Article

Anticancer Activity of Linalool Terpenoid: Apoptosis Induction and Cell Cycle Arrest in Prostate Cancer Cells

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Abstract

Purpose: To evaluate the anticancer activity of linalool against human prostate cancer (DU145) cells. Methods: The anticancer activity of linalool against DU145 cancer cells was evaluated by 3-(4, 5- dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. Flow cytometry, using propidium iodide and Annexin V-FITC, was applied to study apoptosis and cell cycle phase distribution. Inverted light microscopy was used to study the effect of linalool on cell morphology and apoptotic body formation in DU145 cells while gel electrophoresis was employed to evaluate the effect of linalool on DNA fragmentation. Results: Linalool induced a dose-dependent as well as time-dependent growth inhibitory effect on DU145 prostate cancer cells. It induced sub-G1 phase growth arrest which led to increase in sub-G0/G1 cell population after treatment with increasing doses of linalool. DNA ladder appeared to be more evident with increasing linalool concentration. However, no DNA fragments were observed in the control groups. It was observed that 4.36, 11.54, 21.88 and 15.54 % of the cells underwent early apoptosis after treatment with 0 (no linalool treatment), 20, 40, and 80 μM of linalool, respectively. Compared to control cells, linalool treatment resulted in the appearance of cell shrinkage along with membrane blebbing which are characteristic features of cell apoptosis. Conclusion: The findings of this study indicate that linalool can be developed as a plant-based chemotherapeutic agent against prostate cancer © Pharmacotherapy Group, Faculty of Pharmacy, University of Benin, Benin City, 300001 Nigeria. All rights reserved.

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... The pharmacological activities of this 10-carbon isoprenoid were evaluated both in vitro and in vivo and were found having sedative, analgesic, anti-inflammatory, antioxidant, antimicrobial, and antitumor properties among others [17,18]. Linalool was reported to induce cell cycle arrest and/or apoptosis in a wide variety of human cancer cells such as prostate [19], leukemia [20,21], cervical [21], breast [22], sarcoma [23] and epithelial ovarian cancer cells [24], however no reports for HCC cells are available to this respect and the mechanisms by which these effects are produced are not completely understood. We have previously shown the ability of linalool to inhibit the mevalonate pathway and cell growth in HepG2 and A549 cells [25], suggesting that its anticancer activity could be due to the inhibition of Ras prenylation, which is essential to promote tumorigenesis [26]. ...
... Linalool has been investigated as a promising chemopreventive and chemotherapeutic agent in several in vitro and in vivo models including liver [25], lung [25], prostate [19], leukemia [20], cervical [21], breast [22], human cancer cells and in tumor-bearing mice [23]. It has been evaluated as a mono-drug agent or combined with conventional drugs, and it was found that antiproliferative concentrations were strongly dependent on cell line in the micro- [19][20][21][22] or milimolar [23][24][25] range. ...
... Linalool has been investigated as a promising chemopreventive and chemotherapeutic agent in several in vitro and in vivo models including liver [25], lung [25], prostate [19], leukemia [20], cervical [21], breast [22], human cancer cells and in tumor-bearing mice [23]. It has been evaluated as a mono-drug agent or combined with conventional drugs, and it was found that antiproliferative concentrations were strongly dependent on cell line in the micro- [19][20][21][22] or milimolar [23][24][25] range. However, the mechanisms by which linalool exerts its antiproliferative effects in HCC cells are not completely understood. ...
Article
Aims: Linalool is a plant-derived monoterpene with anticancer activity, however its mechanisms of action remain poorly understood. The aim of this work was to elucidate the anticancer mechanisms of action of linalool in hepatocellular carcinoma (HCC) HepG2 cells. Main methods: Cell viability and proliferation were determined by WST-1 assay and BrdU incorporation, respectively. Cell cycle analysis was assessed through flow cytometry (FC) and western blot (WB). Apoptosis was determined by caspase-3 activity, TUNEL assay and WB. Reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) were analyzed by FC and fluorescence microscopy. Expression of Ras, MAPKs (ERK, JNK and p38) and Akt/mTOR pathways were evaluated by WB. Key findings: Linalool (0-2.5 mM) dose-dependently inhibited cell proliferation by inducing G0/G1 cell cycle arrest, through Cdk4 and cyclin A downregulation, p21 and p27 upregulation, and apoptosis, characterized by MMP loss, caspase-3 activation, PARP cleavage and DNA fragmentation. Low concentrations of linalool (1.0 mM) reduced membrane-bound Ras and Akt activity whereas higher amounts (2.0 mM) triggered mTOR inhibition and ROS generation, in correlation with MAPKs activation and Akt phosphorylation. ROS scavenger N-acetyl-L-cysteine partially rescued HepG2 cell growth and prevented MPP depolarization, ERK and JNK activation. Moreover, specific ERK and Akt phosphorylation inhibitors potentiated linalool anti-cancer activity, pointing Akt and ERK activation as pro-survival mechanisms in response to higher concentrations of linalool. Significance: This report reveals that linalool induces G0/G1 arrest and apoptosis in HepG2 cells involving Ras, MAPKs and Akt/mTOR pathways and suggests that linalool is a promising anticancer agent for HCC therapy.
