benzofurans and Melanoma

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

Myeloid-derived suppressor cells (MDSCs) represent a negative prognostic factor in malignant melanoma. These cells are generated under chronic inflammatory conditions typical of cancer. The transcription factor signal transducer and activator of transcription 3 (STAT3) orchestrates MDSC accumulation and acquisition of immunosuppressive properties. Here we studied STAT3 inhibition by Napabucasin as a way to block MDSC accumulation and activity and its potential to treat malignant melanoma.. Napabucasin was able to abrogate the capacity of murine MDSC to suppress CD8. Our findings demonstrate that STAT3 inhibitor Napabucasin completely abrogated the immunosuppressive capacity of murine MDSC and human M-MDSC and improved melanoma-bearing mouse survival. Moreover, patients with malignant melanoma with high expression levels of activated STAT3 in M-MDSC displayed shorter PFS, indicating its role as a promising therapeutic target in patients with malignant melanoma and a predictive marker for their clinical outcome.

Topics: Animals; Benzofurans; Humans; Melanoma; Mice; Mice, Transgenic; Myeloid-Derived Suppressor Cells; Naphthoquinones; STAT3 Transcription Factor

In this study, the cytotoxic activity of acetone extracts of Cladonia mitis was assessed with respect to the content of usnic acid, a secondary metabolite commonly present in this species. Following quantitative HPLC analysis of the extracts, usnic acid was isolated by preparative chromatography. The study of cytotoxic activity was performed using the MTT test on three melanoma cell lines - HTB140, A375 and WM793. The selectivity of action was also assessed by comparing the effect towards normal human keratinocytes HaCaT. The results showed a dose-dependent cytotoxic activity of the extracts tested and usnic acid itself, but no relationship was found between the content of usnic acid and the activity of the extracts. Furthermore, the extracts showed varied, but rather low anti-tyrosinase activity. Other in vitro and in vivo studies are necessary to demonstrate that C. mitis extracts may be useful in the adjuvant external treatment of skin melanoma.

Topics: Acetone; Antineoplastic Agents; Ascomycota; Benzofurans; Humans; Lichens; Melanoma

Very recently, we have produced new resveratrol derived compounds, especially labruscol by culture of elicited grapevine cell suspensions (Vitis labrusca L.). This new polyphenolic oligomer could function as cancer chemopreventive agent in similar manner of resveratrol. In this study, we have determined the efficiency of resveratrol, ε-viniferin and the labruscol on human melanoma cell with or without metastatic phenotype. Our results show a differential activity of the three compounds where the resveratrol remains the polyphenolic compound with the most effective action compared to other oligomers. These three compounds block cell cycle of melanoma cells in S phase by modulating key regulators of cell cycle i.e. cyclins A, E, D1 and their cyclin-dependent kinases 1 and 2. These effects are associated with an increase of cell death while these compounds have no cytotoxic action on normal human dermal fibroblasts.

Topics: Anticarcinogenic Agents; Benzofurans; CDC2 Protein Kinase; Cell Line, Tumor; Cell Proliferation; Cyclin A; Cyclin D1; Cyclin E; Cyclin-Dependent Kinase 2; Fibroblasts; Humans; Melanoma; Resveratrol; S Phase; Skin; Stilbenes; Vitis

New benzofuranhydrazones 3-12 were easily prepared and assayed for their radical-scavenging ability. Hydrazones 3-12 showed different extent antioxidant activity in DPPH, FRAP and ORAC assays. Good antioxidant activity is related to the number and position of hydroxyl groups on the arylidene moiety. High antioxidant activity is showed by the 2-hydroxy-4-(diethylamino)benzylidene derivative 11. Furthermore, hydrazones 3-12 showed photoprotective capacities with satisfactory in vitro SPF as compared to the commercial PBSA sunscreen filter. The antiproliferative effects of the hydrazones 3-12 was tested on erythroleukemia K562 and Colo-38 melanoma human cells. All the compounds showed growth inhibition in the micromolar to sub micromolar concentration range. If taken together these results points to benzofuran hydrazones as potential multifunctional molecules especially in the treatment of neoplastic diseases being the good antioxidant properties of 5, 7 and 11 correlated to their high antiproliferative activity.

Topics: Antineoplastic Agents; Antioxidants; Benzofurans; Cell Line, Tumor; Cell Proliferation; Drug Design; Humans; Hydrazones; Leukemia, Erythroblastic, Acute; Melanoma; Structure-Activity Relationship; Sunscreening Agents

Topics: Animals; Benzofurans; Cancer Vaccines; Cancer-Associated Fibroblasts; Cell Line, Tumor; Disease Models, Animal; Emulsions; Immunologic Factors; Melanoma; Mice; Nanoparticles; Treatment Outcome; Tumor Microenvironment

Loliolide is a monoterpenoid hydroxylactone found in many algae, including fresh water green algae,

