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Chitang Ho - One of the best experts on this subject based on the ideXlab platform.
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a stable quinone identified in the reaction of Carnosol a major antioxidant in rosemary with 2 2 diphenyl 1 picrylhydrazyl radical
Food Chemistry, 2006Co-Authors: Chitang HoAbstract:Carnosol is known as a major antioxidant in rosemary (Rosmarinus officinalis L.). The reaction of Carnosol with 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical was carried out and a novel product was identified as a quinine of Carnosol, carnosylquinone. A mechanism for the Carnosol-DPPH reaction is proposed.
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Carnosol inhibits the invasion of b16 f10 mouse melanoma cells by suppressing metalloproteinase 9 through down regulating nuclear factor kappab and c jun
Biochemical Pharmacology, 2005Co-Authors: Shiu Chen Huang, Chitang Ho, Shoeiyn LinshiauAbstract:Abstract Carnosol, a constant constituent of Rosmarinus officinalis extracts, is a phenolic diterpene shown to have antioxidant and anticarcinogen properties. In our studies, Carnosol inhibited the invasion of highly metastatic mouse melanoma B16/F10 cells in vitro. First, the antimetastatic potentials of Carnosol were examined by soft agar colony formation assay. Second, Carnosol dose-dependently inhibited B16/F10 cell migration and invasion by in vitro transwell assay. Third, the decreasing activity of metalloproteinase was observed by zymographic assay. The result revealed that the treatment of Carnosol could diminish the activity of MMP-9 more than MMP-2. Next, we analyzed the amounts of MMP-9 and MMP-2 proteins in the cells. The data indicated MMP-9 protein was also suppressed by Carnosol in the same manner. In accordance with the above data, the results of reverse transcriptase polymerase chain reaction (RT–PCR) analysis showed a reduced level of MMP-9 mRNA. Furthermore, Carnosol significantly inhibited the tyrosine phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, AKT, p38, JNK and inhibition of activation of transcription factors NFκ-B and c-Jun. These results lead us to conclude that Carnosol could restrict the invasive ability of B16/F10 mouse melanoma cells by reducing MMP-9 expression and activity through suppressing (ERK) 1/2, AKT, p38, and JNK signaling pathway and inhibition of NF-κB and AP-1 binding activity. Taken together, these results indicate that Carnosol targets MMP-mediated cellular events in cancer cells and provides a new mechanism for its anticancer activity.
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Carnosol inhibits the invasion of B16/F10 mouse melanoma cells by suppressing metalloproteinase-9 through down-regulating nuclear factor-kappaB and c-Jun
Biochemical Pharmacology, 2004Co-Authors: Shiu Chen Huang, Chitang Ho, Shoei-yn Lin-shiauAbstract:Abstract Carnosol, a constant constituent of Rosmarinus officinalis extracts, is a phenolic diterpene shown to have antioxidant and anticarcinogen properties. In our studies, Carnosol inhibited the invasion of highly metastatic mouse melanoma B16/F10 cells in vitro. First, the antimetastatic potentials of Carnosol were examined by soft agar colony formation assay. Second, Carnosol dose-dependently inhibited B16/F10 cell migration and invasion by in vitro transwell assay. Third, the decreasing activity of metalloproteinase was observed by zymographic assay. The result revealed that the treatment of Carnosol could diminish the activity of MMP-9 more than MMP-2. Next, we analyzed the amounts of MMP-9 and MMP-2 proteins in the cells. The data indicated MMP-9 protein was also suppressed by Carnosol in the same manner. In accordance with the above data, the results of reverse transcriptase polymerase chain reaction (RT–PCR) analysis showed a reduced level of MMP-9 mRNA. Furthermore, Carnosol significantly inhibited the tyrosine phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, AKT, p38, JNK and inhibition of activation of transcription factors NFκ-B and c-Jun. These results lead us to conclude that Carnosol could restrict the invasive ability of B16/F10 mouse melanoma cells by reducing MMP-9 expression and activity through suppressing (ERK) 1/2, AKT, p38, and JNK signaling pathway and inhibition of NF-κB and AP-1 binding activity. Taken together, these results indicate that Carnosol targets MMP-mediated cellular events in cancer cells and provides a new mechanism for its anticancer activity.