... Linalool and 1,8-cineole have been evaluated as potential chemopreventive and chemotherapeutic molecules as mono-drug agents or combined with conventional drugs. Numerous in vitro and in vivo studies demonstrated the anticancer potential of these monoterpenes in lung [28], liver [16,28,33], breast [23], ovarian [34], skin [35], cervical [36,37], colon [38,39], sarcoma [40], glioma [41], leukemia [36,42,43], prostate [44,45], oral [46] and gastric [47] cancer cells. Nevertheless, to our knowledge, the mechanisms by which linalool and 1,8-cineole impair the proliferation of NSCLC A549 cells remain unexplored. ...
... In this study, we show that linalool (1.0-2.0 mM) and 1,8-cineole (4.0-8.0 mM) significantly inhibited A549 cell viability without showing inhibitory effects on normal lung WI-38 cells. The effective concentrations of linalool and 1,8cineole reported to inhibit in vitro cancer cell proliferation vary from micromolar (μM) [35,36,39,42,43,45,47] to millimolar (mM) [16,33,34,37,38,40,44,46]. This heterogeneity in sensitivity depends on the cancer cell type but also each cell line evaluated. ...
Article
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Linalool and 1,8-cineole are plant-derived isoprenoids with anticancer activities in lung cancer cells, nevertheless, the cellular and molecular mechanisms of action remain poorly understood. The purpose of this study was to determine the anticancer mechanisms of action of linalool and 1,8-cineole in lung adenocarcinoma A549 cells. Linalool (0–2.0 mM) and 1,8-cineole (0–8.0 mM) inhibited cell proliferation by inducing G0/G1 and/or G2/M cell cycle arrest without affecting cell viability of normal lung WI-38 cells. None of the two monoterpenes were able to induce apoptosis, as observed by the lack of caspase-3 and caspase-9 activation, PARP cleavage, and DNA fragmentation. Linalool, but not 1,8-cineole, increased reactive oxygen species production and mitochondrial membrane potential depolarization. Reactive oxygen species were involved in cell growth inhibition and mitochondrial depolarization induced by linalool since the antioxidant N-acetyl-L-cysteine prevented both effects. Besides, linalool (2.0 mM) and 1,8-cineole (8.0 mM) inhibited A549 cell migration. The combination of each monoterpene with simvastatin increased the G0/G1 cell cycle arrest and sensitized cells to apoptosis compared with simvastatin alone. Our results showed that both monoterpenes might be promising anticancer agents with antiproliferative, anti-metastatic, and sensitizer properties for lung cancer therapy.
... Linalool induces cell cycle arrest in certain cancer types. In human prostate cancer cells (DU145), the use of the 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide (MTT) assay by Sun et al. [43] demonstrated that linalool at 20, 40 and 80 μM concentrations induced sub-G1 cell cycle arrest and, consequently, DNA damage. Similarly, Chang, Shieh, Chen, Yeh and Dong [49] demonstrated that, in U937 myeloid leukemia cell line, linalool induces cell cycle arrest at G0/G1 phase, which causes a replication suspension, and consequently leads to the accumulation of damaged DNA and activation of tumor suppression mechanisms. ...
... [63] Activation of the Nrf2/HO-1 signaling pathway [64,65] Inhibition of NO production [66] Anticancer and Anti-proliferative Cell cycle arrest [42,43,49] Apoptosis induction [45,47,48,51,52] Activation of immune cells (T helper cells) [44] Prevention of the overexpression of angiogenic factors (VEGF and TGF-β1) ...
