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Sanjay Gupta - One of the best experts on this subject based on the ideXlab platform.
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plant flavone Apigenin binds to nucleic acid bases and reduces oxidative dna damage in prostate epithelial cells
PLOS ONE, 2014Co-Authors: Haripaul Sharma, Rajnee Kanwal, Natarajan Bhaskaran, Sanjay GuptaAbstract:Oxidative stress has been linked to prostate carcinogenesis as human prostate tissue is vulnerable to oxidative DNA damage. Apigenin, a dietary plant flavone, possesses anti-proliferative and anticancer effects; however, its antioxidant properties have not been fully elucidated. We investigated sub-cellular distribution of Apigenin, it’s binding to DNA and protective effects against H2O2-induced DNA damage using transformed human prostate epithelial RWPE-1 cells and prostate cancer LNCaP, PC-3 and DU145 cells. Exposure of cells to Apigenin exhibited higher accumulation in RWPE-1 and LNCaP cells, compared to PC-3 and DU145 cells. The kinetics of Apigenin uptake in LNCaP cells was estimated with a Km value of 5 µmole/L and Vmax of 190 pmoles/million cells/h. Sub-cellular fractionation demonstrated that nuclear matrix retains the highest concentration of Apigenin (45.3%), followed by cytosol (23.9%), nuclear membranes (17.9%) and microsomes (12.9%), respectively. Spectroscopic analysis of Apigenin with calf-thymus DNA exhibited intercalation as the dominant binding mode to DNA duplex. Apigenin exposure resulted in significant genoprotective effects in H2O2-stressed RWPE-1 cells by reduction in reactive oxygen species levels. In addition, Apigenin exposure suppressed the formation of 8-hydroxy-2′ deoxyguanosine and protected exposed cells from apoptosis. Our studies demonstrate that Apigenin is readily taken up by normal prostatic epithelial cells and prostate cancer cells, and is incorporated into their nuclei, where its intercalation with nucleic acid bases may account for its antioxidant and chemopreventive activities.
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plant flavone Apigenin inhibits hdac and remodels chromatin to induce growth arrest and apoptosis in human prostate cancer cells in vitro and in vivo study
Molecular Carcinogenesis, 2012Co-Authors: Mitali Pandey, Parminder Kaur, Sanjeev Shukla, Ata Abbas, Sanjay GuptaAbstract:Apigenin (4',5,7,-trihydroxyflavone), an anticancer agent, selectively toxic to cancer cells induces cell cycle arrest and apoptosis through mechanisms that have not been fully elucidated. Our studies indicate that Apigenin-mediated growth inhibitory responses are due to inhibition of class I histone deacetylases (HDACs) in prostate cancer cells. Treatment of PC-3 and 22Rv1 cells with Apigenin (20-40 µM) resulted in the inhibition of HDAC enzyme activity, specifically HDAC1 and HDAC3 at the protein and message level. Apigenin-mediated HDAC inhibition resulted in global histone H3 and H4 acetylation, as well as localized hyperacetylation of histone H3 on the p21/waf1 promoter. A corresponding increase was observed in p21/waf1 and bax protein and mRNA expression after Apigenin exposure, consistent with the use of HDAC inhibitor, trichostatin A. The downstream events demonstrated cell cycle arrest and induction of apoptosis in both cancer cells. Studies of PC-3 xenografts in athymic nude mice further demonstrated that oral intake of Apigenin at doses of 20 and 50 µg/mouse/d over an 8-wk period resulted in a marked reduction in tumor growth, HDAC activity, and HDAC1 and HDAC3 protein expression at both doses of Apigenin. An increase in p21/waf1 expression was observed in Apigenin-fed mice, compared to the control group. Furthermore, Apigenin intake caused a significant decrease in bcl2 expression with concomitant increase in bax, shifting the bax/bcl2 ratio in favor of apoptosis. Our findings confirm for the first time that Apigenin inhibits class I HDACs, particularly HDAC1 and HDAC3 and its exposure results in reversal of aberrant epigenetic events that promote malignancy. © 2011 Wiley Periodicals, Inc.
