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Apigenin

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Sanjay Gupta – One of the best experts on this subject based on the ideXlab platform.

  • plant flavone Apigenin binds to nucleic acid bases and reduces oxidative dna damage in prostate epithelial cells
    PLOS ONE, 2014
    Co-Authors: Haripaul Sharma, Rajnee Kanwal, Natarajan Bhaskaran, Sanjay Gupta

    Abstract:

    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.

  • 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, 2012
    Co-Authors: Mitali Pandey, Parminder Kaur, Sanjeev Shukla, Ata Abbas, Sanjay Gupta

    Abstract:

    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.

  • Apigenin induced prostate cancer cell death is initiated by reactive oxygen species and p53 activation
    Free Radical Biology and Medicine, 2008
    Co-Authors: Sanjeev Shukla, Sanjay Gupta

    Abstract:

    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.

  • 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, 2012
    Co-Authors: Mitali Pandey, Parminder Kaur, Sanjeev Shukla, Ata Abbas, Sanjay Gupta

    Abstract:

    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.

  • Apigenin induced prostate cancer cell death is initiated by reactive oxygen species and p53 activation
    Free Radical Biology and Medicine, 2008
    Co-Authors: Sanjeev Shukla, Sanjay Gupta

    Abstract:

    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.

  • 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, 2012
    Co-Authors: Leongperng Chan, Tzunghan Chou, Hsiouyu Ding, Pinru Chen, Fengyu Chiang, Polin Kuo, Chiahua Liang

    Abstract:

    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.