Topics: Animals; Antineoplastic Agents; Antioxidants; Benzofurans; Cell Line; Cell Line, Tumor; Chlorophyta; Gene Expression Regulation, Neoplastic; Humans; Melanins; Melanoma; Mice; Microphthalmia-Associated Transcription Factor; Monophenol Monooxygenase; Oxidative Stress

Activating BRAF mutations promote constitutive activation of the mitogen-activated protein kinase (MAPK) signaling pathway and are common in a variety of human malignancies, including melanoma and colon cancer. Several small molecule BRAF inhibitors such as vemurafenib have been developed and demonstrate remarkable clinical efficacy. However, resistance typically emerges in most melanoma patients. Studies have demonstrated that reactivation of MAPK signaling via CRAF overexpression and dysregulation is a mechanism for vemurafenib resistance in melanoma. Prohibitins (PHBs) are highly conserved proteins that are thought to control the cell cycle, senescence and tumor suppression. PHB1 is essential for CRAF-mediated ERK1/2 activation through direct binding to CRAF. We developed a CRAF-mediated model of vemurafenib resistance in melanoma cells to assess the importance of the interaction between CRAF and PHB1 in resistance to BRAF-targeting agents. We demonstrate that CRAF overexpression renders melanoma cells resistant to BRAF-targeting agents. Moreover, treatment with the natural compound rocaglamide A disrupts the interaction between PHB and CRAF in melanoma cells, thus reducing MEK1/2 and ERK1/2 signaling, inhibiting melanoma cell growth and inducing apoptosis. The efficacy of these compounds was also demonstrated in a human melanoma xenograft model. Taken together, these data suggest that PHB1 may serve as a novel, druggable target in CRAF-mediated vemurafenib resistance.

Topics: Animals; Benzofurans; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; Humans; Indoles; MAP Kinase Signaling System; Melanoma; Mice; Prohibitins; Protein Binding; Proto-Oncogene Proteins c-raf; Repressor Proteins; Sulfonamides; Vemurafenib; Xenograft Model Antitumor Assays

Lichens are an interesting source of potential anti-tumor compounds, among which usnic acid and atranorin seem to be the most promising, but their impact on invasive potential of tumor cells has not yet been comprehensively addressed. The aim of the study was focused on the impact of the two lichen metabolites, on the viability (by Trypan blue test and fluoresceine diacetate and ethidium bromide assay), proliferation (cell counting in a Bürker's chamber), apoptosis (flow cytometry analysis and Western blot) and motile activity (cell movement recording and image analysis) and actin cytoskeleton organization (immunofluorescent staining) of melanoma HTB-140, prostate cancers DU-145 and PC-3, normal human skin fibroblasts and prostate epithelial PNT2 cells, with special emphasis to their selectivity and versatility.. Both compounds exerted strong inhibitory effects on cancer cell proliferation, migration and actin cytoskeleton organization, while their effect on apoptosis process was less relevant. The impact of usnic acid on the examined cancer cells was found more efficient in comparison to atranorin. Also, selective effect of both agents on tumor cells was observed.. The ability of usnic acid and atranorin to inhibit cancer cells motility may have future implications for development of new therapeutic strategies targeted at the interference with the metastatic cascade.

Topics: Actins; Antineoplastic Agents; Apoptosis; Benzofurans; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Cells, Cultured; Cytostatic Agents; Fibroblasts; Humans; Hydroxybenzoates; Male; Melanoma; Prostatic Neoplasms

Melanin is a natural pigment that plays an important role in the protection of skin, however, hyperpigmentation cause by excessive levels of melatonin is associated with several problems. Therefore, melanogenesis inhibitory natural products have been developed by the cosmetic industry as skin medications. The leaves of Morus alba (Moraceae) have been reported to inhibit melanogenesis, therefore, characterization of the melanogenesis inhibitory constituents of M. alba leaves was attempted in this study. Twenty compounds including eight benzofurans, 10 flavonoids, one stilbenoid and one chalcone were isolated from M. alba leaves and these phenolic constituents were shown to significantly inhibit tyrosinase activity and melanin content in B6F10 melanoma cells. To maximize the melanogenesis inhibitory activity and active phenolic contents, optimized M. alba leave extraction conditions were predicted using response surface methodology as a methanol concentration of 85.2%; an extraction temperature of 53.2 °C and an extraction time of 2 h. The tyrosinase inhibition and total phenolic content under optimal conditions were found to be 74.8% inhibition and 24.8 μg GAE/mg extract, which were well-matched with the predicted values of 75.0% inhibition and 23.8 μg GAE/mg extract. These results shall provide useful information about melanogenesis inhibitory constituents and optimized extracts from M. alba leaves as cosmetic therapeutics to reduce skin hyperpigmentation.