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Carnosol an antioxidant in rosemary suppresses inducible nitric oxide synthase through down regulating nuclear factor κb in mouse macrophages
Carcinogenesis, 2002Co-Authors: Ai Hsiang Lo, Yu Chih Liang, Shoeiyn Linshiau, Chitang HoAbstract:Carnosol is a naturally occurring phytopolyphenol found in rosemary. Carnosol functions as antioxidant and anticarcinogen. In the present study, we compared the antioxidant activity of Carnosol and other compounds extracted from rosemary. Carnosol showed potent antioxidative activity in α,α-diphenyl-β-picrylhydrazyl (DPPH) free radicals scavenge and DNA protection from Fenton reaction. High concentrations of nitric oxide (NO) are produced by inducible NO synthase (iNOS) in inflammation and multiple stages of carcinogenesis. Treatment of mouse macrophage RAW 264.7 cell line with Carnosol markly reduced lipopolysaccharide (LPS)-stimulated NO production in a concentration-related manner with an IC50 of 9.4 µM; but other tested compounds had slight effects. Western blot, reverse transcription‐polymerase chain reaction, and northern blot analyses demonstrated that Carnosol decreased LPS-induced iNOS mRNA and protein expression. Carnosol treatment showed reduction of nuclear factor-κB (NF-κB) subunits translocation and NF-κB DNA binding activity in activated macrophages. Carnosol also showed inhibition of iNOS and NF-κB promoter activity in transient transfection assay. These activities were referred to down-regulation of inhibitor κ B( IκB) kinase (IKK) activity by Carnosol (5 µM), thus inhibited LPSinduced phosphorylation as well as degradation of IκBα. Carnosol also inhibited LPS-induced p38 and p44/42 mitogen-activated protein kinase (MAPK) activation at a higher concentration (20 µM). These results suggest that Carnosol suppresses the NO production and iNOS gene expression by inhibiting NF-κB activation, and provide possible mechanisms for its anti-inflammatory and chemopreventive action.
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identification of thermal decomposition products of Carnosol an antioxidant in rosemary and sage
Journal of Food Lipids, 1999Co-Authors: Mingfu Wang, Robert T Rosen, Chitang HoAbstract:Carnosol, an antioxidant isolated from rosemary, was thermally decomposed at 180C in a fat-like paraffin medium. Two known antioxidative quinones were isolated and identified as decomposition products. They are miltirone and dehydrorosmariquinone.
Tahereh Farkhondeh - One of the best experts on this subject based on the ideXlab platform.
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Protective effects of Carnosol against oxidative stress induced brain damage by chronic stress in rats
BMC Complementary and Alternative Medicine, 2017Co-Authors: Saeed Samarghandian, Abasalt Borji, Mohammad Samini, Mohsen Azimi-nezhad, Tahereh FarkhondehAbstract:Oxidative stress through chronic stress destroys the brain function. There are many documents have shown that Carnosol may have a therapeutic effect versus free radical induced diseases. The current research focused the protective effect of Carnosol against the brain injury induced by the restraint stress. The restraint stress induced by keeping animals in restrainers for 21 consecutive days. Thereafter, the rats were injected Carnosol or vehicle for 21 consecutive days. At the end of experiment, all the rats were subjected to his open field test and forced swimming test. Afterwards, the rats were sacrificed for measuring their oxidative stress parameters. To measure the modifications in the biochemical aspects after the experiment, the activities of malondialdehyde (MDA), reduced glutathione (GSH), as well as superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR) and catalase (CAT) were evaluated in the whole brain. Our data showed that the animals received chronic stress had a raised immobility time versus the non-stressed animals (p
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protective effects of Carnosol against oxidative stress induced brain damage by chronic stress in rats
BMC Complementary and Alternative Medicine, 2017Co-Authors: Saeed Samarghandian, Mohsen Aziminezhad, Abasalt Borji, Mohammad Samini, Tahereh FarkhondehAbstract:Oxidative stress through chronic stress destroys the brain function. There are many documents have shown that Carnosol may have a therapeutic effect versus free radical induced diseases. The current research focused the protective effect of Carnosol against the brain injury induced by the restraint stress. The restraint stress induced by keeping animals in restrainers for 21 consecutive days. Thereafter, the rats were injected Carnosol or vehicle for 21 consecutive days. At the end of experiment, all the rats were subjected to his open field test and forced swimming test. Afterwards, the rats were sacrificed for measuring their oxidative stress parameters. To measure the modifications in the biochemical aspects after the experiment, the activities of malondialdehyde (MDA), reduced glutathione (GSH), as well as superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR) and catalase (CAT) were evaluated in the whole brain. Our data showed that the animals received chronic stress had a raised immobility time versus the non-stressed animals (p < 0.01). Furthermore, chronic stress diminished the number of crossing in the animals that were subjected to the chronic stress versus the non-stressed rats (p < 0.01). Carnosol ameliorated this alteration versus the non-treated rats (p < 0.05). In the vehicle treated rats that submitted to the stress, the level of MDA levels was significantly increased (P < 0.001), and the levels of GSH and antioxidant enzymes were significantly decreased versus the non-stressed animals (P < 0.001). Carnosol treatment reduced the modifications in the stressed animals as compared with the control groups (P < 0.001). All of these Carnosol effects were nearly similar to those observed with fluoxetine. The current research shows that the protective effects of Carnosol may be accompanied with enhanced antioxidant defenses and decreased oxidative injury.
