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Hanming She - One of the best experts on this subject based on the ideXlab platform.
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Luteolin a flavonoid with potential for cancer prevention and therapy
Current Cancer Drug Targets, 2008Co-Authors: Ranxi Shi, Xia Wang, Hanming SheAbstract:Luteolin, 3′,4′,5,7-tetrahydroxyflavone, is a common flavonoid that exists in many types of plants including fruits, vegetables, and medicinal herbs. Plants rich in Luteolin have been used in Chinese traditional medicine for treating various diseases such as hypertension, inflammatory disorders, and cancer. Having multiple biological effects such as anti-inflammation, anti-allergy and anticancer, Luteolin functions as either an antioxidant or a pro-oxidant biochemically. The biological effects of Luteolin could be functionally related to each other. For instance, the anti-inflammatory activity may be linked to its anticancer property. Luteolin's anticancer property is associated with the induction of apoptosis, and inhibition of cell proliferation, metastasis and angiogenesis. Furthermore, Luteolin sensitizes cancer cells to therapeutic-induced cytotoxicity through suppressing cell survival pathways such as phosphatidylinositol 3′-kinase (PI3K)/Akt, nuclear factor kappa B (NF-κB), and X-linked inhibitor of apoptosis protein (XIAP), and stimulating apoptosis pathways including those that induce the tumor suppressor p53. These observations suggest that Luteolin could be an anticancer agent for various cancers. Furthermore, recent epidemiological studies have attributed a cancer prevention property to Luteolin. In this review, we summarize the progress of recent research on Luteolin, with a particular focus on its anticancer role and molecular mechanisms underlying this property of Luteolin.
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Luteolin sensitizes the anticancer effect of cisplatin via c jun nh2 terminal kinase mediated p53 phosphorylation and stabilization
Molecular Cancer Therapeutics, 2007Co-Authors: Ranxi Shi, Qing Huang, Xinqiang Zhu, Yeongbing Ong, I Zhao, Choon Nam Ong, Hanming SheAbstract:Luteolin is an important flavonoid with a potential anticancer effect. In this study, we examined the molecular mechanisms involved in the sensitization effect of Luteolin on cancer cell killing induced by cisplatin, an important cancer chemotherapeutic agent. First, we provided evidence that the sensitization effect of Luteolin on cisplatin-induced apoptosis is p53 dependent, as such effect is only found in p53 wild-type cancer cells but not in p53 mutant cancer cells. Moreover, knockdown of p53 by small interfering RNA made p53 wild-type cancer cells resistant to Luteolin and cisplatin. Second, we observed a significant increase of p53 protein level in Luteolin-treated cancer cells without increase of p53 mRNA level, indicating the possible effect of Luteolin on p53 posttranscriptional regulation. Third, we identified the critical role of c-Jun NH2-terminal kinase (JNK) in regulation of p53 protein stability: Luteolin activates JNK, and JNK then stabilizes p53 via phosphorylation, leading to reduced ubiquitination and proteasomal degradation. Finally, by using an in vivo nude mice xenograft model, we confirmed that Luteolin enhanced the cancer therapeutic activity of cisplatin via p53 stabilization and accumulation. In summary, data from this study reveal a novel molecular mechanism involved in the anticancer effect of Luteolin and support its potential clinical application as a chemosensitizer in cancer therapy. [Mol Cancer Ther 2007;6(4):1338–47]
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Luteolin sensitizes tumor necrosis factor α induced apoptosis in human tumor cells
