (2009) with those from samples collected in previous surveys (2003 and 2006) at the same sampling sites. The concentrations of PCDD/Fs in herbage and soil were 0.10 and 1.11 ng I-TEQ·kg⁻¹ dw, respectively, values very similar to those found in our previous surveys. For metals, although a clear tendency could not be observed, there were fluctuations through time. In this study, the levels of metals, which had not been analyzed in previous campaigns, were also determined in air, additionally to soil and vegetation. Airborne metal concentrations were similar to those found in other industrial areas worldwide. The human health risks for the population living around the cement plant were comparable to those obtained in previous studies, when petroleum coke was exclusively used as combustible, being in both cases tolerable according to the international standards.

Topics: Air Pollutants; Benzofurans; Construction Materials; Dibenzofurans, Polychlorinated; Humans; Incineration; Metals; Neoplasms; Plants; Polychlorinated Dibenzodioxins; Power Plants; Risk Assessment; Sewage; Soil Pollutants; Waste Disposal, Fluid

One of the ways for searching for potentially new anti-cancer drugs is the testing of various naturally synthesized compounds. Lichens are a source of unique chemical agents of which some have already been proved to be effective against various cancer in vitro models. Our study reports on the sensitivity of up to nine human cancer cell lines (A2780, HeLa, MCF-7, SK-BR-3, HT-29, HCT-116 p53(+/+), HCT-116 p53(-/-), HL-60 and Jurkat) to the anti-proliferative/cytotoxic effects of four typical secondary metabolites of lichens (parietin, atranorin, usnic acid and gyrophoric acid). Variations in the dynamics of tumour cell line populations were evaluated by the MTT, clonogenic and viability assays, cell proliferation and detachment, cell cycle transition and apoptotic nuclear morphology, thereby confirming their concentration- and time-dependent cytotoxicity. However, in comparison with parietin and gyrophoric acid, the suppression of viability and cell proliferation by usnic acid or atranorin was found to be more efficient at equitoxic doses and correlated more strongly with an increased number of floating cells or a higher apoptotic index. Moreover, the analysis of cell cycle distribution also revealed an accumulation of cells in S-phase. This study has confirmed a differential sensitivity of cancer cell lines to lichen secondary metabolites.

Topics: Antineoplastic Agents; Apoptosis; Benzoates; Benzofurans; Cell Adhesion; Cell Line, Tumor; Cell Nucleus Shape; Cell Proliferation; Cell Survival; Drug Discovery; Drug Screening Assays, Antitumor; Emodin; Humans; Hydroxybenzoates; Lichens; Neoplasms; Osmolar Concentration; S Phase

We evaluate the magnitude of metallic artifacts caused by various implantable cardiac pacing devices (without leads) on both attenuation maps (μ-maps) and positron emission tomography (PET) images using experimental phantom studies. We also assess the efficacy of a metal artifact reduction (MAR) algorithm along with the severity of artifacts in the presence of misalignment between μ-maps and PET images.. Four pacing devices including two pacemakers (pacemakers 1 and 2) and two cardiac resynchronization therapy (CRT) devices of pacemaker (CRT-P) and defibrillator (CRT-D) type were placed in three phantoms including a cylindrical Ge-68 phantom, a water-bath phantom and an anthropomorphic heart/thorax phantom. The μ-maps were derived from computed tomography (CT) images reconstructed using the standard method supplied by the manufacturer and those reconstructed using the MAR algorithm. In addition, the standard reconstructed CT images of the last two phantoms were manually misaligned by 10 mm along the patient's axis to simulate misalignment between CT and PET images.. The least and severest artifacts produced on both μ-maps and PET images of the Ge-68 phantom were induced by CRT-P and pacemaker 1 devices, respectively. In the water-bath phantom, CRT-P induced 17.5% over- and 9.2% underestimation of tracer uptake whereas pacemaker 1 induced 69.6% over- and 65.7% underestimation. In the heart/thorax phantom representing a pacemaker-bearing patient, pacemaker 1 induced 41.8% increase and 36.6% decrease in tracer uptake and attenuation coefficients on average in regions corresponding to bright and dark streak artifacts, respectively. Statistical analysis revealed that the MAR algorithm was successful in reducing bright streak artifacts, yet unsuccessful for dark ones. In the heart/thorax phantom, the MAR algorithm reduced the overestimations to 4.4% and the underestimations to 35.5% on average. Misalignment between μ-maps and PET images increased the peak of pseudo-uptake by approximately 20%.. This study demonstrated that, depending on their elemental composition, different implantable cardiac pacing devices result in varying magnitudes of metal artifacts and thus pseudo-uptake on PET images. The MAR algorithm was not successful in compensating for underestimations which calls for a more efficient algorithm. The results showed that misalignments between PET and CT images render metal-related pseudo-uptake more severe.

