RESUMO
Cancer incidence and mortality rates are increasing worldwide. Cancer treatment remains a real challenge for African countries, especially in sub-Saharan Africa where funding and resources are very limited. High costs, side effects and drug resistance associated with cancer treatment have encouraged scientists to invest in research into new herbal cancer drugs. In order to identify potential anticancer plants for drug development, this review aims to collect and summarize anticancer activities (in vitro/in vivo) and molecular mechanisms of sub-Saharan African medicinal plant extracts against cancer cell lines. Scientific databases such as ScienceDirect, Google Scholar and PubMed were used to search for research articles published from January 2013 to May 2023 on anticancer medicinal plants in sub-Saharan Africa. The data were analyzed to highlight the cytotoxicity and molecular mechanisms of action of these listed plants. A total of 85 research papers covering 204 medicinal plant species were selected for this review. These plants come from 57 families, the most dominant being the plants of the family Amaryllidaceae (16), Fabaceae (14), Annonaceae (10), Asteraceae (10). Plant extracts exert their anticancer activity mainly by inducing apoptosis and stopping the cell cycle of cancer cells. Several plant extracts from sub-Saharan Africa therefore have strong potential for the search for original anticancer phytochemicals. Chemoproteomics, multi-omics, genetic editing technology (CRISPR/Cas9), combined therapies and artificial intelligence tools are cutting edge emerging technologies that facilitate the discovery and structural understanding of anticancer molecules of medicinal plants, reveal their direct targets, explore their therapeutic uses and molecular bases.
Assuntos
Neoplasias , Plantas Medicinais , Humanos , Plantas Medicinais/química , Inteligência Artificial , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Fitoterapia , África Subsaariana , Neoplasias/tratamento farmacológicoRESUMO
Chronic inflammation is now a well-known precursor for cancer development. Infectious prostatitis are the most common causes of prostate inflammation, but emerging evidence points the role of metabolic disorders as a potential source of cancer-related inflammation. Although the widely used treatment for prostate cancer based on androgen deprivation therapy (ADT) effectively decreases tumor size, it also causes profound alterations in immune tumor microenvironment within the prostate. Here, we demonstrate that prostates of a mouse model invalidated for nuclear receptors liver X receptors (LXRs), crucial lipid metabolism and inflammation integrators, respond in an unexpected way to androgen deprivation. Indeed, we observed profound alterations in immune cells composition, which was associated with chronic inflammation of the prostate. This was explained by the recruitment of phagocytosis-deficient macrophages leading to aberrant hyporesponse to castration. This phenotypic alteration was sufficient to allow prostatic neoplasia. Altogether, these data suggest that ADT and inflammation resulting from metabolic alterations interact to promote aberrant proliferation of epithelial prostate cells and development of neoplasia. This raises the question of the benefit of ADT for patients with metabolic disorders.
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Imunidade/fisiologia , Receptores X do Fígado/metabolismo , Próstata/metabolismo , Antagonistas de Androgênios/imunologia , Androgênios/metabolismo , Animais , Modelos Animais de Doenças , Imunidade/imunologia , Receptores X do Fígado/genética , Receptores X do Fígado/imunologia , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Neoplasias/etiologia , Neoplasias/imunologia , Neoplasias/metabolismo , Próstata/patologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Neoplasias da Próstata/terapia , Receptores Citoplasmáticos e Nucleares/metabolismo , Microambiente TumoralRESUMO
The aim of this research was to evaluate the essential oil of Cymbopogon schoenanthus (L.) Spreng. (C. schoenanthus) from Burkina Faso in terms of cytotoxic activity against LNCaP cells, derived from prostate cancer, and HeLa cells, derived from cervical cancer. Antioxidant activities were evaluated in vitro. Essential oil (EO) was extracted by hydrodistillation and analyzed by GC/FID and GC/MS. Thirty-seven compounds were identified, the major compounds being piperitone (49.9%), δ-2-carene (24.02%), elemol (5.79%) and limonene (4.31%). EO exhibited a poor antioxidant activity, as shown by the inhibition of DPPH radicals (IC50 = 1730 ± 80 µg/mL) and ABTS+. (IC50 = 2890 ± 26.9 µg/mL). Conversely, EO decreased the proliferation of LNCaP and HeLa cells with respective IC50 values of 135.53 ± 5.27 µg/mL and 146.17 ± 11 µg/mL. EO also prevented LNCaP cell migration and led to the arrest of their cell cycle in the G2/M phase. Altogether, this work points out for the first time that EO of C. schoenanthus from Burkina Faso could be an effective natural anticancer agent.
