TY - JOUR
T1 - Genistein Combined Polysaccharide (GCP) can inhibit intracrine androgen synthesis in prostate cancer cells
AU - Batra, Neelu
AU - Sam, Anhao
AU - Woldemariam, Tibebe
AU - Talbott, George
AU - de Vere White, Ralph W.
AU - Ghosh, Paramita M.
AU - Gaikwad, Nilesh W.
AU - Kotchoni, Simeon O.
AU - Vinall, Ruth L.
N1 - Funding Information:
Funding: This study is partially funded by the National Natural Science Foundation of China (51678002) and the Major Science and Technology Program for Water Pollution Control and Treatment (2012ZX07307001-03, 2013ZX07304-001-6). J.C. is supported by NASA’s LCLUC program for the Mongolia Plateau (80NSSC20K0410). Kristine Blakeslee of Michigan State University provided valuable editing on the language of this manuscript.
Funding Information:
Funding for this project was provided by an internal grant from California Northstate University College of Pharmacy. The authors would like to thank Bennett Addison for performing all of NMR analyses (all NMR analyses were performed at the UC Davis NMR core facility). The authors would also like to thank Heidi Kucera for her assistance with the HPLC and UPLC-MS analyses. Lastly, we thank the VA Northern California Health System for supporting this project. The contents reported/presented within do not represent the views of the Department of Veterans Aairs or the United States Government.
Publisher Copyright:
© 2020 by the authors.
PY - 2020/8
Y1 - 2020/8
N2 - Our group and others have previously shown that genistein combined polysaccharide (GCP), an aglycone isoflavone-rich extract with high bioavailability and low toxicity, can inhibit prostate cancer (CaP) cell growth and survival as well as androgen receptor (AR) activity. We now elucidate the mechanism by which this may occur using LNCaP and PC-346C CaP cell lines; GCP can inhibit intracrine androgen synthesis in CaP cells. UPLC-MS/MS and qPCR analyses demonstrated that GCP can mediate a ~3-fold decrease in testosterone levels (p < 0.001) and cause decreased expression of intracrine androgen synthesis pathway enzymes (~2.5-fold decrease of 3βHSD (p < 0.001), 17βHSD (p < 0.001), CYP17A (p < 0.01), SRB1 (p < 0.0001), and StAR (p < 0.01), respectively. Reverse-phase HPLC fractionation and bioassay identified three active GCP fractions. Subsequent NMR and LC-MS analysis of the fraction with the highest level of activity, fraction 40, identified genistein as the primary active component of GCP responsible for its anti-proliferative, pro-apoptotic, and anti-AR activity. GCP, fraction 40, and genistein all mediated at least a ~2-fold change in these biological activities relative to vehicle control (p < 0.001). Genistein caused similar decreases in the expression of 17μHSD and CYP17A (2.5-fold (p < 0.001) and 1.5-fold decrease (p < 0.01), respectively) compared to GCP, however it did not cause altered expression of the other intracrine androgen synthesis pathway enzymes; 3βHSD, SRB1, and StAR. Our combined data indicate that GCP and/or genistein may have clinical utility and that further pre-clinical studies are warranted.
AB - Our group and others have previously shown that genistein combined polysaccharide (GCP), an aglycone isoflavone-rich extract with high bioavailability and low toxicity, can inhibit prostate cancer (CaP) cell growth and survival as well as androgen receptor (AR) activity. We now elucidate the mechanism by which this may occur using LNCaP and PC-346C CaP cell lines; GCP can inhibit intracrine androgen synthesis in CaP cells. UPLC-MS/MS and qPCR analyses demonstrated that GCP can mediate a ~3-fold decrease in testosterone levels (p < 0.001) and cause decreased expression of intracrine androgen synthesis pathway enzymes (~2.5-fold decrease of 3βHSD (p < 0.001), 17βHSD (p < 0.001), CYP17A (p < 0.01), SRB1 (p < 0.0001), and StAR (p < 0.01), respectively. Reverse-phase HPLC fractionation and bioassay identified three active GCP fractions. Subsequent NMR and LC-MS analysis of the fraction with the highest level of activity, fraction 40, identified genistein as the primary active component of GCP responsible for its anti-proliferative, pro-apoptotic, and anti-AR activity. GCP, fraction 40, and genistein all mediated at least a ~2-fold change in these biological activities relative to vehicle control (p < 0.001). Genistein caused similar decreases in the expression of 17μHSD and CYP17A (2.5-fold (p < 0.001) and 1.5-fold decrease (p < 0.01), respectively) compared to GCP, however it did not cause altered expression of the other intracrine androgen synthesis pathway enzymes; 3βHSD, SRB1, and StAR. Our combined data indicate that GCP and/or genistein may have clinical utility and that further pre-clinical studies are warranted.
KW - CYP17
KW - Genistein
KW - Genistein combined polysaccharide
KW - Intracrine androgen synthesis
KW - Prostate cancer
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U2 - 10.3390/SU12166404
DO - 10.3390/SU12166404
M3 - Article
AN - SCOPUS:85090010133
SN - 2227-9059
VL - 8
JO - Biomedicines
JF - Biomedicines
IS - 8
M1 - 282
ER -