Topics: Algorithms; Artifacts; Benzofurans; Cardiac Resynchronization Therapy; Humans; Image Processing, Computer-Assisted; Metals; Multimodal Imaging; Neoplasms; Pacemaker, Artificial; Phantoms, Imaging; Positron-Emission Tomography; Prostheses and Implants; Tomography, X-Ray Computed

Two new sorbicillinoids, 1 and 2, together with a novel benzofuranone derivative named phialofurone (3), were isolated from a deep-sea sediment-derived fungus, Phialocephala sp. Their structures were established on the basis of spectroscopic data. All compounds displayed cytotoxic effects against P388 (IC(50) values of 11.5±1.4, 0.1±0.1, and 0.2±0.01 μM, resp.) and K562 (IC(50) values of 22.9±0.8, 4.8±0.3 and 22.4±0.9 μM, resp.) cell lines.

Topics: Antineoplastic Agents; Ascomycota; Benzofurans; Cell Line, Tumor; Cell Survival; Cyclohexanones; Drug Screening Assays, Antitumor; Humans; Neoplasms

Selective inhibitors of human peptide deformylase (HsPDF) are predicted to constitute a new class of antitumor agents. We report the identification of benzofuran-4,5-diones as the first known selective HsPDF inhibitors and we describe their selectivity profile in a panel of metalloproteases. We characterize their structure-activity relationships for antitumor activity in a panel of cancer cell lines, and we assess their in vivo efficacy in a mouse xenograft model. Our results demonstrate that selective HsPDF inhibitors based on the benzofuran-4,5-dione scaffold constitute a novel class of antitumor agents that are potent in vitro and in vivo.

Topics: Amidohydrolases; Animals; Antineoplastic Agents; Benzofurans; Cell Line, Tumor; Drug Screening Assays, Antitumor; Enzyme Inhibitors; Humans; Hydroxamic Acids; Metalloproteases; Mice; Mice, Nude; Neoplasms; Structure-Activity Relationship; Transplantation, Heterologous

Epigenetic modifications, such as DNA methylation or histone deacetylation, are early events in cell tumorigenesis. The consequences of these modifications are repression of gene transcription and, notably, of tumor suppressor gene transcription. New therapeutic strategies aim to 'normalize' the epigenetic status of cancer cells. Histone deacetylase inhibitors (HDACi) have shown promising effects against proliferation and resistance to apoptosis of a large number of cancer cells. Vorinostat (SAHA), a hydroxamate HDACi, has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of refractory cutaneous T-cell lymphoma (CTCL). However, HDACi are poorly specific, present toxicities and many have very low half-lives in the plasma. Thus, the development of new compounds is necessary in order to increase the potential of HDACi in cancer treatment. We designed an assay, based on bioluminescence resonance energy transfer (BRET) technology, to screen and characterize HDACi activity in living cells. Using our specific and reproducible BRET assay, we characterized the pharmacological properties of benzofuranone HDACi compounds for the induction of histone acetylation and performed a comparison with the properties of suberoylanilide hydroxamic acid (SAHA) and valproic acid (VPA). We defined a benzofuranone HDACi compound that induced histone acetylation at nanomolar concentrations and showed an increased duration of histone acetylation. These properties correlated with the pharmacological properties of this HDACi for the growth inhibition of cancer cells. We, thus, demonstrated the applicability of BRET technology for the screening and characterization of new HDACi compounds in living cells, and identified an interesting benzofuranone HDACi.