Assuntos
Cymbopogon , Óleos Voláteis , Neoplasias do Colo do Útero , Masculino , Feminino , Humanos , Óleos Voláteis/farmacologia , Óleos Voláteis/química , Cymbopogon/química , Próstata , Células HeLa , Burkina Faso , Neoplasias do Colo do Útero/tratamento farmacológico , Antioxidantes/farmacologiaRESUMO
: The great majority of breast and prostate tumors are hormone-dependent cancers; hence, estrogens and androgens can, respectively, drive their developments, making it possible to use pharmacological therapies in their hormone-dependent phases by targeting the levels of steroid or modulating their physiological activity through their respective nuclear receptors when the tumors relapse. Unfortunately, at some stage, both breast and prostate cancers become resistant to pharmacological treatments that aim to block their receptors, estrogen (ER) or androgen (AR) receptors, respectively. So far, antiestrogens and antiandrogens used in clinics have been designed based on their structural analogies with natural hormones, 17-ß estradiol and dihydrotestosterone. Plants are a potential source of drug discovery and the development of new pharmacological compounds. The aim of this review article is to highlight the recent advances in the pharmacological modulation of androgen or estrogen levels, and their activity through their cognate nuclear receptors in prostate or breast cancer and the effects of some plants extracts.
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Androgênios/metabolismo , Antineoplásicos Fitogênicos/uso terapêutico , Neoplasias da Mama/metabolismo , Estrogênios/metabolismo , Antagonistas de Hormônios/uso terapêutico , Extratos Vegetais/uso terapêutico , Neoplasias da Próstata/metabolismo , Animais , Neoplasias da Mama/tratamento farmacológico , Feminino , Humanos , Masculino , Extratos Vegetais/química , Neoplasias da Próstata/tratamento farmacológicoRESUMO
Adrenal Cortex Carcinoma (ACC) is an aggressive tumour with poor prognosis. Common alterations in patients include constitutive WNT/ß-catenin signalling and overexpression of the growth factor IGF2. However, the combination of both alterations in transgenic mice is not sufficient to trigger malignant tumour progression, suggesting that other alterations are required to allow development of carcinomas. Here, we have conducted a study of publicly available gene expression data from three cohorts of ACC patients to identify relevant alterations. Our data show that the histone methyltransferase EZH2 is overexpressed in ACC in the three cohorts. This overexpression is the result of deregulated P53/RB/E2F pathway activity and is associated with increased proliferation and poorer prognosis in patients. Inhibition of EZH2 by RNA interference or pharmacological treatment with DZNep inhibits cellular growth, wound healing and clonogenic growth and induces apoptosis of H295R cells in culture. Further growth inhibition is obtained when DZNep is combined with mitotane, the gold-standard treatment for ACC. Altogether, these observations suggest that overexpression of EZH2 is associated with aggressive progression and may constitute an interesting therapeutic target in the context of ACC.
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Neoplasias do Córtex Suprarrenal/genética , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Neoplasias do Córtex Suprarrenal/metabolismo , Animais , Linhagem Celular Tumoral , Proliferação de Células , Bases de Dados de Ácidos Nucleicos , Progressão da Doença , Expressão Gênica , Predisposição Genética para Doença/genética , Humanos , Fator de Crescimento Insulin-Like II/genética , Fator de Crescimento Insulin-Like II/metabolismo , Camundongos , Camundongos Transgênicos , Interferência de RNA , Fatores de Risco , Via de Sinalização Wnt , beta Catenina/genéticaRESUMO
OBJECTIVE: The sterol-responsive nuclear receptors, liver X receptors α (LXRα, NR1H3) and ß (LXRß, NR1H2), are key determinants of cellular cholesterol homeostasis. LXRs are activated under conditions of high cellular sterol load and induce expression of the cholesterol efflux transporters ABCA1 and ABCG1 to promote efflux of excess cellular cholesterol. However, the full set of genes that contribute to LXR-stimulated cholesterol efflux is unknown, and their identification is the objective of this study. APPROACH AND RESULTS: We systematically compared the global transcriptional response of macrophages to distinct classes of LXR ligands. This allowed us to identify both common and ligand-specific transcriptional responses in macrophages. Among these, we identified endonuclease-exonuclease-phosphatase family domain containing 1 (EEPD1/KIAA1706) as a direct transcriptional target of LXRs in human and murine macrophages. EEPD1 specifically localizes to the plasma membrane owing to the presence of a myristoylation site in its N terminus. Accordingly, the first 10 amino acids of EEPD1 are sufficient to confer plasma membrane localization in the context of a chimeric protein with GFP. Functionally, we report that silencing expression of EEPD1 blunts maximal LXR-stimulated Apo AI-dependent efflux and demonstrate that this is the result of reduced abundance of ABCA1 protein in human and murine macrophages. CONCLUSIONS: In this study, we identify EEPD1 as a novel LXR-regulated gene in macrophages and propose that it promotes cellular cholesterol efflux by controlling cellular levels and activity of ABCA1.