Oncogene, 2004Co-Authors: Ranxi Shi, Choon Nam Ong, Hanming SheAbstract:Tumor necrosis factor-α (TNFα) activates both cell death and cell survival pathways, which render most cancer cells resistant to its cytotoxicity. In this study, we found that pretreatment with Luteolin, a plant flavonoid, greatly sensitized TNFα-induced apoptotic cell death in a number of human cancer cell lines; including colorectal cancer COLO205, HCT116 cells and cervical cancer HeLa cells. In the search of the molecular mechanisms responsible for the sensitization effect of Luteolin, we discovered that Luteolin inhibited TNFα-induced activation of nuclear transcription factor-kappa B (NF-κB), the main survival factor in TNFα signaling. As a result, Luteolin suppressed the expression of NF-κB-targeted antiapoptotic genes, including A20 and cellular inhibitor of apoptosis protein-1 (c-IAP1). The role of A20 and c-IAP1 was further confirmed by ectopic expression of these two genes, which significantly protected cell death induced by Luteolin followed by TNFα. In addition, inhibition of NF-κB by Luteolin led to augmentation and prolongation of c-Jun N-terminal kinase (JNK) activation induced by TNFα. Suppression of JNK activation, either by a synthetic JNK inhibitor (SP600125) or by overexpression of the dominant negative forms of JNK kinase 1 (JNKK1) and JNK kinase 2 (JNKK2), conferred significant protection against apoptotic cell death induced by Luteolin and TNFα, suggesting that NF-κB and JNK are closely associated with the sensitization effect of Luteolin. Data from this study reveal a novel function of Luteolin and enhance the value of Luteolin as an anticancer agent.
Theodore Fotsis - One of the best experts on this subject based on the ideXlab platform.
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Luteolin inhibits vascular endothelial growth factor induced angiogenesis inhibition of endothelial cell survival and proliferation by targeting phosphatidylinositol 3 kinase activity
Cancer Research, 2004Co-Authors: Eleni Bagli, Maria Stefaniotou, Lucia Morbidelli, Marina Ziche, Konstantinos Psillas, Carol Murphy, Theodore FotsisAbstract:In an attempt to identify phytochemicals contributing to the well-documented preventive effect of plant-based diets on cancer incidence and mortality, we have previously shown that certain flavonoids inhibit in vitro angiogenesis. Here, we show that the flavonoid Luteolin inhibited tumor growth and angiogenesis in a murine xenograft model. Furthermore, Luteolin inhibited vascular endothelial growth factor (VEGF)-induced in vivo angiogenesis in the rabbit corneal assay. In agreement, Luteolin inhibited both VEGF-induced survival and proliferation of human umbilical vein endothelial cells (HUVECs) with an IC 50 of about 5 μmol/L. Luteolin inhibited VEGF-induced phosphatidylinositol 3′-kinase (PI3K) activity in HUVECs, and this inhibition was critical for both the antisurvival and antimitotic affects of the compound. Indeed, Luteolin abolished VEGF-induced activation of Akt, a downstream target of PI3K conveying both survival and mitotic downstream signals. Because overexpression of a constitutively active form of Akt rescued HUVECs only from the antisurvival effects of Luteolin, the result indicated that Luteolin targeted mainly the survival signals of the PI3K/Akt pathway. With regard to its antimitotic activity, Luteolin inhibited VEGF-induced phosphorylation of p70 S6 kinase (S6K), a downstream effector of PI3K responsible for G 1 progression. Indeed, VEGF-induced proliferation of HUVECs was sensitive to rapamycin, an inhibitor of p70 S6K activation. Surprisingly, Luteolin did not affect VEGF-induced phosphorylation of extracellular signal-regulated kinase 1/2 mitogen-activated protein kinases, a pathway that is considered important for the mitotic effects of VEGF. Thus, blockade of PI3K by Luteolin was responsible for the inhibitory effects of the compound on VEGF-induced survival and proliferation of HUVECs. The antisurvival effects of Luteolin were mediated via blockage of PI3K/Akt-dependent pathways, whereas inhibition of the PI3K/p70 S6K pathway mediated the antimitotic effects of the compound.