Article
The medicinal properties of essential oils from aromatic plants are known since antiquity. Currently, the technological innovation enabled the reinvention of the ancient plant knowledge leading to the identification and extraction of organic compounds present in essential oils. These organic compounds belong mainly to the terpene group and are accountable for the wide range of bioactive properties attributed to essential oils. Linalool (C10H18O), so-called 3,7-dimethyl-1,6-octadien-3-ol, is a monoterpene alcohol broadly present as a major constituent of plant essential oils, particularly lavender and coriander. Linalool per se is non-toxic and, according to recent in vitro and in vivo scientific studies, it has demonstrated to have a comprehensive range of bioactive properties, which can be exploited for pharmaceutic and cosmetic applications. The present review focuses on the anti-inflammatory, anticancer, anti-hyperlipidemic, antimicrobial, antinoceptive, analgesic, anxiolytic, antidepressive and neuroprotective properties of linalool. The advantages of the loading in nanotechnology-based drug delivery systems, with the purpose of enhancing its bioactive properties are also discussed.
... These results confirmed the compounds mentioned above as the main constituents of laurel hydrolate [64,93] and essential oil [94,95] in varying amounts. It is considered that methyl eugenol is a limiting factor that allows the use of laurel essential oil in food applications [96] and, along with linalool, exhibits antioxidant, antimicrobial, anti-inflammatory and anticancer properties [94,[97][98][99][100][101][102] and various effects on the central nervous system [98,103,104]. These compounds are the primary compounds responsible for the aroma of laurel leaves [105]. ...
Article
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Functional beverages based on herbal extracts are highly demanded products due to the presence of bioactives with promising health benefits and interesting and characteristic sensory properties. Mediterranean medicinal and aromatic herbs contain a wide range of bioactives (non-volatile polyphenols, volatile terpenes) that are important constituents of herbal extracts and essential oils. The antioxidant capacity and potential health benefits of these bioactives could be associated with their synergistic effects. Therefore, this study aimed to characterize the non-volatile and volatile bioactives of sage (Salvia officinalis L.), wild thyme (Thymus serpyllum L.) and laurel (Laurus nobilis L.) aqueous extracts and their two- and three-component mixtures as well as their antioxidant capacity. The content of total phenols, flavonoids, hydroxycinnamic acids and flavonols was determined spectrophotometrically. Individual polyphenols were analyzed by LC-MS/MS, the volatiles were analyzed by HS-SPME/GC-MS, and the antioxidant capacity was analyzed by ORAC and DPPH assays. The results showed that aqueous extracts of all examined herbs and their mixtures contained a high content of phenolic compounds ranging from 0.97 to 2.79 g L−1 of the sample, among which the most common were flavonols. At the same time, mono- and sesquiterpenes were the main volatiles. All extracts showed high antioxidant capacity, especially L. nobilis (781.62 ± 5.19 μmol TE mL−1 of the sample in the DPPH assay; 1896.10 ± 8.77 μmol TE mL−1 of the sample in the ORAC assay) and the two-component mixture of L. nobilis and T. serpyllum (679.12 ± 5.19 μmol TE mL−1 in the DPPH assay; 1913.38 ± 8.77 μmol TE mL−1 in the ORAC assay). Mixtures of herbal extracts have been shown to possess additive or synergistic effects, consequently contributing to higher antioxidant capacity. Therefore, two-component mixtures of herbal extracts showed promising potential for the production of functional beverages.
... Considering the close relationship between DNA damage and cancer development, the combination of antigenotoxic with cytotoxic activities of the mastic water constituents would suggest their potential anti-cancer properties and application in anticancer medicinal treatments. Indeed, several mastic extracts or mastic constituents have been shown to exert anti-cancer activities, such as reduced proliferation (cells)/growth (tumors), increased apoptosis, blockage in G1 phase of the cell cycle, and suppressed NF-κB activity, in vitro and in vivo against different tumors or cancer cells [35][36][37][38][39][40][41][42][43][44][45] . ...
Article
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Chios mastic products are well-known for their broad applications in food industry, cosmetics, and healthcare since the antiquity. Given our recent finding that Chios mastic water (CMW) exerts antigenotoxic action, in the present study, we evaluated the genotoxic as well as the antigenotoxic potential of the four major compounds of CMW, namely, verbenone, α-terpineol, linalool, and trans-pinocarveol. The cytokinesis block micronucleus (CBMN) assay in cultured human lymphocytes and the Drosophila Somatic Mutation And Recombination Test (SMART), also known as the wing spot test, were employed. None of the four major CMW's constituents or their mixtures showed genotoxic or recombinogenic activity in either of the assays used. Co-treatment of each of the constituents with MMC revealed that all except trans-pinocarveol exerted antigenotoxic potential. Moreover, co-administration of verbenone with linalool or α-terpineol presented statistically significant reduction of MMC-induced mutagenicity. In conclusion, the major CMW constituents were shown to be free of genotoxic effects, while some exerted antigenotoxic activity either alone or in combinations, suggesting synergistic phenomena. Our results provide evidence on the key antigenotoxicity effectors of the plant extract CMW.