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Apigenin induced prostate cancer cell death is initiated by reactive oxygen species and p53 activation
Free Radical Biology and Medicine, 2008Co-Authors: Sanjeev Shukla, Sanjay GuptaAbstract:Apigenin, a plant flavone, potentially activates wild-type p53 and induces apoptosis in cancer cells. We conducted detailed studies to understand its mechanism of action. Exposure of human prostate cancer 22Rv1 cells, harboring wild-type p53, to growth-suppressive concentrations (10–80 μM) of Apigenin resulted in the stabilization of p53 by phosphorylation on critical serine sites, p14ARF-mediated downregulation of MDM2 protein, inhibition of NF-κB/p65 transcriptional activity, and induction of p21/WAF-1 in a dose- and time-dependent manner. Apigenin at these doses resulted in ROS generation, which was accompanied by rapid glutathione depletion, disruption of mitochondrial membrane potential, cytosolic release of cytochrome c, and apoptosis. Interestingly, we observed accumulation of a p53 fraction to the mitochondria, which was rapid and occurred between 1 and 3 h after Apigenin treatment. All these effects were significantly blocked by pretreatment of cells with the antioxidant N-acetylcysteine, p53 inhibitor pifithrin-α, and enzyme catalase. Apigenin-mediated p53 activation and apoptosis were further attenuated by p53 antisense oligonucleotide treatment. Exposure of cells to Apigenin led to a decrease in the levels of Bcl-XL and Bcl-2 and increase in Bax, triggering caspase activation. Treatment with the caspase inhibitors Z-VAD-FMK and DEVD-CHO partially rescued these cells from Apigenin-induced apoptosis. In vivo, Apigenin administration demonstrated p53-mediated induction of apoptosis in 22Rv1 tumors. These results indicate that Apigenin-induced apoptosis in 22Rv1 cells is initiated by a ROS-dependent disruption of the mitochondrial membrane potential through transcriptional-dependent and -independent p53 pathways.
Sanjeev Shukla - One of the best experts on this subject based on the ideXlab platform.
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plant flavone Apigenin inhibits hdac and remodels chromatin to induce growth arrest and apoptosis in human prostate cancer cells in vitro and in vivo study
Molecular Carcinogenesis, 2012Co-Authors: Mitali Pandey, Parminder Kaur, Sanjeev Shukla, Ata Abbas, Sanjay GuptaAbstract:Apigenin (4',5,7,-trihydroxyflavone), an anticancer agent, selectively toxic to cancer cells induces cell cycle arrest and apoptosis through mechanisms that have not been fully elucidated. Our studies indicate that Apigenin-mediated growth inhibitory responses are due to inhibition of class I histone deacetylases (HDACs) in prostate cancer cells. Treatment of PC-3 and 22Rv1 cells with Apigenin (20-40 µM) resulted in the inhibition of HDAC enzyme activity, specifically HDAC1 and HDAC3 at the protein and message level. Apigenin-mediated HDAC inhibition resulted in global histone H3 and H4 acetylation, as well as localized hyperacetylation of histone H3 on the p21/waf1 promoter. A corresponding increase was observed in p21/waf1 and bax protein and mRNA expression after Apigenin exposure, consistent with the use of HDAC inhibitor, trichostatin A. The downstream events demonstrated cell cycle arrest and induction of apoptosis in both cancer cells. Studies of PC-3 xenografts in athymic nude mice further demonstrated that oral intake of Apigenin at doses of 20 and 50 µg/mouse/d over an 8-wk period resulted in a marked reduction in tumor growth, HDAC activity, and HDAC1 and HDAC3 protein expression at both doses of Apigenin. An increase in p21/waf1 expression was observed in Apigenin-fed mice, compared to the control group. Furthermore, Apigenin intake caused a significant decrease in bcl2 expression with concomitant increase in bax, shifting the bax/bcl2 ratio in favor of apoptosis. Our findings confirm for the first time that Apigenin inhibits class I HDACs, particularly HDAC1 and HDAC3 and its exposure results in reversal of aberrant epigenetic events that promote malignancy. © 2011 Wiley Periodicals, Inc.