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Transportador 1 de Cassete de Ligação de ATP/metabolismo , Membrana Celular/enzimologia , Colesterol/metabolismo , Endodesoxirribonucleases/metabolismo , Receptores X do Fígado/metabolismo , Macrófagos/enzimologia , Transportador 1 de Cassete de Ligação de ATP/genética , Animais , Apolipoproteína A-I/metabolismo , Transporte Biológico , Células COS , Membrana Celular/efeitos dos fármacos , Chlorocebus aethiops , Endodesoxirribonucleases/genética , Perfilação da Expressão Gênica/métodos , Regulação Enzimológica da Expressão Gênica , Células HeLa , Células Hep G2 , Humanos , Ligantes , Receptores X do Fígado/agonistas , Receptores X do Fígado/deficiência , Receptores X do Fígado/genética , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células RAW 264.7 , Interferência de RNA , Transcriptoma , TransfecçãoRESUMO
A close relationship exists between cholesterol and female reproductive physiology. Indeed, cholesterol is crucial for steroid synthesis by ovary and placenta, and primordial for cell structure during folliculogenesis. Furthermore, oxysterols, cholesterol-derived ligands, play a potential role in oocyte maturation. Anomalies of cholesterol metabolism are frequently linked to infertility. However, little is known about the molecular mechanisms. In parallel, increasing evidence describing the biological roles of liver X receptors (LXRs) in the regulation of steroid synthesis and inflammation, two processes necessary for follicle maturation and ovulation. Both of the isoforms of LXRs and their bona fide ligands are present in the ovary. LXR-deficient mice develop late sterility due to abnormal oocyte maturation and increased oocyte atresia. These mice also have an ovarian hyper stimulation syndrome in response to gonadotropin stimulation. Hence, further studies are necessary to explore their specific roles in oocyte, granulosa, and theca cells. LXRs also modulate estrogen signaling and this could explain the putative protective role of the LXRs in breast cancer growth. Altogether, clinical studies would be important for determining the physiological relevance of LXRs in reproductive disorders in women.
Assuntos
Colesterol/metabolismo , Infertilidade Feminina/metabolismo , Receptores X do Fígado/fisiologia , Síndrome Metabólica/metabolismo , Obesidade/metabolismo , Animais , Neoplasias da Mama/metabolismo , Estrogênios/metabolismo , Feminino , Humanos , Infertilidade Feminina/complicações , Infertilidade Feminina/genética , Receptores X do Fígado/genética , Síndrome Metabólica/complicações , Síndrome Metabólica/genética , Camundongos , Obesidade/complicações , Obesidade/genética , Síndrome de Hiperestimulação Ovariana/genética , Síndrome de Hiperestimulação Ovariana/metabolismo , Ovário/fisiologia , Placenta/fisiologia , GravidezRESUMO
Prostate cancer (PCa) incidence has been dramatically increasing these last years in westernized countries. Though localized PCa is usually treated by radical prostatectomy, androgen deprivation therapy is preferred in locally advanced disease in combination with chemotherapy. Unfortunately, PCa goes into a castration-resistant state in the vast majority of the cases, leading to questions about the molecular mechanisms involving the steroids and their respective nuclear receptors in this relapse. Interestingly, liver X receptors (LXRα/NR1H3 and LXRß/NR1H2) have emerged as new actors in prostate physiology, beyond their historical roles of cholesterol sensors. More importantly LXRs have been proposed to be good pharmacological targets in PCa. This rational has been based on numerous experiments performed in PCa cell lines and genetic animal models pointing out that using selective liver X receptor modulators (SLiMs) could actually be a good complementary therapy in patients with a castration resistant PCa. Hence, this review is focused on the interaction among the androgen receptors (AR/NR3C4), estrogen receptors (ERα/NR3A1 and ERß/NR3A2), and LXRs in prostate homeostasis and their putative pharmacological modulations in parallel to the patients' support.