... Linalool possesses an anti-angiogenic activity thus having a role in treating or even preventing the progression of cancer cells [75]. It has been shown to be a promising agent against prostate cancer [76], endothelial ovarian carcinoma [77], colon cancer [78], leukaemia and cervical cancer [79]. Moreover, Ravizza, Gariboldi [80] reported that linalool reverses the doxorubicin resistance in human breast adenocarcinoma cells via enhancing the sensitivity of these carcinogenic cells towards the cytotoxic activity of doxorubicin. ...
Thesis
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The replacement of synthetic conventional compounds by natural ingredients; whether in medicine, food, or cosmetics; has been increasingly requested by consumers, especially since the last decade. Terpenes in general and monoterpenes in particular are secondary metabolites in plants, and they may be a promising natural alternative. Monoterpenes, the main constituents of plants’ essential oils, are odorous compounds that play a significant ecological role in plant evolution. They are primarily utilized by the flavour and fragrance industries due to their characteristic aroma. In addition, a series of representatives belonging to this substance class are antimicrobial, anti-inflammatory, antiseptic, and anticancer agents; or elicit other therapeutic effects. Thereby, acyclic monoterpene alcohols, mainly linalool, geraniol, nerol, and citronellol, are primarily in the focus of scientific research. Besides their aromatic character and their role in aromatherapy, they induce a series of pharmacological and physiological effects. In view of the latter, their metabolic pathways have been previously investigated in both plants and animals. Linalool and geraniol, for example, are metabolized giving 8-hydroxy and 8-carboxy derivatives; i.e. undergoing oxidation at C-8. However, these metabolites have not been tested in terms of odour or other physiological activities. Furthermore, no studies are at hand elucidating which structural features of these substances are responsible for specific odour qualities and potencies of these monoterpenes. In the frame of this doctoral thesis, a comparison between chemical structure and odour character of selected monoterpenes relating to linalool, geraniol, nerol, and β- citronellol has been conducted, complemented by investigations on their acetate derivatives and previously identified oxygenated metabolites. To achieve this aim, a series of oxygenated derivatives, bearing an aldehyde, an alcohol, or an acid functional group at C-8, were synthesized from the aforementioned terpene alcohols and acetates yielding 24 compounds, yielding a comprehensive substance library for future elucidation of the substances’ presence in nature and evaluation of their further potential physiological properties. Within this study, however, the focus lies on a comprehensive characterization of the compounds’ olfactory properties. Accordingly, all compounds were tested in relation to their odour qualities and relative odour thresholds (OTs) in air, as well as potential inter-individual variations in sensory perception for each single substance. Overall, the results show that v almost all investigated parent monoterpene alcohols and their acetates exhibited closely related odour characters; ranging between citrus-like, fresh, fruity, floral-sweet, and fatty. Amongst others, linalool was demonstrated to be the most potent monoterpene of the group of investigated compounds, eliciting an OT of 3.2 ng/Lair. According to this study, the presence of an OH group at C-3 in the linalool basic structure is the main contributor to its characteristic odour quality and high potency. On the other hand, the occurrence of this OH at C-1 in geraniol, nerol, and citronellol does not alter their odour quality but increases their odour threshold levels, with values of 40, 60 and 10 ng/Lair, respectively. Esterification of this OH-group to the respective acetate barely affected the odour quality, but provoked a decline in odour potency. Substitution at C-8 of either the parent monoterpeneols or their acetates by another OH-group retained the smell of the parent compounds but led to a dramatic decrease in the potency. However, the smell potency was only retained when replacing the alcoholic group at C-8 by an aldehyde or an acid group. It is worth mentioning that among the acetate derivatives 8-oxolinalyl acetate elicits similar smell impressions as linalool, thus exhibiting a citrus-like, fresh odour with an OT of 5.9 ng/Lair. Apart from that, further oxidation of C-8 of linalool, geraniol, citronellol, and citronellyl acetate to their corresponding acids led to a total odour loss.
... Other than this, another study demonstrated that 29 protected against CS-induced lung inflammation through inhibiting CS-induced NF-κB activation [37]. e anticancer activity of linalool (29) against human prostate cancer (DU145) cells was evaluated by the MTT assay and it was observed that 4.36%, 11.54%, 21.88%, and 15.54% of the cells underwent early apoptosis after treatment with 0, 20, 40, and 80 μM of 29, respectively [38]. In addition, Okumura et al. confirmed that terpinolene (10) could markedly reduce the expression of protein kinase AKT, which can mediate cell proliferation and survival signals, and contribute to cancer progression [39]. ...
