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The Immune-modulatory and Anti-carcinogenic Mechanisms of the Flavonoid Apigenin

Arango Tamayo, Daniel Alejandro

Abstract Details

2015, Doctor of Philosophy, Ohio State University, Molecular, Cellular and Developmental Biology.
Dietary phytochemicals provide health benefits against several cancers and inflammatory diseases. Flavonoids are amongst the most abundant dietary phytochemicals emerging as key anti-carcinogenic and anti-inflammatory molecules. Yet, the mechanisms underlying their anti-cancer and anti-inflammatory activities are poorly defined. The goal of this project was to study the immune-modulatory and anti-carcinogenic mechanisms of the flavonoid apigenin. I investigated the modes of action of apigenin using different model systems including a monocytic leukemia cell line, breast cancer cell lines, macrophages and mouse models of inflammation and breast cancer development. In monocytic leukemia, I found that apigenin induces DNA strand breaks leading to the activation of a DNA damage response pathway that results in cell cycle arrest and induction of apoptosis. Using mouse models of inflammation, I showed that apigenin reduces lipopolysaccharide (LPS)-induced lethality by inhibiting the activity of the transcription factor NF-kB and the expression of the pro-inflammatory molecules miR-155 and TNFalpha. I established, using a pre-clinical mouse model of breast cancer development, that the immune-modulatory and anti-carcinogenic activities of apigenin work in concert to delay breast tumor progression and metastasis by dually acting on malignant and immune cells. My results show that apigenin induces apoptosis and inhibits proliferation in breast tumors as well as halts macrophages infiltration in the tumor microenvironment by reducing the expression of NF-kB-dependent chemokines and promoting apoptosis in blood monocytes, the macrophage progenitors. Moreover, I implemented the use of a newly formulated celery-based apigenin-rich diet in mouse models of inflammation and breast cancer demonstrating that this diet, as well as apigenin, have anti-inflammatory and anti-carcinogenic activities by immune-modulating monocytes and macrophages and inducing apoptosis in cancer cells. To investigate the molecular mechanisms underlying the biological effects of apigenin, we developed of a new genome-wide approach to identify direct targets of this flavonoid. From these studies, I identified 160 candidate targets of apigenin that revealed unexpected mechanisms on how this dietary phytochemical modulates cellular functions such as apoptosis, immune and DNA damage response signaling pathways. In addition, I observed that apigenin interacts with RNA binding proteins including the heterogeneous nuclear RiboNucleoProtein A2 (hnRNPA2) and affects splicing genome-wide, providing a novel mechanism on how this flavone regulates apoptotic cell fate through modulation of mRNA processing. Altogether, this investigation offers a fresh view on how flavonoids influence human health, by impacting multiple cellular targets with moderate affinity. Thus, in contrast to pharmaceutical drugs selected to have high affinity and specificity for main hubs of biological pathways, the effect of flavonoids would be distributed across the entire cellular network with consequent benefits on human health. In addition, these results support the use of functional foods rich in flavonoids as an alternative for the treatment and prevention of inflammatory diseases and cancer.
Andrea Doseff (Advisor)
308 p.

Recommended Citations

Citations

  • Arango Tamayo, D. A. (2015). The Immune-modulatory and Anti-carcinogenic Mechanisms of the Flavonoid Apigenin [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1437511798

    APA Style (7th edition)

  • Arango Tamayo, Daniel. The Immune-modulatory and Anti-carcinogenic Mechanisms of the Flavonoid Apigenin. 2015. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1437511798.

    MLA Style (8th edition)

  • Arango Tamayo, Daniel. "The Immune-modulatory and Anti-carcinogenic Mechanisms of the Flavonoid Apigenin." Doctoral dissertation, Ohio State University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=osu1437511798

    Chicago Manual of Style (17th edition)