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Luteolin reduces lipopolysaccharide induced lethal toxicity and expression of proinflammatory molecules in mice
American Journal of Respiratory and Critical Care Medicine, 2002Co-Authors: Anastasia Kotanidou, Theodore Fotsis, Angeliki Xagorari, Eleni Agli, Panagiota Kitsanta, Andreas PapapetropoulosAbstract:Luteolin is a flavonoid that has been shown to reduce proinflammatory molecule expression in vitro. In the present study, we have tested the ability of Luteolin to inhibit lipopolysaccharide (LPS)- induced lethal toxicity and proinflammatory molecule expression in vivo. Mice receiving LPS (Salmonella enteriditis LPS, 32 mg/kg, intraperitoneally) exhibited high mortality with only 4.1% of the animals surviving seven days after the LPS challenge. On the contrary, mice that had received Luteolin (0.2 mg/kg, intraperitoneally) before LPS showed an increased survival rate with 48% remaining alive on Day 7. To investigate the mechanism by which Luteolin affords protection against LPS toxicity we measured intercellular adhesion molecule-1 (ICAM-1) and tumor necrosis factor- α (TNF- α ) production in response to LPS in the presence or absence of Luteolin pretreatment. Treatment of animals with LPS increased serum TNF- α levels in a time-dependent manner. The increase in peak serum TNF- α levels was sensitive to l...
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Luteolin inhibits an endotoxin stimulated phosphorylation cascade and proinflammatory cytokine production in macrophages
Journal of Pharmacology and Experimental Therapeutics, 2001Co-Authors: Angeliki Xagorari, Theodore Fotsis, Andreas Papapetropoulos, Antonis Mauromatis, Michalis Economou, Charis RoussosAbstract:Flavonoids are naturally occurring polyphenolic compounds with a wide distribution throughout the plant kingdom. In the present study, we compared the ability of several flavonoids to modulate the production of proinflammatory molecules from lipopolysaccharide (LPS)-stimulated macrophages and investigated their mechanism(s) of action. Pretreatment of RAW 264.7 with Luteolin, Luteolin-7-glucoside, quercetin, and the isoflavonoid genistein inhibited both the LPS-stimulated TNF-alpha and interleukin-6 release, whereas eriodictyol and hesperetin only inhibited TNF-alpha release. From the compounds tested Luteolin and quercetin were the most potent in inhibiting cytokine production with an IC(50) of less than 1 and 5 microM for TNF-alpha release, respectively. To determine the mechanisms by which flavonoids inhibit LPS signaling, we used Luteolin and determined its ability to interfere with total protein tyrosine phosphorylation as well as Akt phosphorylation and nuclear factor-kappaB activation. Pretreatment of the cells with Luteolin attenuated LPS-induced tyrosine phosphorylation of many discrete proteins. Moreover, Luteolin inhibited LPS-induced phosphorylation of Akt. Treatment of macrophages with LPS resulted in increased IkappaB-alpha phosphorylation and reduced the levels of IkappaB-alpha. Pretreatment of cells with Luteolin abolished the effects of LPS on IkappaB-alpha. To determine the functional relevance of the phosphorylation events observed with IkappaB-alpha, macrophages were transfected either with a control vector or a vector coding for the luciferase reporter gene under the control of kappaB cis-acting elements. Incubation of transfected RAW 264.7 cells with LPS increased luciferase activity in a Luteolin-sensitive manner. We conclude that Luteolin inhibits protein tyrosine phosphorylation, nuclear factor-kappaB-mediated gene expression and proinflammatory cytokine production in murine macrophages.
Christoph M Schempp - One of the best experts on this subject based on the ideXlab platform.