Article
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Cinnamomum is a genus of the family Lauraceae, which has been recognized worldwide as an important genus due to its beneficial uses. A great deal of research on its phytochemistry and pharmacological effects has been conducted. It is noteworthy that terpenoids are the characteristic of Cinnamomum due to the peculiar structures and significant biological effects. For a more in-depth study and the better use of Cinnamomum plants in the future, the chemical structures and biological effects of terpenoids obtained from Cinnamomum were summarized in the present study. To date, a total of 181 terpenoids with various skeletons have been isolated from Cinnamomum . These compounds have been demonstrated to play an important role in immunomodulatory, anti-inflammatory, antimicrobial, antioxidant, and anticancer activities. However, studies on the bioactive components from Cinnamomum plants have only focused on a dozen species. Hence, further studies on the potential pharmacological effects need to be conducted in the future.
... Santonin, a sesquiterpene lactone and caryophyllene oxide are well known compound of family Asteraceae (Sakipova et al., 2017). Similar kinds of terpenoids, sesquiterpenes lactone, coumarin and phenols were also identified in a number of other plant extracts and reported to possess strong anticancer activities (Murata et al., 2013;Sun et al., 2015;Takasaki et al., 1999aTakasaki et al., , 1999b. But cytotoxicity of artemorin has never been reported. ...
Article
Ethnopharmacological relevance: Medicinal plants used in traditional medicines are affordable, easily accessible, safer, less toxic and considered as a rich or efficient source of bioactive molecules for modern therapeutics. Artemisia nilagirica (AR) has a long history of use in Indian traditional medicine to combat a wide variety of diseases including cancer. Aim of the study: Considering the vast potential of traditional healing plants to deliver safer, less toxic and efficient chemotherapeutics, we have examined anticancer activity of ethanolic extract, bioactive fractions and sub-fractions of AR against different human cancer cell lines along with their phytochemical analysis to understand the insights of novel anticancer activities for further preclinical studies. Materials and methods: Fresh plant material of AR was procured from the wild, dried and ground. The grinded materials was extracted in ethanol (AR-01) and fractionated into butanol (AR-02), ethyl acetate (AR-03), hexane (AR-04) and water (AR-05). The cytotoxicity was evaluated against three different human cancer cell lines, i.e. colon (DLD-1), lung (A-549), and breast (MCF-7) using Sulforhodamine B (SRB) assay along with non-cancerous VERO cells as control and doxorubicin (DOX) as positive control. As we observed strong cytotoxicity of AR-03 and AR-04 fractions against tested cells and marked cytotoxic effects particularly in colon cancer cell lines, we further re-fractionated, AR-03 into (AR-03A, AR-03B, AR-03C, AR-03D, AR-03E) and AR-04 into (AR-04A, AR-04B, AR-04C) sub-fractions by column chromatography and investigated against the same panel of cell lines in addition to one more colon cancer cell line (HT-29). Phytochemical analysis was performed through HPLC-ESI-QTOF-MS/MS fragmentation. Results: Ethyl acetate (AR-03) and hexane (AR-04) fractions were found to be the most cytotoxic against all the tested cell lines. Further, AR-03E and AR-04A sub-fractions were found more specific cytotoxic selectively against DLD-1 cancer cell lines at 100µg/ml concentration. HPLC-ESI-QTOF-MS/MS determination revealed the presence of 17 compounds in AR-01. Among them, 4 compounds were reported for the first time in this species. However, 3 identified compounds (artemorin, β-santonin and caryophyllene oxide) in AR-03E sub-fraction were commonly present in each bioactive fraction and may be considered as potential and safest cytotoxic agents for anticancer activity. Conclusions: Experimental evidences reported in this paper for anticancer activity validate the traditional wisdom of Artemisia nilagirica as an anticancer herbal drug. To our knowledge, this is our first novel observation of cytotoxicity and selectivity of ethyl acetate and hexane sub-fraction of AR-01 i.e. AR-03E and AR-04A respectively against DLD-1 human cancer cell lines. HPLC-ESI-QTOF-MS/MS determination attributes the identification of cytotoxic compounds which may be used for further preclinical studies.
... Linalool essential oil is prepared through chemical synthesis. 6 Several studies have suggested the anticancer activity of linalool against a wide range of cell lines; 7,8 however, its use is restricted by the high toxicity of the essential oil. 9 Recently, glutathione (GSH) has emerged as s popular biodegradable polymer that is used in the preparation of GSH-coated nanoparticles. ...