Topics: Acetylation; Animals; Antineoplastic Agents; Benzofurans; Bioluminescence Resonance Energy Transfer Techniques; Cell Line, Tumor; Cell Proliferation; Drug Design; Drug Resistance, Neoplasm; High-Throughput Screening Assays; Histone Deacetylase Inhibitors; Histones; Humans; Hydroxamic Acids; Inhibitory Concentration 50; Kinetics; Molecular Targeted Therapy; Neoplasms; Rats; Recombinant Fusion Proteins

A series of benzofuropyrazoles 2a-i were synthesized in 10-92% from the reaction of 2-aroylbenzofuran-3-ols 1a-i with hydrazine hydrate, and screened for their antitumor activities toward four human solid tumor cell lines, including gastric carcinoma cells MKN45, hepatocellular carcinoma cells HepG2, breast cancer cells MCF-7, and lung cancer cells A549. The results indicated that both compounds 1a-i and 2a-i displayed moderate antitumor activities. Among them, compound 2e exhibited potent inhibitory activity toward all the four tumor cell lines. In addition, compounds 1e and 2e showed strong DNA-binding affinities, and induced an increase in the viscosity of calf-thymus DNA, suggesting that they might act as an intercalator.

Topics: Animals; Antineoplastic Agents; Benzofurans; Cattle; Cell Line, Tumor; DNA; Drug Screening Assays, Antitumor; Humans; Neoplasms; Pyrazoles

Induction of apoptosis is a promising strategy that could lead to the discovery of new molecules active in cancer chemotherapy. This property is generally observed when cells are treated with agents that target microtubules, dynamic structures that play a crucial role in cell division. Small molecules such as benzo[b]furans are attractive as inhibitors of tubulin polymerization. A new class of inhibitors of tubulin polymerization based on the 2-(3',4',5'-trimethoxybenzoyl)benzo[b]furan molecular skeleton, with the amino group placed at different positions on the benzene ring, were synthesized and evaluated for antiproliferative activity, inhibition of tubulin polymerization, and cell-cycle effects. The methoxy substitution pattern on the benzene portion of the benzo[b]furan moiety played an important role in affecting antiproliferative activity. In the series of 5-amino derivatives, the greatest inhibition of cell growth occurred if the methoxy substituent is placed at the C6 position, whereas C7 substitution decreases potency. The most promising compound in this series is 2-(3',4',5'-trimethoxybenzoyl)-3-methyl-5-amino-6-methoxybenzo[b]furan (3 h), which inhibits cancer cell growth at nanomolar concentrations (IC(50) =16-24 nM), and interacts strongly with tubulin by binding to the colchicine site. Sub-G(1) apoptotic cells in cultures of HL-60 and U937 cells were observed by flow cytometric analysis after treatment with 3 h in a concentration-dependent manner. We also show that compound 3 h induces apoptosis by activation of caspase-3, -8, and -9, and this is associated with cytochrome c release from mitochondria. The introduction of an α-bromoacryloyl group increased antiproliferative activity with respect to the parent amino derivatives.

Topics: Animals; Anisoles; Antineoplastic Agents; Apoptosis; Benzofurans; Binding Sites; Caspases; Cell Cycle Checkpoints; Cell Line, Tumor; Colchicine; Humans; Mice; Neoplasms; Tubulin; Tubulin Modulators

Four new 2-arylbenzofuran derivatives, moracins V-Y (1-4), together with two known compounds, moracin N (5) and moracin P (6), were isolated from the leaves of Morus alba L. Their structures were elucidated by spectroscopic analysis. Moracins X (3) and Y (4) represent unusual substituted group compared with 2-arylbenzofuran derivatives, which were isolated from the genus Morus. Compounds 2-5 were evaluated for cytotoxicity against several human cancer cell lines.

Topics: Antineoplastic Agents, Phytogenic; Benzofurans; Cell Line, Tumor; Cell Survival; Humans; Molecular Structure; Morus; Neoplasms; Plant Leaves

We discovered 2-(4-substituted-pyrrolo[2,3-b]pyridin-3-yl)methylene-4-hydroxybenzofuran-3(2H)-ones as potent and selective ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR). Since phenolic OH groups pose metabolic liability, one of the two hydroxyl groups was selectively removed. The SAR data showed the structural features necessary for subnanomolar inhibitory activity against mTOR kinase as well as selectivity over PI3Kalpha. An X-ray co-crystal structure of one inhibitor with the mTOR-related PI3Kgamma revealed the key hydrogen bonding interactions.