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anti carcinogenic effects of Carnosol an updated review
Current Drug Discovery Technologies, 2017Co-Authors: Saeed Samarghandian, Mohsen Aziminezahad, Tahereh FarkhondehAbstract:Background: Despite the newly treatment procedures, cancer is considered as the main health threat nowadays and, therefore, new therapeutic options such as traditional medicine should be investigated. Rosemary (Rosmarinus officinalis L.) has been found to possess antitumor effects due to its major ingredients, including carnosic acid, Carnosol, ursolic acid, and rosmarinic acid. Objective: This study was designed to gather the recent literature findings from 2010 to 2016 on the cancer anti-tumor activities of Carnosol and probably involved mechanisms. Method: The online English papers were gathered through the various search websites, including PubMed, Iran Medex, Medline, Google Scholar, and Scopus from 2010 to 2016. Results: Carnosol, the specific composition of rosemary, has been shown to have beneficial effects in keeping humans healthy and may be acted as an antitumor agent. Conclusion: This review revealed that Carnosol may be effective as an anti-tumor agent in the different types of cancer by inducing apoptosis and inhibiting the cell cycle division. However, more studies are needed to confirm Carnosol therapeutic effects in human.
Andrew J Dannenberg - One of the best experts on this subject based on the ideXlab platform.
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Carnosol a constituent of zyflamend inhibits aryl hydrocarbon receptor mediated activation of cyp1a1 and cyp1b1 transcription and mutagenesis
Cancer Prevention Research, 2012Co-Authors: Arash Mohebati, Joseph B Guttenplan, Amit Kochhar, Zhong Lin Zhao, Wieslawa Kosinska, Kotha Subbaramaiah, Andrew J DannenbergAbstract:The aryl hydrocarbon receptor (AhR), a ligand-activated member of the basic-helix-loop-helix family of transcription factors, plays a significant role in polycyclic aromatic hydrocarbon (PAH) induced carcinogenesis. In the upper aerodigestive tract of humans, tobacco smoke, a source of PAHs, activates the AhR leading to increased expression of CYP1A1 and CYP1B1, which encode proteins that convert PAHs to genotoxic metabolites. Inhibitors of Hsp90 ATPase cause a rapid decrease in levels of AhR, an Hsp90 client protein, and thereby block PAH-mediated induction of CYP1A1 and CYP1B1. The main objective of this study was to determine whether Zyflamend, a polyherbal preparation, suppressed PAH-mediated induction of CYP1A1 and CYP1B1 and inhibited DNA adduct formation and mutagenesis. We also investigated whether Carnosol, one of multiple phenolic antioxidants in Zyflamend, had similar inhibitory effects. Treatment of cell lines derived from oral leukoplakia (MSK-Leuk1) and skin (HaCaT) with benzo[a]pyrene (B[a]P), a prototypic PAH, induced CYP1A1 and CYP1B1 transcription, resulting in enhanced levels of message and protein. Both Zyflamend and Carnosol suppressed these effects of B[a]P. Notably, both Zyflamend and Carnosol inhibited Hsp90 ATPase activity and caused a rapid reduction in AhR levels. The formation of B[a]P induced DNA adducts and mutagenesis were also inhibited by Zyflamend and Carnosol. Collectively, these results show that Zyflamend and Carnosol inhibit Hsp90 ATPase leading to reduced levels of AhR, suppression of B[a]P-mediated induction of CYP1A1 and CYP1B1 and inhibition of mutagenesis. Carnosol-mediated inhibition of Hsp90 ATPase activity can help explain the chemopreventive activity of herbs such as Rosemary, which contain this phenolic antioxidant.
