Extraction, Purification and Evaluation of PRMT5-Inhibitory Phytochemical Compounds for the Treatment of Prostate Adenocarcinoma, 2019

Richmond, Oliver H.

2010-2019

The development and advancement of prostate cancer is supported by a plethora of genetic and proteomic abnormalities, including events of post-translational modifications. The protein arginine methyltransferase 5 (PRMT5) enzyme regulates epigenetic events of histone modifications and protein post-translational modifications within protein signaling pathways. PRMT5 functions by catalyzing the symmetric dimethylation of terminal arginine residues on target protein substrates. Under abnormal conditions of overexpression and upregulation, PRMT5 methyltransferase activity constitutively drives the growth and proliferation of dysregulated cells. Overexpression or upregulation of PRMT5 correlates with disease progression as observed among numerous cancer types, including breast, colorectal, leukemia, lung, melanoma and prostate cancers. We demonstrated previously that PRMT5 knockdowns attenuated both growth and proliferation of lung and prostatic tumors, in vitro and in vivo. Plants naturally produce chemical toxins as mechanisms of defense against microbial and other biological threats. Human exploitation, consumption and application of agents isolated from plants for therapeutic intervention dates back throughout the millennia. In this study, we extracted, purified and evaluated natural, small, chemical compounds from plant products that antagonize PRMT5 activity in prostate cancer cells. We found that crude and purified extracts of Dendrobium aurantiacum var. denneanum (D. denneanum) plants attenuated prostate tumor growth and proliferation by selective inhibition of PRMT5 methyltransferase activity. These findings establish the first set of natural PRMT5-specific inhibitors reported. KEYWORDS: Alternative and Complementary Medicine, Biochemistry, Cancer Biology, Cell Biology, Medicinal Chemistry and Pharmaceutics, Molecular Biology

text

application/pdf

2019-05-20

dissertation

Doctor of Philosophy (PhD)

Clark Atlanta University

Biological Science

Wang, Zhengxin
Odero-Marah, Valerie
Hinton, Cimona

Clark Atlanta University
Atlanta University Center Robert W. Woodruff Library

Georgia--Atlanta

http://hdl.handle.net/20.500.12322/cau.td:2019_richmondiii_oliver_h