Topics: Adenosine Triphosphate; Animals; Antineoplastic Agents; Benzofurans; Crystallography, X-Ray; Humans; Inhibitory Concentration 50; Intracellular Signaling Peptides and Proteins; Mice; Mice, Nude; Microsomes; Models, Molecular; Neoplasms; Phosphatidylinositol 3-Kinases; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Structure-Activity Relationship; TOR Serine-Threonine Kinases

Vascular disruption agents (VDA) cause occlusion of tumor vasculature, resulting in hypoxia-driven tumor cell necrosis. Tumor vascular disruption is a therapeutic strategy of great potential; however, VDAs currently under development display a narrow therapeutic margin, with cardiovascular toxicity posing a dose-limiting obstacle. Discovery of new VDAs, which display a wider therapeutic margin, may allow attainment of improved clinical outcomes. To identify such compounds, we used an in vitro selectivity screening approach that exploits the fact that tumor endothelial cells are in a constant state of activation and angiogenesis and do not undergo senescence. Our effort yielded the compound BNC105. This compound acts as a tubulin polymerization inhibitor and displays 80-fold higher potency against endothelial cells that are actively proliferating or are engaged in the formation of in vitro capillaries compared with nonproliferating endothelial cells or endothelium found in stable capillaries. This selectivity was not observed with CA4, a VDA currently under evaluation in phase III clinical trials. BNC105 is more potent and offers a wider therapeutic window. CA4 produces 90% vascular disruption at its no observed adverse event level (NOAEL), whereas BNC105 causes 95% vascular disruption at 1/8th of its NOAEL. Tissue distribution analysis of BNC105 in tumor-bearing mice showed that while the drug is cleared from all tissues 24 hours after administration, it is still present at high concentrations within the solid tumor mass. Furthermore, BNC105 treatment causes tumor regressions with complete tumor clearance in 20% of treated animals.

Topics: Animals; Anisoles; Antineoplastic Agents; Benzofurans; Capillaries; Cell Line; Cell Membrane Permeability; Cell Proliferation; Cell Surface Extensions; Endothelial Cells; Humans; Mice; Neoplasms; Neovascularization, Pathologic; Remission Induction; Treatment Outcome; Tubulin Modulators; Xenograft Model Antitumor Assays

Certain iminonaphtho[2,3-b]furan derivatives were synthesized from their respective carbonyl precursors in the regiospecific and the stereospecific manners. These compounds were evaluated for their antiproliferative effects against four human carcinoma cells (MCF7, NCI-H460, SF-268, and K562) and the normal fibroblast cell line (Detroit 551). Among them, (Z)-4-(hydroxyimino)naphtho[2,3-b]furan-9(4H)-one (8) and (Z)-4-methoxy-iminonaphtho[2,3-b]furan-9(4H)-one (9) exhibited GI(50) values of 0.82 and 0.60 microM, respectively, against the growth of K562 cells and were inactive against the normal fibroblast Detroit 551. The selectivity index (SI) on K562 cell for 8 and 9 was >121.95 and >166.67, respectively, which is comparable to daunorubicin (SI=239) and is more favorable than camptothecin (SI=16.5). The cell cycle analysis on K562 indicated that these compounds arrest the cell cycle at the G2/M phase. The morphological assessment and DNA fragmentation analysis indicated that 9-induced cell apoptosis in K562 cells. The apoptotic induction may through caspase-3 activity and cleavage of PARP.