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Transformação Celular Neoplásica/metabolismo , Neoplasias da Próstata/etiologia , Neoplasias da Próstata/metabolismo , Androgênios/metabolismo , Animais , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/imunologia , Gerenciamento Clínico , Disruptores Endócrinos/efeitos adversos , Exposição Ambiental/efeitos adversos , Estrogênios/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Metabolismo dos Lipídeos , Receptores X do Fígado/genética , Receptores X do Fígado/metabolismo , Masculino , Neovascularização Patológica/imunologia , Neovascularização Patológica/metabolismo , Oxisteróis/metabolismo , Próstata/metabolismo , Próstata/patologia , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/terapia , Receptores Citoplasmáticos e Nucleares/metabolismo , Transdução de SinaisRESUMO
Human pregnancy is associated with enhanced de novo lipogenesis in the early stages followed by hyperlipidemia during advanced gestation. Liver X receptors (LXRs) are oxysterol-activated nuclear receptors that stimulate de novo lipogenesis and also promote the efflux of cholesterol from extrahepatic tissues followed by its transport back to the liver for biliary excretion. Although LXR is recognized as a master regulator of triglyceride and cholesterol homeostasis, it is unknown whether it facilitates the gestational adaptations in lipid metabolism. To address this question, biochemical profiling, protein quantification, and gene expression studies were used, and gestational metabolic changes in T0901317-treated wild-type mice and Lxrab-/- mutants were investigated. Here, we show that altered LXR signaling contributes to the enhanced lipogenesis in early pregnancy by increasing the expression of hepatic Fas and stearoyl-CoA desaturase 1 (Scd1). Both the pharmacological activation of LXR with T0901317 and the genetic ablation of its two isoforms disrupted the increase in hepatic fatty acid biosynthesis and the development of hypertriglyceridemia during early gestation. We also demonstrate that absence of LXR enhances maternal white adipose tissue lipolysis, causing abnormal accumulation of triglycerides, cholesterol, and free fatty acids in the fetal liver. Together, these data identify LXR as an important factor in early-pregnancy lipogenesis that is also necessary to protect against abnormalities in fetoplacental lipid homeostasis.
Assuntos
Metabolismo dos Lipídeos , Lipogênese , Receptores X do Fígado/genética , Gravidez/metabolismo , Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Animais , Western Blotting , Feminino , Feto/metabolismo , Perfilação da Expressão Gênica , Homeostase , Hidrocarbonetos Fluorados/farmacologia , Receptores X do Fígado/agonistas , Receptores X do Fígado/metabolismo , Proteínas de Membrana Transportadoras/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Placenta/metabolismo , Gravidez/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Estearoil-CoA Dessaturase/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Sulfonamidas/farmacologia , Receptor fas/genéticaRESUMO
LXR (Liver X Receptors) act as "sensor" proteins that regulate cholesterol uptake, storage, and efflux. LXR signaling is known to influence proliferation of different cell types including human prostatic carcinoma (PCa) cell lines. This study shows that deletion of LXR in mouse fed a high-cholesterol diet recapitulates initial steps of PCa development. Elevation of circulating cholesterol in Lxrαß-/- double knockout mice results in aberrant cholesterol ester accumulation and prostatic intra-epithelial neoplasia. This phenotype is linked to increased expression of the histone methyl transferase EZH2 (Enhancer of Zeste Homolog 2), which results in the down-regulation of the tumor suppressors Msmb and Nkx3.1 through increased methylation of lysine 27 of histone H3 (H3K27) on their promoter regions. Altogether, our data provide a novel link between LXR, cholesterol homeostasis, and epigenetic control of tumor suppressor gene expression.
