Flavonoids: Promising Natural Products for Treatment of Skin Cancer (Melanoma)

Melanoma, which is the most malignant skin cancer type, has got one of the fastest increasing incidence rates of all cancer types in the world. When belatedly diagnosed, melanoma is extremely invasive and metastatic. Although there are effective drugs used to treat melanoma, some cell lines have proven resistant to chemotherapy. In this context, several research groups on natural products have investigated the anticancer effect of new natural molecules in the treatment of melanoma. Flavonoids have shown to play an important role in chemoprevention and inhibition of the proliferation, migration, and invasion of melanoma cells. In this chapter, we present a systematic review performed through a literature search over a period of 20 years, using specialized databases. Analysis of all selected manuscripts demonstrated that at least 97 flavonoids have already been investigated for the treatment of melanoma using in vitro or in vivo models. Most of the bioactive flavonoids belong to the classes of flavones (38.0%), flavonols (17.5%), or isoflavonoids (17.5%). Apigenin, diosmin, fisetin, luteolin, and quercetin were considered as the most studied flavonoids for melanoma treatment. In general, flavonoids have shown to be a promising source of molecules with great potential for the treatment of melanoma

Carotenoids from Marine Microalgae as Antimelanoma Agents

Melanoma cells are highly invasive and metastatic tumor cells and commonly express molecular alterations that contribute to multidrug resistance (e.g., BRAFV600E mutation). Conventional treatment is not effective in a long term, requiring an exhaustive search for new alternatives. Recently, carotenoids from microalgae have been investigated as adjuvant in antimelanoma therapy due to their safety and acceptable clinical tolerability. Many of them are currently used as food supplements. In this review, we have compiled several studies that show microalgal carotenoids inhibit cell proliferation, cell migration and invasion, as well as induced cell cycle arrest and apoptosis in various melanoma cell lines. MAPK and NF-ĸB pathway, MMP and apoptotic factors are frequently affected after exposure to microalgal carotenoids. Fucoxanthin, astaxanthin and zeaxanthin are the main carotenoids investigated, in both in vitro and in vivo experimental models. Preclinical data indicate these compounds exhibit direct antimelanoma effect but are also capable of restoring melanoma cells sensitivity to conventional chemotherapy (e.g., vemurafenib and dacarbazine)

UTILIZAÇÃO DE FLAVONOIDES NO SETOR INDUSTRIAL FARMACÊUTICO: UM ESTUDO DE PROSPECÇÃO TECNOLÓGICA

Os produtos naturais vêm ganhando espaço na pesquisa nacional, sendo cada vez mais utilizados também no setor industrial como fonte de novos produtos. Entre as principais classes de metabólitos secundários estudadas, encontram-se os flavonoides, conhecidos pela sua diversidade química e pelas suas propriedades biológicas. O objetivo deste estudo foi realizar uma prospecção tecnológica de flavonoides, analisando a participação do país nos depósitos de pedidos de patentes em bases nacionais e internacionais até o momento. Para isso, a prospecção foi realizada no Banco Europeu de Patentes, no banco da Organização Mundial de Propriedade Intelectual, no Banco Americano de Marcas e Patentes, no Banco de Patentes Latinoamericano e no banco de dados do Instituto Nacional de Propriedade Industrial do Brasil. Os resultados demonstraram que os Estados Unidos é o principal país depositário. O maior número de patentes foi depositado no ano de 2010, sendo que as classificações internacionais de patentes mais abundantes nessa prospecção foram as subclasses A61K, A61P e A61Q. </p

Pre-clinical investigations of β-carboline alkaloids as antidepressant agents: A systematic review

International audienceDepressive disorders remain a current public health problem whose prevalence has increased in the past decades. In the constant search for new therapeutic alternatives, β-carboline alkaloids have been identified as good candidates for new antidepressant drugs. In this systematic review, we summarized all pre-clinical investigations involving the use of natural or semisynthetic β-carboline in depression models. A literature search was conducted in August 2018, using PubMed, Scopus and Science Direct databases. All reports were carefully analyzed, and data extraction was conducted through standardized forms. Methodological quality assessment of in vivo studies was also performed. The entire systematic review was performed according to PRISMA statement. From a total of 373 articles, 26 met all inclusion criteria. In vitro and in vivo studies have evaluated a wide variety of β-carbolines through enzymatic and binding assays, and acute or chronic animal models. Most of the in vivo and in vitro studies is concentrated on two molecules: harman and harmine. They have been investigated in several animal models and some mechanisms of action have been proposed for their antidepressant activity. In general, β-carbolines modulate 5-HT and GABA systems, promote neurogenesis, induce neuroendocrine response and restore astrocytic function, being effective when administrated acutely or chronically in different animal models, including chronic mild stress protocols. In short, β-carbolines are multi-target antidepressant compounds and may be useful in the treatment of depressive disorders

Sensitization of tumor cells to chemotherapy by natural products: a systematic review of preclinical data and molecular mechanisms