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retinoids and Carnosol suppress cyclooxygenase 2 transcription by creb binding protein p300 dependent and independent mechanisms
Cancer Research, 2002Co-Authors: Kotha Subbaramaiah, Philip A Cole, Andrew J DannenbergAbstract:Treatment with retinoic acid (RA) or Carnosol, two structurally unrelated compounds with anticancerproperties, inhibited phorbol ester (PMA)-mediated induction of activator protein-1 (AP-1) activity and cyclooxygenase-2 (COX-2) expression in human mammary epithelial cells. The induction of COX-2 transcription by PMA was mediated by increased binding of AP-1 to the cyclic AMP response element (CRE) of the COX-2 promoter. Inhibition of the histone acetyltransferase activity of CREB- binding protein (CBP)/p300 blocked the induction of COX-2 by PMA. Treatment with Carnosol but not RA blocked increased binding of AP-1 to the COX-2 promoter. Because AP-1 binding was unaffected by RA, we investigated whether RA inhibited COX-2 transcription via effects on the coactivator CBP/p300. Treatment with RA stimulated an interaction between RA receptor-α and CBP/p300; a corresponding decrease in the interaction between CBP/p300 and c-Jun was observed. Importantly, overexpressing CBP/p300 or dominant-negative RA receptor-α relieved the suppressive effect of RA on PMA-mediated stimulation of the COX-2 promoter. To elucidate the mechanism by which Carnosol inhibited COX-2 transcription, its effects on protein kinase C (PKC) signaling were determined. Carnosol but not RA inhibited the activation of PKC, ERK1/2, p38, and c-Jun NH2-terminal kinase mitogen-activated protein kinase. Overexpressing c-Jun but not CBP/p300 reversed the suppressive effect of Carnosol on PMA-mediated stimulation of COX-2 promoter activity. Thus, RA acted by a receptor-dependent mechanism to limit the amount of CBP/p300 that was available for AP-1-mediated induction of COX-2. By contrast, Carnosol inhibited the induction of COX-2 by blocking PKC signaling and thereby the binding of AP-1 to the CRE of the COX-2 promoter. Taken together, these results show that small molecules can block the activation of COX-2 transcription by distinct mechanisms.
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Retinoids and Carnosol Suppress Cyclooxygenase-2 Transcription by CREB-binding Protein/p300-dependent and -independent Mechanisms
Cancer Research, 2002Co-Authors: Kotha Subbaramaiah, Philip A Cole, Andrew J DannenbergAbstract:Treatment with retinoic acid (RA) or Carnosol, two structurally unrelated compounds with anticancerproperties, inhibited phorbol ester (PMA)-mediated induction of activator protein-1 (AP-1) activity and cyclooxygenase-2 (COX-2) expression in human mammary epithelial cells. The induction of COX-2 transcription by PMA was mediated by increased binding of AP-1 to the cyclic AMP response element (CRE) of the COX-2 promoter. Inhibition of the histone acetyltransferase activity of CREB- binding protein (CBP)/p300 blocked the induction of COX-2 by PMA. Treatment with Carnosol but not RA blocked increased binding of AP-1 to the COX-2 promoter. Because AP-1 binding was unaffected by RA, we investigated whether RA inhibited COX-2 transcription via effects on the coactivator CBP/p300. Treatment with RA stimulated an interaction between RA receptor-α and CBP/p300; a corresponding decrease in the interaction between CBP/p300 and c-Jun was observed. Importantly, overexpressing CBP/p300 or dominant-negative RA receptor-α relieved the suppressive effect of RA on PMA-mediated stimulation of the COX-2 promoter. To elucidate the mechanism by which Carnosol inhibited COX-2 transcription, its effects on protein kinase C (PKC) signaling were determined. Carnosol but not RA inhibited the activation of PKC, ERK1/2, p38, and c-Jun NH2-terminal kinase mitogen-activated protein kinase. Overexpressing c-Jun but not CBP/p300 reversed the suppressive effect of Carnosol on PMA-mediated stimulation of COX-2 promoter activity. Thus, RA acted by a receptor-dependent mechanism to limit the amount of CBP/p300 that was available for AP-1-mediated induction of COX-2. By contrast, Carnosol inhibited the induction of COX-2 by blocking PKC signaling and thereby the binding of AP-1 to the CRE of the COX-2 promoter. Taken together, these results show that small molecules can block the activation of COX-2 transcription by distinct mechanisms.