Article
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Background: Linalool is a monoterpene compound with various potential therapeutic applications in several medical fields. Previous studies have indicated the activity of linalool against cell lines; however, its high level of toxicity restricts its use. The aim of this study was to design and manufacture compounds with a novel structure that can be used for loading linalool, to reduce its toxicity and improve its reachable ability. Methods: We synthesized and characterized a new molecule for loading linalool onto gold nanoparticles (GNPs) capped with glutathione and conjugated with a CALNN peptide. Linalool was loaded onto the GNPs via the reaction of the surface groups of both linalool and the GNPs. Moreover, the target peptide could be loaded onto the surface of the GNPs via a chemical reaction. The cytotoxic effects of linalool-GNP (LG) and linalool-GNP-CALNN peptide (LGC) conjugates against ovarian cancer cells were investigated, as were the possible mechanisms underlying the induction of apoptosis. Results: Our findings illustrated the significant antiproliferative effect of LG and LGC on SKOV-3 cells. The cytotoxicity assay demonstrated that LG and LGC were selectively toxic in cancer cells and induced apoptosis by activating caspase-8, the p53 protein, and various proteins involved in apoptosis. The present data demonstrated that LG and LGC have a high therapeutic potential and should be given particular consideration as anticancer drug-delivery systems, as LG and LGC were remarkably more cytotoxic against a cancer cell line than were linalool and GNPs alone. Conclusion: We concluded that LG and LGC are promising compounds that can be used for treating ovarian cancer (SKOV-3) cells via the induction of apoptosis through extrinsic and intrinsic pathways.
... Arora et al. (2016) have also reported fungal extractinduced sub-G1 phase arrest. Interestingly, anticancer agents (linalool and subamolide E) also induce cell death by leading to the activation of DNA damage checkpoints and sub-G1 phase cell cycle arrest (Wang et al., 2011;Sun et al., 2015). The fungal secondary metabolic profiling remains uncharacterized to recognize the bioactive compounds contributing to the cytotoxic and apoptotic activities exhibited by BpME and BpCE from B. petrensis. ...
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Hypersaline environments are known to support diverse fungal species from various orders. The production of secondary metabolites is one of the strategies that fungi adopt to thrive under such extreme environments, bringing up the stress tolerance response. Some such unique secondary metabolites also exhibit clinical significance. The increasing prevalence of drug resistance in cancer therapy demands further exploration of these novel bioactive compounds as cancer therapeutics. In the present study, a total of 31 endophytic fungi harboring inside red, green, and brown marine algae have been isolated and identified. The maximum likelihood analysis and diversity indices of fungal endophytes revealed the phylogenetic relationship and species richness. The genus Aspergillus was found to be the dominating fungus, followed by Cladosporium spp. All the isolated endophytic fungal extracts were tested for their cytotoxicity against HeLa and A431 cancer cell lines. Nine isolates were further analyzed for their cytotoxic activity from the culture filtrate and mycelia extract. Among these isolates, Biscogniauxia petrensis showed potential cytotoxicity with CC 50 values of 18.04 and 24.85 μg/ml against HeLa and A431 cells, respectively. Furthermore, the media and solvent extraction optimization revealed the highest cytotoxic active compounds in ethyl acetate extract from the potato dextrose yeast extract broth medium. The compound-induced cell death via apoptosis was 50–60 and 45% when assayed using propidium iodide-live/dead and loss of mitochondrial membrane potential assay, respectively, in HeLa cells. Four bioactive fractions (bioassay-based) were obtained and analyzed using chromatography and spectroscopy. This study reports, for the first time, the cytotoxic activity of an endophytic fungal community that was isolated from marine macro-algae in the Rameswaram coastal region of Tamil Nadu, India. In addition, B. petrensis is a prominent apoptotic agent, which can be used in pharmaceutical applications as a therapeutic.
... In the current reports revealed that the cell cycle arrest was taken place in the G0 and M phase and most of the cytokinetic and pharmacological research was also shows accurate cell cycle analysis [35]. Other report revealed that cell cycle arrest leads to increase in sub-G0/G1cell population after treatment with increasing doses of linalool terpenoid [36]. Phlorotanninsenriched extract of brown alga of H. grandifolius exhibited cytotoxicity against tumor cell line including Hep-2 and promoting cell death trough apoptosis mechanisms [34]. ...