Assuntos
Carcinoma/genética , Colesterol/metabolismo , Neoplasias Experimentais/genética , Receptores Nucleares Órfãos/genética , Neoplasia Prostática Intraepitelial/genética , Neoplasias da Próstata/genética , Animais , Carcinoma/metabolismo , Carcinoma/patologia , Dieta Hiperlipídica , Regulação para Baixo , Proteína Potenciadora do Homólogo 2 de Zeste , Regulação Neoplásica da Expressão Gênica , Histonas/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Receptores X do Fígado , Masculino , Metilação , Camundongos , Camundongos Knockout , Neoplasias Experimentais/patologia , Receptores Nucleares Órfãos/metabolismo , Complexo Repressor Polycomb 2/metabolismo , Neoplasia Prostática Intraepitelial/patologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Proteínas Secretadas pela Próstata/metabolismo , Fatores de Transcrição/metabolismoRESUMO
UNLABELLED: Bile acids (BAs) are signaling molecules that are involved in many physiological functions, such as glucose and energy metabolism. These effects are mediated through activation of the nuclear and membrane receptors, farnesoid X receptor (FXR-α) and TGR5 (G-protein-coupled bile acid receptor 1; GPBAR1). Although both receptors are expressed within the testes, the potential effect of BAs on testis physiology and male fertility has not been explored thus far. Here, we demonstrate that mice fed a diet supplemented with cholic acid have reduced fertility subsequent to testicular defects. Initially, germ cell sloughing and rupture of the blood-testis barrier occur and are correlated with decreased protein accumulation of connexin-43 (Cx43) and N-cadherin, whereas at later stages, apoptosis of spermatids is observed. These abnormalities are associated with increased intratesticular BA levels in general and deoxycholic acid, a TGR5 agonist, in particular. We demonstrate here that Tgr5 is expressed within the germ cell lineage, where it represses Cx43 expression through regulation of the transcriptional repressor, T-box transcription factor 2 gene. Consistent with this finding, mice deficient for Tgr5 are protected against the deleterious testicular effects of BA exposure. CONCLUSIONS: These data identify the testis as a new target of BAs and emphasize TGR5 as a critical element in testicular pathophysiology. This work may open new perspectives on the potential effect of BAs on testis physiology during liver dysfunction.
Assuntos
Ácido Cólico/metabolismo , Fertilidade , Infertilidade Masculina/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Testículo/efeitos dos fármacos , Animais , Ácido Cólico/administração & dosagem , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais , Espermatozoides/efeitos dos fármacos , Testosterona/sangueRESUMO
Liver X receptors LXRα (NR1H3) and LXRß (NR1H2) are transcription factors belonging to the nuclear receptor superfamily, activated by specific oxysterols, oxidized derivatives of cholesterol. These receptors are involved in the regulation of testis physiology. Lxr-deficient mice pointed to the physiological roles of these nuclear receptors in steroid synthesis, lipid homeostasis and germ cell apoptosis and proliferation. Diethylstilbestrol (DES) is a synthetic estrogen considered as an endocrine disruptor that affects the functions of the testis. Various lines of evidences have made a clear link between estrogens, their nuclear receptors ERα (NR3A1) and ERß (NR3A2), and Lxrα/ß. As LXR activity could also be regulated by the nuclear receptor small heterodimer partner (SHP, NR0A2) and DES could act through SHP, we wondered whether LXR could be targeted by estrogen-like endocrine disruptors such as DES. For that purpose, wild-type and Lxr-deficient mice were daily treated with 0.75 µg DES from days 1 to 5 after birth. The effects of DES were investigated at 10 or 45 days of age. We demonstrated that DES induced a decrease of the body mass at 10 days only in the Lxr-deficient mice suggesting a protective effect of Lxr. We defined three categories of DES-target genes in testis: those whose accumulation is independent of Lxr; those whose accumulation is enhanced by the lack of both Lxrα/ß; those whose accumulation is repressed by the absence of Lxrα/ß. Lipid accumulation is also modified by neonatal DES injection. Lxr-deficient mice present different lipid profiles, demonstrating that DES could have its effects in part due to Lxrα/ß. Altogether, our study shows that both nuclear receptors Lxrα and Lxrß are not only basally important for testicular physiology but could also have a preventive effect against estrogen-like endocrine disruptors.