Jeremy J Johnson - One of the best experts on this subject based on the ideXlab platform.
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Carnosol a dietary diterpene from rosemary rosmarinus officinalis activates nrf2 leading to sestrin 2 induction in colon cells
Integrative molecular medicine, 2018Co-Authors: Bhaskar Vemu, Jacob P Veenstra, Sakina M Petiwala, Jeremy J JohnsonAbstract:Background: Rosemary is abundant with phytochemicals and has recently been approved as an antioxidant food preservative in the European Union. The safety of rosemary is well established, however, the benefits on gastrointestinal health are less known. Our overall hypothesis is that the phytochemicals in rosemary including Carnosol have the potential to promote gastrointestinal health by activation of the antioxidant sestrin-2 when consumed in our diet. Methods: Colon cells HCT116 and SW480 were treated with Carnosol and evaluated by MTT, immunofluorescence, ELISA, and Western blot analysis to understand the modulation of the PERK/Nrf2/Sestrin-2 pathway. Results: Carnosol was found to modulate PERK and increase the concentration of nuclear Nrf2. Furthermore, a downstream marker of Nrf2 expression, Sestrin-2 was shown to be upregulated. Conclusion: Based on these observations Carnosol modulates the PERK and Nrf2 pathways along with increased expression of sestrin-2, a known stress inducible antioxidant.
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abstract 2573 Carnosol and carnosic acid from rosemary promote endoplasmic reticulum stress and androgen receptor degradation in prostate cancer cells
Cancer Research, 2012Co-Authors: Sakina M Petiwala, Gongbo Li, Jeremy J JohnsonAbstract:Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Background: Prostate cancer is one of the most prevalent forms of cancer among men, especially in the United States. Previously, we have shown that Carnosol, a dietary diterpene from rosemary (Rosmarinus officinalis), has a unique function in that it is a dual disruptor of androgen and estrogen receptor alpha. Herein, we examined how Carnosol and another dietary diterpene from rosemary, carnosic acid, promote endoplasmic reticulum (ER) stress and modulate the activity and expression of androgen receptor (AR). Materials and Methods: Experiments were performed using the prostate cancer cell lines 22Rv1 and LNCaP cells. Cell proliferation and cell viability were studied using BrdU and MTT assay respectively. Western blotting, ELISA and siRNA were used to evaluate the relationship between ER stress and androgen receptor degradation. Results: Both, carnosic acid and Carnosol, inhibited growth and decreased the cell viability of 22Rv1 and LNCaP cells in a dose-dependent manner. The anti-proliferative effect was associated with apoptosis as evidenced by a significant increase in levels of cleaved caspase-3 protein. Interestingly, these diterpenes modulated proteins associated with ER stress including BiP, IRE1 and CHOP. Furthermore, we saw a dose-dependent decrease in expression of AR in 22Rv1 and LNCaP cells when treated with either Carnosol or carnosic acid. The proteasome has been shown to be regulated by multiple proteins including proteins associated with ER stress. The AR expression increased in presence of proteasome inhibitor, MG-132, suggesting that decrease in AR expression was due to proteasomal degradation. Carnosic acid and Carnosol, also showed a decrease in expression of prostate-specific antigen (PSA) levels in a dose-dependent manner. Conclusion: Both, carnosic acid and Carnosol, induce ER stress-mediated apoptotic cell death in prostate cancer cell lines, 22Rv1and LNCaP cells, leading to disruption of AR expression. Our data suggests that these natural diterpenes possess strong anticancer activity and should be evaluated further as potential chemopreventive and/or chemotherapeutic agents for controlling prostate cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2573. doi:1538-7445.AM2012-2573
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disruption of androgen and estrogen receptor activity in prostate cancer by a novel dietary diterpene Carnosol implications for chemoprevention