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uvb induced dna damage generation of reactive oxygen species and inflammation are effectively attenuated by the flavonoid Luteolin in vitro and in vivo
Free Radical Biology and Medicine, 2011Co-Authors: Ute Wolfle, Philipp R Esse, Irgi Simonhaarhaus, Stefa F Marti, Jurge Ladema, Christoph M SchemppAbstract:Abstract Ultraviolet (UV) radiation induces DNA damage, oxidative stress, and inflammatory processes in human keratinocytes resulting in skin inflammation, photoaging, and photocarcinogenesis. The flavonoid Luteolin is one of the most potent antioxidative plant polyphenols. We investigated the UV protective and antioxidant properties of Luteolin in human keratinocytes in vitro, ex vivo, and in vivo. Spectrophotometric measurements revealed extinction maxima of Luteolin in the UVB and UVA range. UV transmission below 370 nm was
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anti carcinogenic effects of the flavonoid Luteolin
Molecules, 2008Co-Authors: Gunte Seelinge, Irmgard Merfo, Ute Wolfle, Christoph M SchemppAbstract:Luteolin is a flavonoid which is part of our daily nutrition in relatively low amounts (less than 1 mg/day). Nevertheless, some epidemiological studies suggest an inverse correlation between Luteolin intake and the risk of some cancer types. Luteolin displays specific anti-inflammatory and anti-carcinogenic effects, which can only partly be explained by its anti-oxidant and free radical scavenging capacities. Luteolin can delay or block the development of cancer cells in vitro and in vivo by protection from carcinogenic stimuli, by inhibition of tumor cell proliferation, by induction of cell cycle arrest and by induction of apoptosis via intrinsic and extrinsic signaling pathways. When compared to other flavonoids, Luteolin was usually among the most effective ones, inhibiting tumor cell proliferation with IC(50) values between 3 and 50 microM in vitro and in vivo by 5 to 10 mg/kg i.p., intragastric application of 0.1-0.3 mg/kg/d, or as food additive in concentrations of 50 to 200 ppm. Luteolin has been shown to penetrate into human skin, making it also a candidate for the prevention and treatment of skin cancer.
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anti oxidant anti inflammatory and anti allergic activities of Luteolin
Planta Medica, 2008Co-Authors: Gunte Seelinge, Irmgard Merfo, Christoph M SchemppAbstract:Luteolin is a flavone which occurs in medicinal plants as well as in some vegetables and spices. It is a natural anti-oxidant with less pro-oxidant potential than the flavonol quercetin, the best studied flavonoid, but apparently with a better safety profile. It displays excellent radical scavenging and cytoprotective properties, especially when tested in complex biological systems where it can interact with other anti-oxidants like vitamins. Luteolin displays specific anti-inflammatory effects at micromolar concentrations which are only partly explained by its anti-oxidant capacities. The anti-inflammatory activity includes activation of anti-oxidative enzymes, suppression of the NFkappaB pathway and inhibition of pro-inflammatory substances. In vivo, Luteolin reduced increased vascular permeability and was effective in animal models of inflammation after parenteral and oral application. Although Luteolin is only a minor component in our nutrition (less than 1 mg/day) epidemiological studies indicate that it has the potential to protect from diseases associated with inflammatory processes such as cardiovascular disease. Luteolin often occurs in the form of glycosides in plants, but these are cleaved and the aglycones are conjugated and metabolized after nutritional uptake which has to be considered when evaluating in vitro studies. Some data for oral and topical bioavailability exist, but more quantitative research in this field is needed to evaluate the physiological and therapeutical potential of Luteolin.
Xiuwe Tang - One of the best experts on this subject based on the ideXlab platform.