Assuntos
Dietilestilbestrol/toxicidade , Receptores Nucleares Órfãos/genética , Testículo/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Apoptose/efeitos dos fármacos , Apoptose/genética , Peso Corporal/efeitos dos fármacos , Dietilestilbestrol/metabolismo , Células Intersticiais do Testículo/efeitos dos fármacos , Células Intersticiais do Testículo/patologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Receptores X do Fígado , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Receptores Nucleares Órfãos/metabolismo , Células de Sertoli/efeitos dos fármacos , Células de Sertoli/patologia , Testículo/patologiaRESUMO
Bile acids are cholesterol metabolites that have been extensively studied in recent decades. In addition to having ancestral roles in digestion and fat solubilization, bile acids have recently been described as signaling molecules involved in many physiological functions, such as glucose and energy metabolisms. These signaling pathways involve the activation of the nuclear receptor farnesoid X receptor (FXRα) or of the G protein-coupled receptor TGR5. In this review, we will focus on the emerging role of FXRα, suggesting important functions for the receptor in steroid metabolism. It has been described that FXRα is expressed in the adrenal glands and testes, where it seems to control steroid production. FXRα also participates in steroid catabolism in the liver and interferes with the steroid signaling pathways in target tissues via crosstalk with steroid receptors. In this review, we discuss the potential impacts of bile acid (BA), through its interactions with steroid metabolism, on glucose metabolism, sexual function, and prostate and breast cancers. Although several of the published reports rely on in vitro studies, they highlight the need to understand the interactions that may affect health. This effect is important because BA levels are increased in several pathophysiological conditions related to liver injuries. Additionally, BA receptors are targeted clinically using therapeutics to treat liver diseases, diabetes, and cancers.
Assuntos
Ácidos e Sais Biliares/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Transdução de Sinais , Esteroides/metabolismo , Neoplasias da Mama/metabolismo , Feminino , Humanos , Masculino , Modelos Biológicos , Neoplasias da Próstata/metabolismoRESUMO
Pinus halepensis Mill. is a Mediterranean aromatic plant largely used, in addition to its nutritional value, in traditional medicine as antiseptic, antifungal, antituberculotic, and antirheumatic. Thus, the objective of this work was to appraise the antioxidant and cytotoxic activity of the essential oil (EO) of P. halepensis from Tunisia on cancer cell cultures, along with chemical composition evaluation by GC-MS. To attain the best yield and also highest quality in extraction of the EOs, conventional hydrodistillation (HD) and novel microwave-assisted extraction (MAE) methods have been performed and compared. The antioxidant activity was evaluated through the inhibition of 2,2-diphenyl-1-picrylhydrazyl (DPPH)⢠radicals. The cytotoxic activity in prostate cancer cells (LNCaP and PC3) and cervical cancer cells (HeLa) of EO was evaluated by the MTT assay and effect on the cell cycle by flow cytometry analysis. A total of 38 and 37 components were identified from HD (HD-EO)- and MAE (MAE-EO)-extracted EOs, respectively, which were dominated by hydrocarbon compounds (HD-EO = 86.65%; MAE-EO = 77.36%), especially monoterpenes (HD-EO = 32.11%; MAE-EO = 21.55%) and sesquiterpenes (HD-EO = 44.29%; MAE-EO = 61.32%). Both extracted EOs showed significant antioxidant activity, as shown by the inhibition of DPPH⢠radicals [IC50 (HD-EO) = 4102.30 ± 159.73 µg mL-1 and IC50 (MAE-EO) = 3430.13 ± 78.46 µg mL-1]. Also, the EOs exhibited substantial (p < 0.001) antiproliferative activities with G0-G1 arrest on PC3, LNCaP, and HeLa cells by yielding very low IC50 values more conspicuous in MAE-EO with respective IC50 values of 25.70 ± 6.58, 14.97 ± 3.21, and 14.55 ± 2.30 µg mL-1. This finding points out for the first time that the EO of P. halepensis Mill. from Tunisia can be an effective natural antitumor agent with more pronounced activity when extracted with the MAE method that, after further in vivo studies, can be harnessed as a putative phytopharmaceutical for prostate and cervical cancer treatment.
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Epidemiological studies point to cholesterol as a possible key factor for both prostate cancer incidence and progression. It could represent a targetable metabolite as the most aggressive tumors also appear to be sensitive to therapies designed to decrease hypercholesterolemia, such as statins. However, it remains unknown whether and how cholesterol, through its dietary uptake and its metabolism, could be important for early tumorigenesis. Oncogene clonal induction in the Drosophila melanogaster accessory gland allows us to reproduce tumorigenesis from initiation to early progression, where tumor cells undergo basal extrusion to form extra-epithelial tumors. Here we show that these tumors accumulate lipids, and especially esterified cholesterol, as in human late carcinogenesis. Interestingly, a high-cholesterol diet has a limited effect on accessory gland tumorigenesis. On the contrary, cell-specific downregulation of cholesterol uptake, intracellular transport, or metabolic response impairs the formation of such tumors. Furthermore, in this context, a high-cholesterol diet suppresses this impairment. Interestingly, expression data from primary prostate cancer tissues indicate an early signature of redirection from cholesterol de novo synthesis to uptake. Taken together, these results reveal that during early tumorigenesis, tumor cells strongly increase their uptake and use of dietary cholesterol to specifically promote the step of basal extrusion. Hence, these results suggest the mechanism by which a reduction in dietary cholesterol could lower the risk and slow down the progression of prostate cancer.