Topics: Antineoplastic Agents; Benzofurans; Cell Cycle; Cell Line; Cell Line, Tumor; Cell Proliferation; DNA Fragmentation; Drug Screening Assays, Antitumor; Fibroblasts; Humans; Imines; Neoplasms

Lecanoric acid (1), orsellinic acid methyl ester (2), orcinol (3), and usnic acid (4) were isolated from the lichen Parmelia subrudecta, collected on Palma of the Canary Islands, Spain. Compounds 1, 2, 3, and 4 were purified by solvent extraction, silica gel column chromatography, and preparative high-performance liquid chromatography (HPLC) consecutively. The structures of the four compounds were elucidated by one- and two-dimensional nuclear magnetic resonance (NMR) experiments and mass spectrometric investigations. These compounds showed activity against important gram-positive and gram-negative pathogens like mycobacteria and multiresistant staphylococci. This activity is combined with antiproliferative activity and cytotoxicity.

Topics: Anti-Infective Agents; Antineoplastic Agents; Bacteria; Bacterial Infections; Benzofurans; Cell Line, Tumor; Cell Proliferation; Humans; Lichens; Magnetic Resonance Spectroscopy; Molecular Structure; Neoplasms; Resorcinols; Salicylates; Spectrometry, Mass, Electrospray Ionization

A 40-year follow-up study was conducted to examine mortality among 1,664 patients in Japan suffering from "Yusho," a disease caused by ingestion of rice oil contaminated with polychlorinated biphenyls and polychlorinated dibenzofurans. To evaluate the effects of exposure on mortality, the authors calculated standardized mortality ratios. National mortality rates for major causes of death were used as reference points. A total of 1,596 Yusho patients (95.9%) were followed until death or the end of the study (December 31, 2007). The standardized mortality ratios for most major causes of death were not significantly elevated, with the exceptions of all types of cancer (standardized mortality ratio (SMR) = 1.37, 95% confidence interval (CI): 1.11, 1.66), liver cancer (SMR = 1.82, 95% CI: 1.06, 2.91), and lung cancer (SMR = 1.75, 95% CI: 1.14, 2.57) in males. In addition, the standardized mortality ratios for all cancers, liver cancer, and lung cancer among males tended to decrease over time. Results from this study suggest that the carcinogenicity of polychlorinated biphenyls and polychlorinated dibenzofurans must be taken into account when evaluating mortality risk.

Topics: Adult; Aged; Aged, 80 and over; Benzofurans; Cohort Studies; Confidence Intervals; Dibenzofurans, Polychlorinated; Environmental Pollutants; Female; Follow-Up Studies; Food Contamination; Humans; Japan; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Neoplasms; Oryza; Plant Oils; Polychlorinated Biphenyls; Soil Pollutants; Survival Rate

Five compounds representative of major structural classes of lichen polyketides, VIZ. (+)-usnic (1), salazinic (2), vulpinic (3), gyrophoric (4), and evernic acids (5), were investigated for their ability to affect cell proliferation or wound healing, two functional targets of relevance for research on cancer or tissue regeneration. The experiments were carried out on MM98 malignant mesothelioma cells, A431 vulvar carcinoma cells, and HaCaT keratinocytes. The NRU and CV cytotoxicity assays showed high toxicity for (+)-usnic acid, intermediate toxicity for vulpinic acid, and low toxicity for salazinic, gyrophoric and evernic acids. Scratch wounding experiments on HaCaT monolayers, in the presence of subtoxic doses of lichen compounds, showed strong wound closure effects by (+)-usnic and gyrophoric acid, an intermediate effect by vulpinic and salazinic acids, and no effect by evernic acid. A combination of (+)-usnic and gyrophoric acids gave a further increase in the wound closure rates. The results of a cell migration test correlated with the wound healing data. In conclusion, (+)-usnic acid might be a particularly interesting compound for the prevention of hyperproliferation syndromes, while (+)-usnic and gyrophoric acids qualify as interesting leads in the promotion of tissue regeneration.