Article
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Background Cancer causes leading death in the world population due to exposure of various carcinogenic/mutagenic agents, radiation and life style. There are 2.6 million new cases diagnosed each year. Therefore, the objective is aimed to study the antibacterial and antioxidant activities of solvent fractions of ethanolic extract of T. conoides and its anticancer activity also evaluated by analyzing cytotoxicity, cell cycle arrest and apoptosis in HepG2 cell line. Methods Antibacterial activity was done by disc diffusion method and expressed as in millimeter diameter of zone inhibition. Antioxidant activity was done by ABTS radical assay, superoxide radical assay, iron chelation and uric acid formation inhibitory assays. The cytotoxicity efficacy was estimated using MTT assay. Annexin-V FITC kit was used to estimate the apoptosis and cell cycle arrest by flowcytometer. Morphological changes of cell through alteration of nuclear content and mitochondrial membrane potential were also examined using Hoechst and JC1 stains under fluorescence microscopy, respectively. ResultsHighest antibacterial activity, TAA and RAA were found in EAF followed by DMF, HF and AF. Cytotoxicity of EAF was found to be 67% at 24 h and 83% at 48 h over the standard of quercetin (86% at 48 h). The cancer cells were found to be significantly (p < 0.05) higher in the proliferative G0/G1 phase where as significantly decreased in the S phase. Hence, treatment with T. conoides fraction showed statistically (p < 0.05) significant increase of apoptotic cells than that of quercetin standard (32%, 80 μg/mL). The apoptotic cell formation might be due to the change of nuclear content and mitochondrial membrane potential were further confirmed in HepG2 cells under fluorescence microscopy. Conclusion Ethyl acetate fraction of T. conoides showed highest antibacterial, antioxidant and anticancer activity through exhibiting synergistic effects over the respective standard compounds.
... Nature is the big source of natural medicine and compounds derived from plants, animals, marines, and microbes [13][14][15][16][17][18]. Among them, plants provide many novel anticancer compounds [19] such as alkaloids [20,21], flavonoids [22,23], glycosides [24], saponins, tannins [25], and terpenoids [26] which are found from a plant having antioxidant and anticancer properties in a various cancer cell line, especially in a liver cancer cell line. HCC development is a multistep process that may include the alteration in host gene expression, DNA methylation, loss of heterozygosity, and point mutation, but still, we are lacking to determine the rate limiting step for initiation and progression of HCC [27]. ...
Article
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Hepatocellular carcinoma (HCC) is due to poor prognosis and lack of availability of effective treatment. Novel therapeutic strategies will be the fine tuning of intracellular ROS signaling to effectively deprive cells of ROS-induced tumor-promoting events. This review discusses the generation of ROS, the major signaling their modulation in therapeutics. We explore some of the major pathways involved in HCC, which include the VEGF, MAPK/ERK, mTOR, FGF, and Ser/Thr kinase pathways. In this review, we study cornerstone on natural bioactive compounds with their effect on hepatocarcinomas. Furthermore, we focus on oxidative stress and FDA-approved signaling pathway inhibitors, along with chemotherapy and radiotherapy enhancers which with early evidence of success. While more in vivo testing is required to confirm the findings presented here, our findings will aid future nonclinical, preclinical, and clinical studies with these compounds, as well as inspire medicinal chemistry scientists to conduct appropriate research on this promising natural compound and their derivatives.
... Our results show that linalool, the main component of two essential oils, has a stronger cytotoxic activity against SH-SY5Y cells, with 92% cell death after a treatment with 800 µg/mL for 24 h. Ravizza and coworkers [32] demonstrated that linalool possesses antiproliferative effects against two human breast adenocarcinoma cell lines (MCF7 WT and MCF7 AdrR), and Sun and coworkers [33] reported similar results in human prostate cancer cells (DU145), at concentrations of 50 and 80 µM, respectively. ...
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The aims of this study are to determine the chemical composition of Lavandula angustifolia Mill. and Coriandrum sativum L. essential oils, to evaluate their cytotoxic effects in SH-SY5Y human neuroblastoma cells, to investigate whether an alteration of adenylate cyclase 1 (ADCY1) and of extracellular signal-regulated kinase (ERK) expression can take part in the molecular mechanisms of the essential oils, and to study their possible neuronal electrophysiological effects. The essential oils were obtained by hydrodistillation, and studied by GC and GC-MS. In the oils from L. angustifolia and C. sativum, linalool was the main component (33.1% and 67.8%, respectively). SH-SY5Y cells were incubated with different concentrations of essential oils and of linalool. Cell viability and effects on ADCY1 and ERK expression were analyzed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide MTT and Western blotting, respectively. Variation in cellular electrophysiology was studied in primary cultures of rat cortical neurons with a multi-electrode array (MEA)-based approach. The essential oils and linalool revealed different cytotoxic activities. Linalool inhibited ADCY1 and ERK expression. Neuronal networks subjected to L. angustifolia and C. sativum essential oils showed a concentration-dependent inhibition of spontaneous electrical activity.