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Apigenin induced prostate cancer cell death is initiated by reactive oxygen species and p53 activation
Free Radical Biology and Medicine, 2008Co-Authors: Sanjeev Shukla, Sanjay GuptaAbstract:Apigenin, a plant flavone, potentially activates wild-type p53 and induces apoptosis in cancer cells. We conducted detailed studies to understand its mechanism of action. Exposure of human prostate cancer 22Rv1 cells, harboring wild-type p53, to growth-suppressive concentrations (10–80 μM) of Apigenin resulted in the stabilization of p53 by phosphorylation on critical serine sites, p14ARF-mediated downregulation of MDM2 protein, inhibition of NF-κB/p65 transcriptional activity, and induction of p21/WAF-1 in a dose- and time-dependent manner. Apigenin at these doses resulted in ROS generation, which was accompanied by rapid glutathione depletion, disruption of mitochondrial membrane potential, cytosolic release of cytochrome c, and apoptosis. Interestingly, we observed accumulation of a p53 fraction to the mitochondria, which was rapid and occurred between 1 and 3 h after Apigenin treatment. All these effects were significantly blocked by pretreatment of cells with the antioxidant N-acetylcysteine, p53 inhibitor pifithrin-α, and enzyme catalase. Apigenin-mediated p53 activation and apoptosis were further attenuated by p53 antisense oligonucleotide treatment. Exposure of cells to Apigenin led to a decrease in the levels of Bcl-XL and Bcl-2 and increase in Bax, triggering caspase activation. Treatment with the caspase inhibitors Z-VAD-FMK and DEVD-CHO partially rescued these cells from Apigenin-induced apoptosis. In vivo, Apigenin administration demonstrated p53-mediated induction of apoptosis in 22Rv1 tumors. These results indicate that Apigenin-induced apoptosis in 22Rv1 cells is initiated by a ROS-dependent disruption of the mitochondrial membrane potential through transcriptional-dependent and -independent p53 pathways.
Leongperng Chan - One of the best experts on this subject based on the ideXlab platform.
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Apigenin induces apoptosis via tumor necrosis factor receptor and bcl 2 mediated pathway and enhances susceptibility of head and neck squamous cell carcinoma to 5 fluorouracil and cisplatin
Biochimica et Biophysica Acta, 2012Co-Authors: Leongperng Chan, Tzunghan Chou, Hsiouyu Ding, Pinru Chen, Fengyu Chiang, Polin Kuo, Chiahua LiangAbstract:Abstract Background Apigenin, a natural plant flavone, may have chemopreventive and therapeutic potentials for anti-inflammatory, antioxidant, and anti-cancer. Nevertheless, the anti-tumor effect of Apigenin on human head and neck squamous cell carcinoma (HNSCC) is not fully understood. Methods The antioxidant capacity and protective effects of Apigenin against oxidative stress in murine normal embryonic liver BNLCL2 cells are examined. Cell viability, morphologic change, clonogenic survival, cell cycle distribution, reactive oxygen species (ROS) production, glutathione formation, and death receptors- and Bcl-2-mediated caspase pathways of HNSCC SCC25 cells and A431 cells with Apigenin are investigated. Results Apigenin inhibits the growth of SCC25 and A431 cells and induces cell cycle arrest in the G 2 /M phase. Apigenin has an antioxidant capacity as well as the ability to inhibit lipid peroxidation. It protects BNLCL2 cells against oxidative damage, and is potentially able to prevent cancer. Apigenin increases intracellular ROS levels and reduces levels of glutathione; it also induces cell apoptosis via tumor necrosis factor receptor (TNF-R)-, TNF-related apoptosis-inducing ligand receptor (TRAIL-R)-, and Bcl-2-mediated caspase-dependent cell death pathways in SCC25 cells. The combination of Apigenin with 5-fluorouracil (5-Fu) or cisplatin induces the dramatic death of SCC25 cells. Conclusions Apigenin induces SCC25 cell apoptosis via the up-regulation of both TNF-R and TRAIL-R signaling pathways, and has a synergistic effect on the inhibition of cell proliferation in combination with 5-Fu or cisplatin. General significance These analytical findings suggest that Apigenin may be a good therapeutic agent against HNSCC cells.