Cancer Prevention Research, 2010Co-Authors: Jeremy J Johnson, Deeba N Syed, Chenelle R Heren, Mohammad Saleem, Imtiaz A Siddiqui, Hasan MukhtarAbstract:Emerging data are suggesting that estrogens, in addition to androgens, may also be contributing to the development of prostate cancer (PCa). In view of this notion, agents that target estrogens, in addition to androgens, may be a novel approach for PCa chemoprevention and treatment. Thus, the identification and development of nontoxic dietary agents capable of disrupting androgen receptor (AR) in addition to estrogen receptor (ER) could be extremely useful in the management of PCa. Through molecular modeling, we found that Carnosol, a dietary diterpene, fits within the ligand-binding domain of both AR and ER-α. Using a time-resolved fluorescence resonance energy transfer assay, we found that Carnosol interacts with both AR and ER-α and additional experiments confirmed that it functions as a receptor antagonist with no agonist effects. LNCaP, 22Rv1, and MCF7 cells treated with Carnosol (20-40 μmol/L) showed decreased protein expression of AR and ER-α. Oral administration of Carnosol at 30 mg/kg 5 days weekly for 28 days to 22Rv1 PCa xenografted mice suppressed tumor growth by 36% ( P = 0.028) and was associated with a decrease in serum prostate-specific antigen by 26% ( P = 0.0042). These properties make Carnosol unique to any known antiandrogen or antiestrogen investigated thus far for the simultaneous disruption of AR and ER-α. We suggest that Carnosol may be developed or chemically modified through more rigorous structure-activity relationship studies for a new class of investigational agents—a dual AR/ER modulator. Cancer Prev Res; 3(9); 1112–23. ©2010 AACR.
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abstract a44 Carnosol a dietary diterpene functions as a dual ar and er alpha antagonist in prostate cancer
Cancer Prevention Research, 2008Co-Authors: Jeremy J Johnson, Deeba N Syed, Chenelle R Heren, Imtiaz A Siddiqui, Hasan MukhtarAbstract:A44 Emerging evidence suggest that androgens may not be the only hormone responsible for the etiology of prostate cancer (PCa). Recent data has suggested that estrogens may be another important piece to the PCa puzzle. For example the use of the Selective Estrogen Receptor Modulator (SERM) toremifene in HG-PIN patients for one year resulted in a 21% reduction in the conversion of HG-PIN to PCa after one year of treatment. It is well established that race correlates with the levels of androgens with African Americans having the highest, followed by Caucasians and lowest in Japanese males. A similar trend has been observed in regard to serum estrogen levels and it is noteworthy that with age estrogen levels remain constant while androgens levels decrease. Given that experimental animal models suggest that both estrogens and androgens are necessary for PCa development it may be a reasonable approach to simultaneously disrupt both androgen and estrogen signaling in PCa. Several SERMs that include tamoxifen, toremifine, and fulvestrant have been evaluated for their ability to also target the AR and function as a dual AR and ER antagonist, however, experiments have suggested these effects are saturable and in some instances SERMs exert AR agonist properties. In our quest to find a dual AR and ER antagonist present in dietary substances that humans consume we found that the dietary diterpene Carnosol displays growth inhibitory properties in the hormone sensitive prostate (LNCaP and CWR22Rv1) and breast (MCF7 and AU565) cancer cell lines. Given the structural similarity between Carnosol to dihydrotestosterone and estradiol we hypothesized that it may interact with both the androgen and estrogen receptor alpha (ER-α). Using a TR-FRET cell free biochemical assay we found that Carnosol can interact with both AR and ER-alpha with similar potencies. Next, we evaluated the antagonist and agonist properties of Carnosol using a functional assay where the AR and ER-alpha ligand binding domains are expressed as a fusion protein in HEK293 cells. We observed that Carnosol exhibits antagonist properties that are dose responsive and even more interestingly, regardless of dose, did not exert agonist properties. In LNCaP, CWR22Rv1, and MCF7 cells Carnosol was found to disrupt both androgen and estrogen signaling in a dose and time dependent manner. Our finding that Carnosol displays the ability to disrupt both androgen and estrogen signaling simultaneously suggesting that Carnosol may be developed or chemically modified through more rigorous structure activity relationship studies of other such chemical entities for a new class of investigational agents - a dual AR/ER modulator. Citation Information: Cancer Prev Res 2008;1(7 Suppl):A44.