Topics: Antineoplastic Agents, Phytogenic; Benzoates; Benzofurans; Cell Line, Tumor; Cell Proliferation; Female; Furans; Humans; Hydroxybenzoates; Keratinocytes; Lactones; Lichens; Neoplasms; Phenylacetates; Phytotherapy; Plant Extracts; Salicylates; Wound Healing

The Escambia Wood Treating Company (ETC) Superfund site, Pensacola, FL, is contaminated with polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDD/F), benzo(a)pyrene, lead and arsenic from pentachlorophenol (PCP), creosote, and other compounds used to treat utility poles and foundation pilings. Although ETC's operations ceased in 1982, soils in the areas surrounding the facility continue to exhibit elevated levels of contaminants attributable to ETC operations. In July 2000, individuals who may have been affected by contamination from the ETC site, including current and former residents and former workers and their household members were invited to participate in a study, which included a health and exposure history and routine blood analysis. We also conducted a toxicological health evaluation of a subset of these eligible workers/residents by analyzing serum levels of 17 PCDD/F congeners. Members of the ETC cohort exhibited elevated serum PCDD/F relative to the general population, and congener profiles in members of the cohort reflected patterns commonly observed in persons exposed to PCP. Hypertension prevalence in the cohort was found to correlate with PCDD/F levels, although no other significant relationships were identified with monitored health indices.

Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Benzofurans; Diabetes Mellitus; Dibenzofurans, Polychlorinated; Environmental Monitoring; Environmental Pollutants; Epidemiological Monitoring; Female; Florida; Humans; Hypertension; Industrial Waste; Liver Function Tests; Male; Middle Aged; Neoplasms; Polychlorinated Dibenzodioxins

A nation-wide questionnaire survey on the past history of diseases and symptoms was conducted in 2005. The questionnaire was administered by mail to the 1258 registered Yusho patients, inguiring about the past incidence of 15 regions of malignant neoplasm, 42 diseases, and 5 symptoms. Out of the 717 patients responded to the questionnaire, 34 patients born after the Yusho outbreak were excluded, leaving 683 patients as the study subjects. Their mean age (SD) was 62.7 (14.0) years, ranging from 39 to 97 years old. Seven percent of the patients acknowledged the past history of malignant neoplasm in one or more regions. More than 40% admitted the past history of dental diseases, pain of joints, numbness of limbs, fatigue, headache, cough and sputum. Osteoporosis and myoma of the uterus, respectively, were reported by 22.8% and 15.6% of women. 14.2% of men reported prostatic hypertrophy. Logistic regression analysis was performed to estimate the association of the past history of diseases with the blood lipid level of 2,3,4,7,8-pentachlorodibenzofuran adjusting for sex and age. In the whole study subjects, 306 patients were measured the PeCDF level once or more in the years from 2001 to 2005. We found statistically significant elevation of the proportion of the patients with the past history of prostatic hypertrophy with increasing blood lipid level of 2,3,4,7,8-PeCDF (P = 0.03). The marginally significant positive association between the proportion of the patients with the past history of hypertension and 2,3,4,7,8-PeCDF was observed (P = 0.06).

Topics: Adult; Aged; Aged, 80 and over; Benzofurans; Biomarkers; Comorbidity; Female; Food Contamination; Humans; Incidence; Japan; Lipids; Logistic Models; Male; Medical History Taking; Middle Aged; Neoplasms; Oryza; Plant Oils; Polychlorinated Biphenyls; Prostatic Hyperplasia; Stomatognathic Diseases; Surveys and Questionnaires

Many components derived from dietary or medicinal plants showing antioxidant and anti-inflammatory potential have been found to possess chemopreventive properties. In our previous study, we achieved the total synthesis of ailanthoidol (AT), a neolignan from Zanthoxylum ailanthoides or Salvia miltiorrhiza Bunge, which are used in Chinese traditional herbal medicine. In the present study, preliminarily, AT exhibited a radical quenching property by DPPH assay. Following this, we assessed the effect of AT on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced oxidative stress and inflammation in female CD-1 mouse skin which was closely linked to tumor promotion. The topical application of AT (0.5-2.5 mM; 200 microl) reduced the formation of hydrogen peroxide and inhibited the myeloperoxidase (MPO) activity in the mouse skin when compared with that of the TPA-treated alone group. In addition, AT presented a suppression effect on the TPA-induced hyperplasia and leukocyte infiltration in the epidermis and edema of mouse ears. Furthermore, it showed that AT inhibited the TPA-induced expression of COX-2 protein and ornithine decarboxylase (ODC) activity in epidermis. Finally, AT was evaluated for its ability to inhibit the TPA-induced promotion in skin tumors of female CD-1 mice. Topical application of AT 5 min prior to TPA (5 nmol) three times weekly for 12 weeks to mice which were initiated with benzo[a]pyrene (B[a]P) inhibited the incidence of skin tumors in mice and the average number of tumors per mice as compared to TPA-treated alone. These results indicate that AT possesses potential as a chemopreventive agent against tumor promotion.