Diane F. Birt - One of the best experts on this subject based on the ideXlab platform.
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cell cycle arrest at g2 m and growth inhibition by Apigenin in human colon carcinoma cell lines
Molecular Carcinogenesis, 2000Co-Authors: Weiqun Wang, Jill C. Pelling, Laura Heideman, Chilly S Chung, Kenneth J Koehler, Diane F. BirtAbstract:Apigenin, a common dietary flavonoid, has been shown to induce cell cycle arrest in both epidermal and fibroblast cells and inhibit skin tumorigenesis in murine models. The present study assessed the influence of Apigenin on cell growth and the cell cycle in the human colon carcinoma cell lines SW480, HT-29, and Caco-2. Treatment of each cell line with Apigenin (0-80 microM) resulted in a dose-dependent reduction in both cell number and cellular protein content, compared with untreated control cultures. DNA flow cytometric analysis indicated that treatment with Apigenin resulted in G2/M arrest in all three cell lines in a time- and dose-dependent manner. Apigenin treatment (80 microM) for 48 h produced maximum G2/M arrest of 64%, 42%, and 26% in SW480 cells, HT-29 cells, and Caco-2 cells, respectively, in comparison with control cells (15%). The proportion of S-phase cells was not altered by Apigenin treatment in each of the three cell lines. The G2/M arrest was reversible after 48 h of Apigenin treatment in the most sensitive cell line SW480. The degree of G2/M arrest by Apigenin was inversely correlated with the corresponding inhibition of cell growth measurements in all three cell lines (r = -0.626 to -0.917, PApigenin (50-80 microM). Western blot analyses indicated that both p34(cdc2) and cyclin B1 proteins were also decreased after Apigenin treatment. These results indicate that Apigenin inhibits colon carcinoma cell growth by inducing a reversible G2/M arrest and that this arrest is associated, at least in part, with inhibited activity of p34(cdc2) kinase and reduced accumulation of p34(cdc2) and cyclin B1 proteins. Differences in induction of G2/M arrest by Apigenin in the three colon carcinoma cell lines suggest that dietary Apigenin may be differentially effective against tumors with specific mutational spectra. Mol. Carcinog. 28:102-110, 2000.
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Evaluation of Properties of Apigenin and [G-3H]Apigenin and Analytic Method Development
Journal of Pharmaceutical Sciences, 1997Co-Authors: Dennis H. Robinson, Diane F. BirtAbstract:Abstract This study provides baseline data and analytical methods to assist in the evaluation of Apigenin, a plant flavonoid with promising chemopreventive activity against skin cancer. Apigenin was freely soluble in dimethylsulfoxide (> 100 mg/mL), but it had low solubility (0.001357ndash;1.63 mg/mL) in all the other solvents and surfactants tested, especially in highly hydrophilic or nonpolar solvents. The partition coefficient (log K ) calculated from the solubility ratio of Apigenin in n -octanol and water was 2.87. Apigenin strongly absorbed UV light, with three maximum absorption wavelengths at 212, 269, and 337 nm (ϵ = 29 800, 19 020, and 18 930 M −1 cm −1 , respectively). Using quercetin as the internal standard, a reversed-phase HPLC method was developed to quantitatively analyze Apigenin in epidermal cells obtained from SENCAR mice. Apigenin was labeled at position 6, 8, 3′, and 5′ with tritium by a platinum-catalyzed proton–tritium exchange as confirmed indirectly by 1 H NMR analysis of the deuterated Apigenin. The tritium label was stable in aqueous environments, especially under acidic and neutral conditions, so [G- 3 H]Apigenin was considered suitable for subsequent absorption and metabolic studies.
