TY - JOUR
T1 - Prostate Cancer Xenograft Inhibitory Activity and Pharmacokinetics of Decursinol, a Metabolite of Angelica gigas Pyranocoumarins, in Mouse Models
AU - Wu, Wei
AU - Tang, Su Ni
AU - Zhang, Yong
AU - Puppala, Manohar
AU - Cooper, Timothy K.
AU - Xing, Chengguo
AU - Jiang, Cheng
AU - Lü, Junxuan
N1 - Funding Information:
The study was supported by National Center for Complementary and Integrative Health (NCCIH) grant R01AT007395. The authors thank TTUHSC Animal Care staff for excellent assistance with animal care, Charles Sawyers, MD, of Memorial Sloan Kettering Cancer Center, New York, NY for generous gift of the LNCaP/AR-Luc cells, and Peixin Jiang for assistance with animal work. We thank Marianne Klinger and Kang Li, PhD of the Molecular and Histopathology Core of Penn State College of Medicine for IHC and H&E staining of the tumor tissues. We thank Yuka Imamura, PhD and Genomic Sciences Core of Penn State College of Medicine for next-gen sequencing to validate cell lines. We thank Dongxiao Sun, PhD, Arun Sharma, PhD and Sinivasa Ramisetti, PhD of Penn State College of Medicine Department of Pharmacology for discussion and verification efforts of potential decursinol metabolites.
Publisher Copyright:
© 2017 World Scientific Publishing Company.
PY - 2017
Y1 - 2017
N2 - We have previously shown that the ethanol extract of dried Angelica gigas Nakai (AGN) root exerts anticancer activity against androgen receptor (AR)-negative human DU145 and PC-3 prostate cancer xenografts and primary carcinogenesis in the transgenic adenocarcinoma of mouse prostate (TRAMP) model. The major pyranocoumarin isomers decursin (D) and decursinol angelate (DA), when provided at equi-molar intake to that provided by AGN extract, accounted for the inhibitory efficacy against precancerous epithelial lesions in TRAMP mice. Since we and others have shown in rodents and humans that D and DA rapidly and extensively convert to decursinol, here we tested whether decursinol might be an in vivo active compound for suppressing xenograft growth of human prostate cancer cells expressing AR. In SCID-NSG mice carrying subcutaneously inoculated human LNCaP/AR-Luc cells overexpressing the wild type AR, we compared the efficacy of 4.5mg decursinol per mouse with equi-molar dose of 6mg D/DA per mouse. The result showed that decursinol decreased xenograft tumor growth by 75% and the lung metastasis, whereas D/DA exerted a much less effect. Measurement of plasma decursinol concentration, at 3h after the last dose of respective dosing regimen, showed higher circulating level in the decursinol-treated NSG mice than in the D/DA-treated mice. In a subsequent single-dose pharmacokinetic experiment, decursinol dosing led to 3.7-fold area under curve (AUC) of plasma decursinol over that achieved by equi-molar D/DA dosing. PK advantage notwithstanding, decursinol represents an active compound to exert in vivo prostate cancer growth and metastasis inhibitory activity in the preclinical model.
AB - We have previously shown that the ethanol extract of dried Angelica gigas Nakai (AGN) root exerts anticancer activity against androgen receptor (AR)-negative human DU145 and PC-3 prostate cancer xenografts and primary carcinogenesis in the transgenic adenocarcinoma of mouse prostate (TRAMP) model. The major pyranocoumarin isomers decursin (D) and decursinol angelate (DA), when provided at equi-molar intake to that provided by AGN extract, accounted for the inhibitory efficacy against precancerous epithelial lesions in TRAMP mice. Since we and others have shown in rodents and humans that D and DA rapidly and extensively convert to decursinol, here we tested whether decursinol might be an in vivo active compound for suppressing xenograft growth of human prostate cancer cells expressing AR. In SCID-NSG mice carrying subcutaneously inoculated human LNCaP/AR-Luc cells overexpressing the wild type AR, we compared the efficacy of 4.5mg decursinol per mouse with equi-molar dose of 6mg D/DA per mouse. The result showed that decursinol decreased xenograft tumor growth by 75% and the lung metastasis, whereas D/DA exerted a much less effect. Measurement of plasma decursinol concentration, at 3h after the last dose of respective dosing regimen, showed higher circulating level in the decursinol-treated NSG mice than in the D/DA-treated mice. In a subsequent single-dose pharmacokinetic experiment, decursinol dosing led to 3.7-fold area under curve (AUC) of plasma decursinol over that achieved by equi-molar D/DA dosing. PK advantage notwithstanding, decursinol represents an active compound to exert in vivo prostate cancer growth and metastasis inhibitory activity in the preclinical model.
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U2 - 10.1142/S0192415X17500963
DO - 10.1142/S0192415X17500963
M3 - Article
C2 - 29121805
AN - SCOPUS:85033464160
VL - 45
SP - 1773
EP - 1792
JO - Comparative Medicine East and West
JF - Comparative Medicine East and West
SN - 0192-415X
IS - 8
ER -