Topics: Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Benzo(a)pyrene; Benzofurans; Carcinogens; Female; Mice; Mice, Inbred ICR; Neoplasms; Peroxidase; Skin; Skin Neoplasms; Tetradecanoylphorbol Acetate; Time Factors

The River Kymijoki in southern Finland is heavily polluted with polychlorinated dibenzo-p-dioxins and dibenzofurans and may pose a health threat to local residents, especially farmers. In this study we investigated cancer risk in people living near the river (less than 20.0 km) in 1980. We used a geographic information system, which stores registry data, in 500 m times 500 m grid squares, from the Population Register Centre, Statistics Finland, and Finnish Cancer Registry. From 1981 to 2000, cancer incidence in all people (N = 188884) and in farmers (n = 11132) residing in the study area was at the level expected based on national rates. Relative risks for total cancer and 27 cancer subtypes were calculated by distance of individuals to the river in 1980 (reference: 5.0-19.9 km, 1.0-4.9 km, less than 1.0 km), adjusting for sex, age, time period, socioeconomic status, and distance of individuals to the sea. The respective relative risks for total cancer were 1.00, 1.09 [95% confidence interval (CI), 1.04-1.13], and 1.04 (95% CI, 0.99-1.09) among all residents, and 1.00, 0.99 (95% CI, 0.85-1.15), and 1.13 (95% CI, 0.97-1.32) among farmers. A statistically significant increase was observed for basal cell carcinoma of the skin (not included in total cancers) in all residents less than 5.0 km. Several other common cancers, including cancers of the breast, uterine cervix, gallbladder, and nervous system, showed slightly elevated risk estimates at less than 5.0 km from the river. Despite the limitations of exposure assessment, we cannot exclude the possibility that residence near the river may have contributed to a small increase in cancer risk, especially among farmers.

Topics: Adolescent; Adult; Aged; Benzofurans; Child; Child, Preschool; Dibenzofurans, Polychlorinated; Epidemiologic Studies; Female; Finland; Humans; Infant; Infant, Newborn; Male; Middle Aged; Neoplasms; Polychlorinated Biphenyls; Registries; Risk Assessment; Rivers; Water Pollutants, Chemical

The Damage-Function method is an efficient tool recently used in decision-making processes concerning environmental management. It is based on finding the relation between the origin of an environmental charge, and its impact on human health and the environment. The aim of the present investigation was to assess the positive impacts, also called benefits, of changes in environmental quality, and the economic viability of an industrial project on reduction of PCDD/F emissions. It has been developed with monetary criteria of two worldwide ambits: USA and European-Union countries.. The current study is a continuation of a previous investigation in which Substance Flow Analysis and Control Analysis Techniques were used to identify and to analyze all main flow values of PCDD/Fs inside the system of Tarragona Province (Spain). In the present study, Cost-Benefit Analysis (CBA) has been employed. The benefits derived from a minimization in the incidence of cancer due to a reduction in the emission of PCDD/Fs have been evaluated considering the value of a statistically saved life (VSL). Statistical analysis about uncertainty has also been incorporated. Here, the Monte Carlo simulation technique has been used.. It is shown that CBS results depend firstly on the kind of VSL used. In fact, the differences between the decisions as a result of applying monetary criteria in USA and EU can be explained by differences between VSL values.. It is concluded that, for prices estimated in Euros, the emission cleaning project in the industrial plant is not feasible under any circumstance. However, although CBA seems to be a good analytical method, the final decision corresponds to the managers, who must weigh up not only the monetary criteria, but factors such as social questions.