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Luteolin inhibits the nrf2 signaling pathway and tumor growth in vivo
Biochemical and Biophysical Research Communications, 2014Co-Authors: Song Chia, Xiu Ju Wang, Ruby Thapa, Zhexu Chi, Xiuwe TangAbstract:Abstract Nuclear factor erythroid 2-related factor 2 (Nrf2) is over-expressed in many types of tumor, promotes tumor growth, and confers resistance to anticancer therapy. Hence, Nrf2 is regarded as a novel therapeutic target in cancer. Previously, we reported that Luteolin is a strong inhibitor of Nrf2 in vitro. Here, we showed that Luteolin reduced the constitutive expression of NAD(P)H quinone oxidoreductase 1 in mouse liver in a time- and dose-dependent manner. Further, Luteolin inhibited the expression of antioxidant enzymes and glutathione transferases, decreasing the reduced glutathione in the liver of wild-type mice under both constitutive and butylated hydroxyanisole-induced conditions. In contrast, such distinct responses were not detected in Nrf2−/− mice. In addition, oral administration of Luteolin, either alone or combined with intraperitoneal injection of the cytotoxic drug cisplatin, greatly inhibited the growth of xenograft tumors from non-small-cell lung cancer (NSCLC) cell line A549 cells grown subcutaneously in athymic nude mice. Cell proliferation, the expression of Nrf2, and antioxidant enzymes were all reduced in tumor xenograft tissues. Furthermore, Luteolin enhanced the anti-cancer effect of cisplatin. Together, our findings demonstrated that Luteolin inhibits the Nrf2 pathway in vivo and can serve as an adjuvant in the chemotherapy of NSCLC.
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Luteolin inhibits nrf2 leading to negative regulation of the nrf2 are pathway and sensitization of human lung carcinoma a549 cells to therapeutic drugs
Free Radical Biology and Medicine, 2011Co-Authors: Xiuwe Tang, Hongya Wang, Xiu Ju WangAbstract:Abstract Nuclear factor erythroid 2-related factor 2 (Nrf2) is a redox-sensitive transcription factor regulating the expression of a battery of cytoprotective genes. Constitutive Nrf2 activation in many tumors enhances cell survival and resistance to anticancer drugs. Using a cell-based ARE-reporter assay we discovered that the flavonoid Luteolin is a potent Nrf2 inhibitor. Luteolin inhibited ARE-driven gene expression redox-independently. In non-small-cell lung cancer A549 cells, which possess constitutively active Nrf2, Luteolin elicited a dramatic reduction in Nrf2 at both the mRNA and the protein levels, leading to decreased Nrf2 binding to AREs, down-regulation of ARE-driven genes, and depletion of reduced glutathione. After transcription was blocked with actinomycin D, 1 μM Luteolin decreased the Nrf2 mRNA level by 34% in 30 min, indicating its role in accelerating Nrf2 mRNA turnover. At physiological concentrations, Luteolin significantly sensitized A549 cells to the anticancer drugs oxaliplatin, bleomycin, and doxorubicin. However, knockdown of Nrf2 using siRNA essentially abolished the induced sensitivity by the flavonoid, implying the importance of inhibiting Nrf2 for its activity. Our study demonstrates that an Nrf2 inhibitor can enhance the responsiveness of cancer cells to chemotherapeutic drugs and indicates the potential application of Luteolin as a natural sensitizer in chemotherapy.
Ranxi Shi - One of the best experts on this subject based on the ideXlab platform.
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Luteolin a flavonoid with potential for cancer prevention and therapy
Current Cancer Drug Targets, 2008Co-Authors: Ranxi Shi, Xia Wang, Hanming SheAbstract:Luteolin, 3′,4′,5,7-tetrahydroxyflavone, is a common flavonoid that exists in many types of plants including fruits, vegetables, and medicinal herbs. Plants rich in Luteolin have been used in Chinese traditional medicine for treating various diseases such as hypertension, inflammatory disorders, and cancer. Having multiple biological effects such as anti-inflammation, anti-allergy and anticancer, Luteolin functions as either an antioxidant or a pro-oxidant biochemically. The biological effects of Luteolin could be functionally related to each other. For instance, the anti-inflammatory activity may be linked to its anticancer property. Luteolin's anticancer property is associated with the induction of apoptosis, and inhibition of cell proliferation, metastasis and angiogenesis. Furthermore, Luteolin sensitizes cancer cells to therapeutic-induced cytotoxicity through suppressing cell survival pathways such as phosphatidylinositol 3′-kinase (PI3K)/Akt, nuclear factor kappa B (NF-κB), and X-linked inhibitor of apoptosis protein (XIAP), and stimulating apoptosis pathways including those that induce the tumor suppressor p53. These observations suggest that Luteolin could be an anticancer agent for various cancers. Furthermore, recent epidemiological studies have attributed a cancer prevention property to Luteolin. In this review, we summarize the progress of recent research on Luteolin, with a particular focus on its anticancer role and molecular mechanisms underlying this property of Luteolin.