Topics: Benzofurans; Cell Line, Tumor; Chalcone; Flavonoids; Humans; Hyperpigmentation; Melanins; Melanoma; Monophenol Monooxygenase; Morus; Phenols; Plant Extracts; Plant Leaves; Stilbenes

The RAS-RAF-MEK-ERK pathway is hyperactivated in 30% of human cancers. BRAF is a serine-threonine kinase, belonging to this pathway that is mutated with high frequency in human melanoma and other cancers thus BRAF is an important therapeutic target in melanoma. We have designed inhibitors of BRAF based on 2,4,5-trisubstituted imidazoles with naphthyl and benzothiophene-4-substituents. Two compounds were discovered to be potent BRAF inhibitors: 1-(6-{2-[4-(2-dimethylamino-ethoxy)phenyl]-5-(pyridin-4-yl)-1H-imidazol-4-yl} benzo[b]thiophen-3-yl)-2,2,2-trifluoroethanol (1i) with BRAF IC(50)=190 nM and with cellular GI(50)=2100 nM, and 6-{2-[4-(2-dimethylamino-ethoxy)-phenyl]-5-pyridin-4-yl-3H-imidazol-4-yl}-naphthalen-1-ol (1q) with IC(50)=9 nM and GI(50)=220 nM.

Topics: Benzofurans; Cell Line, Tumor; Cell Survival; Humans; Imidazoles; Melanoma; Naphthols; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Structure-Activity Relationship; Thiophenes

A unique benzofuran named suillusin was isolated from the methanolic extract of the fruiting body of the mushroom Suillus granulatus. Its structure was assigned on the basis of various spectroscopic analyses as a highly substituted novel 1H-cyclopenta[b]benzofuran (1). Suillusin is suggested to be biogenerated from polyporic acid.

Topics: Antineoplastic Agents, Phytogenic; Antioxidants; Basidiomycota; Benzofurans; Cell Survival; Chromatography, High Pressure Liquid; Colonic Neoplasms; Drug Screening Assays, Antitumor; Female; Humans; Inhibitory Concentration 50; Korea; Lung Neoplasms; Magnetic Resonance Spectroscopy; Male; Melanoma; Molecular Structure; Ovarian Neoplasms; Prostatic Neoplasms; Spectrophotometry, Infrared; Spectrophotometry, Ultraviolet; Spectroscopy, Fourier Transform Infrared; Structure-Activity Relationship; Tumor Cells, Cultured; Vitamin E

(1) To compare scintigraphy using the new dopamine D2 receptor binding radioligand iodobenzofuran (IBF) versus whole-body positron emission tomography (PET) in demonstrating metastasizing melanoma, and (2) to determine, for the first time using a panel of histochemical techniques, whether the ability of D2 receptor binding radioligands to detect melanoma metastases is due to tumor-expressed D2 receptors.. Seven patients with metastatic melanoma were examined using 123I-IBF scintigraphy. Findings were compared to the results of PET and metastasis histochemistry: D2 receptor mRNA assay (metastases: n = 5; melanoma cell lines: n = 4) using the reverse transcriptase polymerase chain reaction (RT-PCR) versus D2 receptor-transfected Chinese hamster ovary cell controls: in vitro 125I-IBF binding (n = 19), and immunohistochemical staining for dopamine D2 receptor protein (n = 19).. IBF scintigraphy detected 2/10 melanoma metastases detected by PET (sensitivity 20%). No dopamine D2 receptor mRNA was found in melanoma cells using RT-PCR. The binding of 125I-IBF correlated with the amount of melanin present in the metastases; two amelanotic melanomas both failed to bind 125I-IBF. Immunohistochemical staining was negative in all metastases.. Melanoma cells do not appear to express dopamine D2 receptors. Although IBF had high dopamine D2 receptor affinity, its ability to detect melanoma metastases is more likely explained by low affinity binding to melanin than by the presence of dopamine receptors.

Topics: Adult; Aged; Animals; Benzofurans; Cell Line, Transformed; Cricetinae; Cricetulus; Female; Gene Expression Regulation, Neoplastic; Histocytochemistry; Humans; Immunohistochemistry; Iodine Radioisotopes; Male; Melanins; Melanoma; Middle Aged; Polymerase Chain Reaction; Radiopharmaceuticals; Receptors, Dopamine; RNA, Messenger; Skin Neoplasms; Tomography, Emission-Computed; Transcription, Genetic; Tumor Cells, Cultured

In recent publications dopamine-D2 receptor scintigraphy with benzamides was postulated for specific imaging of melanoma. In a prospective study the value of 123I-iodobenzofuran (IBF), a highly specific and affine dopamine-D2 receptor ligand was evaluated for the detection of melanoma metastases. With IBF-D2 receptor scintigraphy only 2 of 17 melanoma metastases could be detected. The interpretation of the abdomen was impaired by the hepatobiliary and renal excretion of the radionuclide. The ratio striatum/frontal cortex of 2.75 +/- 0.49 3 h p.i. demonstrated a high D2-receptor binding of the ligand. IBF-D2-receptor scintigraphy is not suitable as a method of staging melanoma.

Topics: Adult; Aged; Benzofurans; Brain Neoplasms; Corpus Striatum; Female; Frontal Lobe; Humans; Iodine Radioisotopes; Male; Melanoma; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Prospective Studies; Radionuclide Imaging; Receptors, Dopamine D2; Sensitivity and Specificity