Topics: Benzofurans; Cost-Benefit Analysis; Decision Making; Dibenzofurans, Polychlorinated; Environment Design; Environmental Pollution; Forecasting; Humans; Models, Theoretical; Neoplasms; Polychlorinated Dibenzodioxins; Risk Assessment; Soil Pollutants; Spain

Topics: Benzofurans; Environmental Pollutants; Humans; Incidence; Incineration; Japan; Neoplasms; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins; Refuse Disposal; Soil Pollutants

Topics: Benzofurans; Dioxins; Epidemiologic Studies; Humans; Neoplasms; Public Health; Risk Assessment; Risk Factors

For a cohort of 1189 male German former herbicide and insecticide workers with exposure to polychlorinated dibenzo-p-dioxins and -furans (PCDD/F), we report an extended standardized mortality ratio (SMR) analysis based on a new quantitative exposure index. This index characterizes the cumulative lifetime exposure by integrating the estimated concentration of PCDD/F at every point in time (area under the curve). Production department-specific dose rates were derived from blood levels and working histories of 275 workers by applying a first-order kinetic model. These dose rates were used to estimate exposure levels for all cohort members. Total mortality was elevated in the cohort; 413 deaths yielded an SMR of 1.15 (95% confidence interval [Cl] 1.05, 1.27) compared to the mortality of the population of Germany. Overall cancer mortality (n = 124) was significantly increased (SMR = 1.41, 95% Cl 1.17, 1.68). Various cancer sites showed significantly increased SMRs. The exposure index was used for an SMR analysis of total cancer mortality by dose. For 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) a significant trend (p = 0.01) for the SMRs with increasing cumulative PCDD/F exposure was observed. The SMR in the first exposure quartile (0-125.2 ng/kg x years) was 1.24 (95% Cl 0.82, 1.79), increasing to 1.73 (95% Cl 1.21, 2.40) in the last quartile (> or = 2503.0 ng/kg x years). For all congeners combined as toxic equivalencies (TEQ) using international toxic equivalency factors, a significant increase in cancer mortality was observed in the second quartile (360.9-1614.4 ng/kg x years, SMR 1.64; 95% Cl 1.13, 2.29) and the fourth quartile (> or = 5217.7 ng/kg x years TEQ, SMR 1.64, 95% Cl 1.13, 2.29). The trend test was not significant. The results justify the use of this cohort for a quantitative risk assessment for TCDD and to a lesser extent for TEQ.

Topics: Adult; Aged; Benzofurans; Chemical Industry; Cohort Studies; Dioxins; Dose-Response Relationship, Drug; Germany; Humans; Male; Middle Aged; Neoplasms; Occupational Exposure; Risk Assessment

Depending on process conditions, polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) may be generated as low-level byproducts of chlorophenol and chlorophenoxy herbicides manufacture. A stratified random sample of 20 active employees from a cohort of phenoxy herbicide workers was selected in 1995 for determining PCDD and PCDF congeners in blood lipids to assess the extent of past PCDD and PCDF exposure in this cohort and whether that exposure might explain site-specific cancer findings in the total cohort. This cohort is included in the IARC International Registry of Persons Exposed to Phenoxyacid Herbicides and Their Contaminants. For the 19 persons who participated, median PCDD and PCDF concentrations were comparable to background concentrations in the general population. Median levels of 2,3,7,8-tetrachlorodibenzo-p-dioxin, the sum of hexachlorodibenzo-p-dioxin, pentachlorodibenzofurans, and two dioxin toxicity equivalents values were statistically higher in 7 employees assigned to synthesis operations than for 12 employees assigned to other operations. However, the PCDD and PCDF concentrations were low relative to those seen in other dioxin-exposed cohorts. We conclude that PCDD and PCDF exposures of cohort members are unlikely to explain the elevated standardized mortality ratios observed in this cohort for several cancer sites.

Topics: Adult; Benzofurans; Chemical Industry; Chlorophenols; Cohort Studies; Dioxins; Germany; Herbicides; Humans; Middle Aged; Neoplasms; Occupational Exposure; Registries

Topics: Animals; Benzofurans; Carcinogens; Cattle; Dibenzofurans, Polychlorinated; Dioxins; Environmental Exposure; Female; Fishes; Humans; Male; Meat; Mice; Neoplasms; Polychlorinated Biphenyls; Poultry