International audiencePurpose: Tumor cells are spontaneously or adaptively resistant to chemotherapeutic drugs, eventually leading to the selection of multiresistant cells responsible for tumor growth and metastasis. Chemosensitization of tumor cells to conventional drugs using non-toxic natural products is a recent and innovative strategy aiming to increase the cytotoxic efficiency of anticancer drugs, limit their toxic side effects and delay the appearance of acquired chemoresistance. This systematic review summarizes data obtained from preclinical studies reporting the use of natural products to sensitize tumor cells to chemotherapeutic agents. It also details the cellular and molecular mechanisms involved in chemosensitization.Design: Search terms were combined and used to retrieve English language reports in PubMed, Science Direct and Scopus databases, published until October 2017. All articles were carefully analyzed and data extraction was conducted through standardized forms. Methodological quality assessment of in vivo studies was also performed.Results: From a total of 669 articles surveyed, 104 met the inclusion criteria established. The main studied compounds as chemosensitizers were phenolic derivatives (26.9%) and flavonoids (17.3%). Most reports were authored by researchers from China (33.7%) and USA (26.9%). A large number of articles were published from 2011 to 2015 (50.0%), suggesting that the use of natural products as chemosensitizers is a recent issue. In vivo studies were conducted mainly using xenograft models, which were considered of moderate methodological quality.Conclusion: Several natural products, belonging to diverse chemical families, are potent chemosentisizers in tumor cells enhancing the cytotoxicity of conventional drugs. These molecules usually have a pleiotropic effect on different molecular targets, acting on several cellular and molecular processes with low selectivity. All studied molecules were obtained from terrestrial plants and major developments should arise from future studies, considering the chemodiversity of molecules purified from other terrestrial taxa and marine organisms

Bixin, an apocarotenoid isolated from Bixa orellana L., sensitizes human melanoma cells to dacarbazine-induced apoptosis through ROS-mediated cytotoxicity

International audienceCutaneous melanoma has a high capacity to metastasize and significant resistance to conventional therapeutic protocols, which makes its treatment difficult. The combination of conventional drugs with cytostatic molecules of low toxicity has been shown to be an interesting alternative for sensitization of tumor cells to chemotherapy. In this study, we evaluated the effect of bixin, an abundant apocarotenoid present in Bixa orellana, on the sensitization of human melanoma cells (A2058) to dacarbazine treatment, an anticancer agent clinically used for the therapy of metastatic melanoma. UPLC-DAD-MS/MS analyses of bioactive extracts from B. orellana seeds led to the identification of two new apocarotenoids: 6,8′-diapocarotene-6,8′-dioic acid and 6,7′-diapocarotene-6,7′-dioic acid. After being identified as its major compound, bixin (Z-bixin) was evaluated on A2058 cells expressing the oncogenic BRAF VE600 mutation and resistant to dacarbazine treatment. Bixin promoted growth inhibition, reduced cell migration, induced apoptosis and cell cycle arrest in the G2/M phase. When associated with dacarbazine, bixin restored the sensitivity of A2058 cells to chemotherapy, enhancing its antiproliferative, anti-migratory and pro-apoptotic effects. Combined treatment also induced higher ROS (reactive oxygen species) and MDA (malondialdehyde, a lipid peroxidation marker) generation than monotreatment, suggesting that the oxidative stress caused by bixin contributes significantly to its sensitizing effect. Taken together, these data suggest that bixin exerts intrinsic antimelanoma activity by mechanisms complementary to those of dacarbazine, encouraging its use in combined therapy for cutaneous melanoma treatment

Complexation with β-cyclodextrin enhances apoptosis-mediated cytotoxic effect of harman in chemoresistant BRAF-mutated melanoma cells

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Phytochemical and pharmacological aspects of Cnidoscolus Pohl species: a systematic review

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Phytochemical analysis and evaluation of antioxidant and photoprotective activities of extracts from flowers of Bromelia laciniosa (Bromeliaceae)

In this study, the phytochemical profile of extracts from the flowers of Bromelia laciniosa was characterized. The total phenolic and flavonoids contents were determined and the antioxidant and photoprotective activities were evaluated using in vitro assays. Phytochemical analysis demonstrated that the extracts were found to be positive for the presence of anthracene derivatives, anthraquinones, coumarins, flavonoids and tannins, lignans, mono and diterpenes. The ethanol extract (Bl-EtOH) presented the most significant total phenolic content (53.75 ± 1.25 mg GAE/g). The dichloromethane extract (Bl-CH2Cl2) showed the highest flavonoid content (46.06 ± 1.18 mg CE/g). The methanol extract (Bl-MeOH) was the most effective extract in the DPPH (2,2-diphenyl-1-picrylhydrazil) assay (EC50 141.90 ± 3.01 μg/mL). Bl-EtOH and Bl-MeOH showed higher sun protection factor at a concentration of 100 mg/L (3.38 ± 0.04 and 3.78 ± 0.11, respectively). Therefore, the extracts proved to be interesting for the development of new studies aiming their incorporation into photoprotective cosmetic formulations

Bis-nor-diterpene from Cnidoscolus quercifolius (Euphorbiaceae) induces tubulin depolymerization-mediated apoptosis in BRAF-mutated melanoma cells

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