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Cancer is one of the leading causes of death worldwide. In recent years, African countries have been faced with a rapid increase in morbidity and mortality due to this pathology. Management is often complicated by the high treatment costs, side effects and the increasing occurrence of resistance to treatments. The identification of new active ingredients extracted from endemic medicinal plants is definitively an interesting approach for the implementation of new therapeutic strategies: their extraction is often lower cost; their identification is based on an ethnobotanical history and a tradipratic approach; their use by low-income populations is simpler; this can help in the development of new synthetic molecules that are more active, more effective and with fewer side effects. The objective of this review is to document the molecules derived from African medicinal plants whose in vitro anti-cancer activities and the mechanisms of molecular actions have been identified. From the scientific databases Science Direct, PubMed and Google Scholar, we searched for publications on compounds isolated from African medicinal plants and having activity on cancer cells in culture. The data were analyzed in particular with regard to the cytotoxicity of the compounds and their mode of action. A total of 90 compounds of these African medicinal plants were selected. They come from nine chemical groups: alkaloids, flavonoids, polyphenols, quinones, saponins, steroids, terpenoids, xanthones and organic sulfides. These compounds have been associated with several cellular effects: i) Cytotoxicity, including caspase activation, alteration of mitochondrial membrane potential, and/or induction of reactive oxygen species (ROS); ii) Anti-angiogenesis; iii) Anti-metastatic properties. This review points out that the cited African plants are rich in active ingredients with anticancer properties. It also stresses that screening of these anti-tumor active ingredients should be continued at the continental scale. Altogether, this work provides a rational basis for the selection of phytochemical compounds for use in clinical trials.
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Prostate cancer (PCa) is one of the most common cancers in men. Metastasis is the leading cause of death in prostate cancer patients. One of the crucial processes involved in metastatic spread is the "epithelial-mesenchymal transition" (EMT), which allows cells to acquire the ability to invade distant organs. Liver X Receptors (LXRs) are nuclear receptors that have been demonstrated to regulate EMT in various cancers, including hepatic cancer. Our study reveals that the LXR pathway can control pro-invasive cell capacities through EMT in prostate cancer, employing ex vivo and in vivo approaches. We characterized the EMT status of the commonly used LNCaP, DU145, and PC3 prostate cancer cell lines through molecular and immunohistochemistry experiments. The impact of LXR activation on EMT function was also assessed by analyzing the migration and invasion of these cell lines in the absence or presence of an LXR agonist. Using in vivo experiments involving NSG-immunodeficient mice xenografted with PC3-GFP cells, we were able to study metastatic spread and the effect of LXRs on this process. LXR activation led to an increase in the accumulation of Vimentin and Amphiregulin in PC3. Furthermore, the migration of PC3 cells significantly increased in the presence of the LXR agonist, correlating with an upregulation of EMT. Interestingly, LXR activation significantly increased metastatic spread in an NSG mouse model. Overall, this work identifies a promoting effect of LXRs on EMT in the PC3 model of advanced prostate cancer.
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BACKGROUND & AIMS: Nutrients influence non-alcoholic fatty liver disease. Essential fatty acids deficiency promotes various syndromes, including hepatic steatosis, through increased de novo lipogenesis. The mechanisms underlying such increased lipogenic response remain unidentified. METHODS: We used wild type mice and mice lacking Liver X Receptors to perform a nutrigenomic study that aimed at examining the role of these transcription factors. RESULTS: We showed that, in the absence of Liver X Receptors, essential fatty acids deficiency does not promote steatosis. Consistent with this, Liver X Receptors are required for the elevated expression of genes involved in lipogenesis in response to essential fatty acids deficiency. CONCLUSIONS: This work identifies, for the first time, the central role of Liver X Receptors in steatosis induced by essential fatty acids deficiency.