... Using an in vitro cell culture assay, Cherng and colleagues also demonstrated anti-proliferative activity of linalool towards bladder (J82), lung (H661 and H520), cervix (HeLa), stomach (AGS), skin (BCC-1/KMC), bone (U2OS), mouth (OSCC-1/KMC), and kidney (RTCC-1/KMC) carcinoma cell lines [54]. Furthermore, linalool treatment was also found able to suppress the growth of breast (T-47D), colorectal (SW620), liver (Hep G2), lung (A549), and prostate (DU145, 22Rv1) cancer cell lines [55][56][57]. In addition to M. alba, linalool is also found present in several other plants. ...
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... Linalool, the major alcohol in leaf oil (23.25 %), could be responsible for the oil's strong cytotoxic activity, where it was previously reported to have a potent cytotoxic effect against human prostate cancer (DU145) cells 30 , leukemia cells, cervical cancer cells 31 and breast carcinoma 32 . In addition, terpinen-4-ol, present at 8.33 % in the leaf oil, was also previously reported to have cytotoxic effects against colorectal, pancreatic, prostate and gastric cancer cells 33 , lung cancer cells 34 and human M14 melanoma cells 35 . ...
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The use of complementary and alternative medicine (CAM) has been used since antiquity for the relief of symptoms related to many diseases including urologic ailments. CAM is typically defined as those healing philsophies, approaches and therapies that are generally not taught in medical schools and are not usually reimbursed by medical insurance companies. Complementary and alternative medicine therapies are distinguished as those used alone (alternative) or in addition to conventional therapies (complementary). Few studies have focused on the urologic population. In this article, we summarize recent studies assessing the prevalence rate of CAM use with special emphasis in prostate cancer patients.
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Prostate cancer mortality rates in the United States declined sharply after 1991 in white men and declined after 1992 in black men. The current study was conducted to investigate possible mechanisms for the declining prostate cancer mortality rates in the United States. The authors examined and compared patterns of prostate cancer incidence, survival rates, and mortality rates among black men and white men in the United States using the 1969-1999 U.S. prostate cancer mortality rates and the 1975-1999 prostate cancer incidence, survival, and incidence-based mortality rates from the Surveillance, Epidemiology, and End Results (SEER) Program for the U.S. population. The SEER data represent approximately 10% of the U.S. population. Prostate cancer incidence and mortality rates showed transient increases after 1986, when the U.S. Food and Drug Administration approved the use of prostate specific antigen (PSA) testing. The age-adjusted prostate cancer mortality rates for men age 50-84 years, however, have dropped below the rate in 1986 since 1995 for white men and since 1997 for black men. In fact, for white men ages 50-79 years, the 1998 and 1999 rates were the lowest observed since 1950. Incidence-based mortality rates by disease stage revealed that the recent declines were due to declines in distant disease mortality. Moreover, the decrease in distant disease mortality was due to a decline in distant disease incidence, and not to improved survival of patients with distant disease. Similar incidence, survival, and mortality rate patterns are seen in black men and white men in the United States, although with differences in the timing and magnitude of recent rate decreases. Increased detection of prostate cancer before it becomes metastatic, possibly reflecting increased use of PSA testing after 1986, may explain much of the recent mortality decrease in both white men and black men.
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This review is an updated and expanded version of a paper that was published in this journal in 1997. The time frame has been extended in both directions to include the 22 years from 1981 to 2002, and a new secondary subdivision related to the natural product source but applied to formally synthetic compounds has been introduced, using the concept of a "natural product mimic" or "NM" to join the original primary divisions. From the data presented, the utility of natural products as sources of novel structures, but not necessarily the final drug entity, is still alive and well. Thus, in the area of cancer, the percentage of small molecule, new chemical entities that are nonsynthetic has remained at 62% averaged over the whole time frame. In other areas, the influence of natural product structures is quite marked, particularly in the antihypertensive area, where of the 74 formally synthetic drugs, 48 can be traced to natural product structures/mimics. Similarly, with the 10 antimigraine drugs, seven are based on the serotonin molecule or derivatives thereof. Finally, although combinatorial techniques have succeeded as methods of optimizing structures and have, in fact, been used in the optimization of a number of recently approved agents, we have not been able to identify a de novo combinatorial compound approved as a drug in this time frame.
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