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Carnosol a dietary diterpene displays growth inhibitory effects leading to g1 phase cell cycle arrest and targets the 5 amp activated protein kinase ampk pathway in human prostate cancer pc3 cells
Cancer Research, 2008Co-Authors: Jeremy J Johnson, Deeba N Syed, Vaqar M Adhami, Hasan MukhtarAbstract:AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA 3813 Prostate cancer (PCa) will be diagnosed in 218,890 males in the United States in 2007 and unfortunately, there are limited options for the successful management of this disease. Recently, there have been considerable activities directed toward the identification of dietary agents for both chemoprevention and the treatment of PCa. Carnosol, a dietary diterpene found in herbs that include basil, oregano, and sage, has been shown to display potent antioxidant properties. Additionally, traditional Chinese medicine uses rosemary extracts that contain high amounts of diterpenes and triterpenes to treat inflammatory conditions. Here, we evaluated Carnosol for its potential anti-cancer properties in the human PCa PC3 cells. Using an MTT assay we found that Carnosol (10 - 70 µM) decreases cell viability in a time and dose dependent manner. Next, we determined whether the decrease in cell viability was due to the induction of apoptosis and/or cell cycle arrest. We evaluated the effect of Carnosol (20-60 uM) using flow cytometry and found that it induces G1-phase cell cycle arrest with limited proapoptotic effect. Cell cycle and apoptosis related proteins that were found to be modulated with Carnosol included cyclins, cyclin dependent kinases, p21, Bax, and Bcl-2. To establish a more precise mechanism, we performed a protein array that evaluated 639 proteins involved in cell signaling pathways. A target of interest was identified as 5'-AMP-activated protein kinase (AMPK), a serine/threonine protein kinase involved in the regulation of energy balance of a cell. Significant upregulation of AMPK over a 48 hour period in PC3 cells treated with Carnosol (40 µM) was observed. The role of AMPK has been studied in cardiovascular disease and metabolic disorders and shown to regulate fatty acid synthase and HMG-CoA reductase. It has been suggested that AMPK has an important role in carcinogenesis and should be considered as a novel target for anti-cancer drugs. We found that Carnosol induces the upregulation of AMPK-β regulatory subunit having downstream effects consistent with cancer inhibition. As a result we are evaluating the role of Carnosol in upregulating AMPK to modulate and interact with pathways directly or indirectly that include PTEN/PI3K/AKT and TSC2/mTOR/HSP70S6k1. Carnosol may be a novel dietary diterpene for the management of PCa.
Rabah Iratni - One of the best experts on this subject based on the ideXlab platform.
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Carnosol a natural polyphenol inhibits migration metastasis and tumor growth of breast cancer via a ros dependent proteasome degradation of stat3
Frontiers in Oncology, 2019Co-Authors: Halima Alsamri, Samir Attoub, Hussain El Hasasna, Yusra Al Dhaheri, Rabah IratniAbstract:We have previously demonstrated that Carnosol, a natural compound, inhibited in vitro cell viability and colony growth, induced cell cycle arrest, autophagy and apoptosis in human triple negative breast cancer (TNBC) cells. In the present study, we evaluated the ability of Carnosol to inhibit tumor growth and metastasis in vivo. We found that non-cytotoxic concentrations of Carnosol inhibited the migration and the invasion of MDA-MB-231 cells in wound healing and matrigel invasion assays. Gelatin zymography, ELISA, and RT-PCR assay revealed that Carnosol inhibited the activity and downregulation the expression of MMP-9. Mechanistically, we demonstrated that Carnosol suppressed the activation of STAT3 signaling pathway through a ROS-dependent targeting of STAT3 protein to proteasome-degradation in breast cancer (MDA-MB-231, Hs578T, MCF-7 and T47D) but not in colon cancer cells. We show that blockade of proteasome activity, by MG-132 and bortezomib, and ROS accumulation, by N-acetylcysteine, restored the level of STAT3 protein. In addition, using chick embryo tumor growth assay, we showed that Carnosol significantly and markedly suppressed, in vivo, tumor growth and metastasis of breast cancer xenografts. To the best of our knowledge, we show for the first time that Carnosol specifically target STAT3 for proteasome degradation in breast cancer. Our study further provide evidence that Carnosol may represent a promising therapeutic candidate that modulate breast cancer growth and metastasis.