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The chemopreventive flavonoid Apigenin induces G2/M arrest in keratinocytes
Carcinogenesis, 1996Co-Authors: Denise M. Lepley, Diane F. Birt, Jill C. PellingAbstract:Apigenin is a plant flavonoid which has been shown to significantly inhibit UV-induced mouse skin tumorigenesis when applied topically, and may represent an alternative sunscreen agent in humans. We have investigated the molecular mechanism(s) by which Apigenin inhibits skin tumorigenesis. Initial studies examined the effects of Apigenin on the cell cycle. DNA flow cytometric analysis indicated that culturing cells for 24 h in medium containing Apigenin induced a G 2 /M arrest in two mouse skin derived cell lines, C50 and 308, as well as in human HL-60 cells. The G 2 /M arrest was fully reversible after an additional 24 h in medium without Apigenin. We investigated the effects of Apigenin on cyclin B1 and p34 cdc2 , since cyclin B1/p34 cdc2 complexes regulate G 2 /M progression. Western blot and immune complex kinase assays using whole cell lysates from 308 and C50 cells treated for 24 h with 0-70 μM doses of Apigenin demonstrated that Apigenin treatment did not change the steady-state level of p34 cdc2 protein, but did inhibit p34 cdc2 H1 kinase activity in 308 cells. Western blot analysis showed that Apigenin treatment of C50 cells and 308 cells inhibited the accumulation of cyclin B1 protein in a dose-dependent manner. The Apigenin levels detected in cultured keratinocytes were relevant to those detected in epidermal cells of Sencar mice treated with tumor inhibitory doses of Apigenin. In conclusion, we present evidence that Apigenin induces a reversible G 2 /M arrest in cultured keratinocytes, the mechanism of which is in part due to inhibition of the mitotic kinase activity of p34 cdc2 , and perturbation of cyclin B1 levels.
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the chemopreventive flavonoid Apigenin induces g2 m arrest in keratinocytes
Carcinogenesis, 1996Co-Authors: Denise M. Lepley, Diane F. Birt, Jill C. PellingAbstract:Apigenin is a plant flavonoid which has been shown to significantly inhibit UV-induced mouse skin tumorigenesis when applied topically, and may represent an alternative sunscreen agent in humans. We have investigated the molecular mechanism(s) by which Apigenin inhibits skin tumorigenesis. Initial studies examined the effects of Apigenin on the cell cycle. DNA flow cytometric analysis indicated that culturing cells for 24 h in medium containing Apigenin induced a G 2 /M arrest in two mouse skin derived cell lines, C50 and 308, as well as in human HL-60 cells. The G 2 /M arrest was fully reversible after an additional 24 h in medium without Apigenin. We investigated the effects of Apigenin on cyclin B1 and p34 cdc2 , since cyclin B1/p34 cdc2 complexes regulate G 2 /M progression. Western blot and immune complex kinase assays using whole cell lysates from 308 and C50 cells treated for 24 h with 0-70 μM doses of Apigenin demonstrated that Apigenin treatment did not change the steady-state level of p34 cdc2 protein, but did inhibit p34 cdc2 H1 kinase activity in 308 cells. Western blot analysis showed that Apigenin treatment of C50 cells and 308 cells inhibited the accumulation of cyclin B1 protein in a dose-dependent manner. The Apigenin levels detected in cultured keratinocytes were relevant to those detected in epidermal cells of Sencar mice treated with tumor inhibitory doses of Apigenin. In conclusion, we present evidence that Apigenin induces a reversible G 2 /M arrest in cultured keratinocytes, the mechanism of which is in part due to inhibition of the mitotic kinase activity of p34 cdc2 , and perturbation of cyclin B1 levels.