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Luteolin sensitizes the anticancer effect of cisplatin via c jun nh2 terminal kinase mediated p53 phosphorylation and stabilization
Molecular Cancer Therapeutics, 2007Co-Authors: Ranxi Shi, Qing Huang, Xinqiang Zhu, Yeongbing Ong, I Zhao, Choon Nam Ong, Hanming SheAbstract:Luteolin is an important flavonoid with a potential anticancer effect. In this study, we examined the molecular mechanisms involved in the sensitization effect of Luteolin on cancer cell killing induced by cisplatin, an important cancer chemotherapeutic agent. First, we provided evidence that the sensitization effect of Luteolin on cisplatin-induced apoptosis is p53 dependent, as such effect is only found in p53 wild-type cancer cells but not in p53 mutant cancer cells. Moreover, knockdown of p53 by small interfering RNA made p53 wild-type cancer cells resistant to Luteolin and cisplatin. Second, we observed a significant increase of p53 protein level in Luteolin-treated cancer cells without increase of p53 mRNA level, indicating the possible effect of Luteolin on p53 posttranscriptional regulation. Third, we identified the critical role of c-Jun NH2-terminal kinase (JNK) in regulation of p53 protein stability: Luteolin activates JNK, and JNK then stabilizes p53 via phosphorylation, leading to reduced ubiquitination and proteasomal degradation. Finally, by using an in vivo nude mice xenograft model, we confirmed that Luteolin enhanced the cancer therapeutic activity of cisplatin via p53 stabilization and accumulation. In summary, data from this study reveal a novel molecular mechanism involved in the anticancer effect of Luteolin and support its potential clinical application as a chemosensitizer in cancer therapy. [Mol Cancer Ther 2007;6(4):1338–47]
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Luteolin sensitizes tumor necrosis factor α induced apoptosis in human tumor cells
Oncogene, 2004Co-Authors: Ranxi Shi, Choon Nam Ong, Hanming SheAbstract:Tumor necrosis factor-α (TNFα) activates both cell death and cell survival pathways, which render most cancer cells resistant to its cytotoxicity. In this study, we found that pretreatment with Luteolin, a plant flavonoid, greatly sensitized TNFα-induced apoptotic cell death in a number of human cancer cell lines; including colorectal cancer COLO205, HCT116 cells and cervical cancer HeLa cells. In the search of the molecular mechanisms responsible for the sensitization effect of Luteolin, we discovered that Luteolin inhibited TNFα-induced activation of nuclear transcription factor-kappa B (NF-κB), the main survival factor in TNFα signaling. As a result, Luteolin suppressed the expression of NF-κB-targeted antiapoptotic genes, including A20 and cellular inhibitor of apoptosis protein-1 (c-IAP1). The role of A20 and c-IAP1 was further confirmed by ectopic expression of these two genes, which significantly protected cell death induced by Luteolin followed by TNFα. In addition, inhibition of NF-κB by Luteolin led to augmentation and prolongation of c-Jun N-terminal kinase (JNK) activation induced by TNFα. Suppression of JNK activation, either by a synthetic JNK inhibitor (SP600125) or by overexpression of the dominant negative forms of JNK kinase 1 (JNKK1) and JNK kinase 2 (JNKK2), conferred significant protection against apoptotic cell death induced by Luteolin and TNFα, suggesting that NF-κB and JNK are closely associated with the sensitization effect of Luteolin. Data from this study reveal a novel function of Luteolin and enhance the value of Luteolin as an anticancer agent.