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Carnosol induces ros mediated beclin1 independent autophagy and apoptosis in triple negative breast cancer
PLOS ONE, 2014Co-Authors: Yusra Al Dhaheri, Samir Attoub, Kholoud Arafat, Gaber A Ramadan, Khuloud Bajbouj, Noushad Karuvantevida, Synan Abuqamar, Rabah IratniAbstract:Background In this study we investigated the in vitro and in vivo anticancer effect of Carnosol, a naturally occurring polyphenol, in triple negative breast cancer. Results We found that Carnosol significantly inhibited the viability and colony growth induced G2 arrest in the triple negative MDA-MB-231. Blockade of the cell cycle was associated with increased p21/WAF1 expression and downregulation of p27. Interestingly, Carnosol was found to induce beclin1-independent autophagy and apoptosis in MDA-MB-231 cells. The coexistence of both events, autophagy and apoptosis, was confirmed by electron micrography. Induction of autophagy was found to be an early event, detected within 3 h post-treatment, which subsequently led to apoptosis. Carnosol treatment also caused a dose-dependent increase in the levels of phosphorylated extracellular signal-regulated kinase 1 and 2 (pERK1/2). Moreover, we show that Carnosol induced DNA damage, reduced the mitochondrial potential and triggered the activation of the intrinsic and extrinsic apoptotic pathway. Furthermore, we found that Carnosol induced a dose-dependent generation of reactive oxygen species (ROS) and inhibition of ROS by tiron, a ROS scavenger, blocked the induction of autophagy and apoptosis and attenuated DNA damage. To our knowledge, this is the first report to identify the induction of autophagy by Carnosol. Conclusion In conclusion our findings provide strong evidence that Carnosol may be an alternative therapeutic candidate against the aggressive form of breast cancer and hence deserves more exploration.
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p0174 anti metastatic and anti tumour growth effects of Carnosol on breast cancer through autophagy and apoptosis
European Journal of Cancer, 2014Co-Authors: Rabah Iratni, Al Y Dhaheri, Samir Attoub, N Karuventevida, Kholoud ArafatAbstract:Background The aim of this study was to investigate the effect of Carnosol, a naturally occurring polyphenol found in rosemary, on the viability, migration, invasion, and tumour growth of the triple-negative human breast cancer cell line MDA-MB-231. Methods Antiproliferative effects of Carnosol were measured with a cell viability kit (Millipore). Autophagy was determined by transmission electronic microscopy, acidic vesicular formation, and increased accumulation of LC3-II. Apoptosis was assessed by annexin V, caspase 3, 8 and 9, and PARP cleavage. Wound-healing assay and invasion matrigel assays were used to assess the anti-migration and anti-invasion potential of Carnosol. MMP-9 activity was measured using gelatin zymography. A chick embryo chorioallantoic tumour growth assay was used for in vivo tumour growth and metastasis experiments. Findings Carnosol was able to inhibit the viability of the MDA-MB-231 cells in a time- and dose- dependent manner and induce G2 cell cycle arrest. Carnosol induced autophagy followed by apoptotic cell death in the MDA-MB-231 cell lines. Carnosol induced a dose-dependent accumulation of reactive oxygen species. Abrogation of reactive oxygen species by tiron, a reactive oxygen species scavenger, dramatically reduced both apoptosis and autophagy. Carnosol treated-cells exhibited histone H3 and H4 hypoacetylation associated with downregulation of two histone acetyl transferases, p300 and PCAF. Furthermore, non-cytotoxic concentrations of Carnosol significantly inhibited the migration and invasion of MDA-MB-231 cells and decreased the activities of matrix metalloproteinase-9. Carnosol inhibited tumour growth and metastasis in vivo. Carnosol targeted pSTAT3, TNF-α, and DAPK. Interpretation Carnosol exerts its anti-breast cancer effects through multiple targets, including histone modifications, autophagy, and apoptosis. Hence, Carnosol has potential to be a new anticancer drug against breast cancer.