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inhibitory effect of Apigenin a plant flavonoid on epidermal ornithine decarboxylase and skin tumor promotion in mice
Cancer Research, 1990Co-Authors: Huachen Wei, Laura Tye, Edward Bresnick, Diane F. BirtAbstract:Abstract This investigation studied the effect of topical application of Apigenin on skin tumorigenesis initiated by 7,12-dimethylbenz( a )anthracene (DMBA) and promoted by 12- O -tetradecanoylphorbol-13-acetate (TPA) in SENCAR mice. Apigenin was a potent inhibitor of epidermal ornithine decarboxylase induction by TPA in a dose-dependent manner from 1 to 20 µmol. Two tumorigenesis studies were conducted. In the first study, 20 µmol of Apigenin was applied topically and no effect on body weight was observed. By week 33 after DMBA initiation, 48% of DMBA/TPA-treated mice developed carcinomas, while none occurred in DMBA/Apigenin/TPA-treated groups. In the second study, doses of 5 and 20 µmol of Apigenin were used. The papilloma incidence for 0, 5, and 20 µmol Apigenin at 26 weeks after DMBA was 93.3, 58, and 39.3%, and papilloma numbers per mouse were 7.5, 2.5, and 1.8, respectively. Apigenin prolonged by 3 weeks the latency period of tumor appearance. In addition, Apigenin significantly inhibited the incidence of carcinoma and the numbers of carcinomas. The incidence of carcinomas per tumorbearing animal and the ratio of carcinomas/papillomas in two Apigenintreated groups decreased although there were no significant differences between the three groups. These data indicate that Apigenin inhibited skin papillomas and showed the tendency to decrease conversion of papillomas to carcinomas.
Kathlee J Gree - One of the best experts on this subject based on the ideXlab platform.
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the chemopreventive bioflavonoid Apigenin inhibits prostate cancer cell motility through the focal adhesion kinase src signaling mechanism
Cancer Prevention Research, 2009Co-Authors: Carrie A Franze, Evangeline V Amargo, Vikto Todorovic, Husha V Desai, Sabil Huda, Salida Mirzoeva, Kare Chiu, Artosz A Grzybowski, Teng Leong Chew, Kathlee J GreeAbstract:Prostate cancer mortality is primarily attributed to metastatic rather than primary, organ-confined disease. Acquiring a motile and invasive phenotype is an important step in development of tumors and ultimately metastasis. This step involves remodeling of the extracellular matrix and of cell-matrix interactions, cell movement mediated by the actin cytoskeleton, and activation of focal adhesion kinase (FAK)/Src signaling. Epidemiologic studies suggest that the metastatic behavior of prostate cancer may be an ideal target for chemoprevention. The natural flavone Apigenin is known to have chemopreventive properties against many cancers, including prostate cancer. Here, we study the effect of Apigenin on motility, invasion, and its mechanism of action in metastatic prostate carcinoma cells (PC3-M). We found that Apigenin inhibits PC3-M cell motility in a scratch-wound assay. Live cell imaging studies show that Apigenin diminishes the speed and affects directionality of cell motion. Alterations in the cytoskeleton are consistent with impaired cell movement in Apigenin-treated cells. Apigenin treatment leads to formation of “exaggerated filopodia,” which show accumulation of focal adhesion proteins at their tips. Furthermore, Apigenin-treated cells adhere more strongly to the extracellular matrix. Additionally, Apigenin decreases activation of FAK and Src, and phosphorylation of Src substrates FAK Y576/577 and Y925. Expression of constitutively active Src blunts the effect of Apigenin on cell motility and cytoskeleton remodeling. These results show that Apigenin inhibits motility and invasion of prostate carcinoma cells, disrupts actin cytoskeleton organization, and inhibits FAK/Src signaling. These studies provide mechanistic insight into developing novel strategies for inhibiting prostate cancer cell motility and invasiveness.