Assuntos
Ácidos Graxos Essenciais/deficiência , Fígado Gorduroso/fisiopatologia , Expressão Gênica/fisiologia , Lipogênese/genética , Lipogênese/fisiologia , Receptores Nucleares Órfãos/fisiologia , Animais , Colesterol/metabolismo , Deficiências Nutricionais/fisiopatologia , Gorduras na Dieta/farmacologia , Modelos Animais de Doenças , Feminino , Expressão Gênica/efeitos dos fármacos , Lipogênese/efeitos dos fármacos , Fígado/metabolismo , Receptores X do Fígado , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Receptores Nucleares Órfãos/deficiência , Receptores Nucleares Órfãos/genética , Fatores de Transcrição/fisiologia , Triglicerídeos/metabolismo , Regulação para Cima/fisiologiaRESUMO
Increasing evidence points towards a causal link between exposure to persistent organic pollutants (POPs) with increased incidence and aggressivity of various cancers. Among these POPs, dioxin and PCB-153 are widely found in our environment and represent a significant source of contamination. Dioxin exposure has already been linked to cancer such as non-Hodgkin's lymphoma, but remains to be more extensively investigated in other cancers. Potential implications of dioxin and PCB-153 in prostate cancer progression spurred us to challenge both ex vivo and in vivo models with low doses of these POPs. We found that dioxin or PCB-153 exposure increased hallmarks of growth and metastasis of prostate cancer cells ex vivo and in grafted NOD-SCID mice. Exposure induced histopathological carcinoma-like patterns in the Ptenpc-/- mice. We identified up-regulation of Acetyl-CoA Acetyltransferase-1 (ACAT1) involved in ketone bodies pathway as a potential target. Mechanistically, genetic inhibition confirmed that ACAT1 mediated dioxin effect on cell migration. Using public prostate cancer datasets, we confirmed the deregulation of ACAT1 and associated gene encoded ketone bodies pathway enzymes such as OXCT1, BDH1 and HMGCL in advanced prostate cancer. To further explore this link between dioxin and ACAT1 deregulation, we analyzed a unique prostate-tumour tissue collection from the USA veterans exposed to agent orange, known to be highly contaminated by dioxin because of industrial production. We found that ACAT1 histoscore is significantly increased in exposed patients. Our studies reveal the implication of dioxin and PCB-153 to induce a prometastatic programme in prostate tumours and identify ACAT1 deregulation as a key event in this process.
Assuntos
Dioxinas , Dibenzodioxinas Policloradas , Neoplasias da Próstata , Masculino , Humanos , Animais , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Poluentes Orgânicos Persistentes , Dioxinas/toxicidade , Neoplasias da Próstata/induzido quimicamente , Neoplasias da Próstata/genética , AcetiltransferasesRESUMO
Lipid and cholesterol metabolism play a crucial role in tumor cell behavior and in shaping the tumor microenvironment. In particular, enzymatic and non-enzymatic cholesterol metabolism, and derived metabolites control dendritic cell (DC) functions, ultimately impacting tumor antigen presentation within and outside the tumor mass, dampening tumor immunity and immunotherapeutic attempts. The mechanisms accounting for such events remain largely to be defined. Here we perturbed (oxy)sterol metabolism genetically and pharmacologically and analyzed the tumor lipidome landscape in relation to the tumor-infiltrating immune cells. We report that perturbing the lipidome of tumor microenvironment by the expression of sulfotransferase 2B1b crucial in cholesterol and oxysterol sulfate synthesis, favored intratumoral representation of monocyte-derived antigen-presenting cells, including monocyte-DCs. We also found that treating mice with a newly developed antagonist of the oxysterol receptors Liver X Receptors (LXRs), promoted intratumoral monocyte-DC differentiation, delayed tumor growth and synergized with anti-PD-1 immunotherapy and adoptive T cell therapy. Of note, looking at LXR/cholesterol gene signature in melanoma patients treated with anti-PD-1-based immunotherapy predicted diverse clinical outcomes. Indeed, patients whose tumors were poorly infiltrated by monocytes/macrophages expressing LXR target genes showed improved survival over the course of therapy. Thus, our data support a role for (oxy)sterol metabolism in shaping monocyte-to-DC differentiation, and in tumor antigen presentation critical for responsiveness to immunotherapy. The identification of a new LXR antagonist opens new treatment avenues for cancer patients.