Chemopreventive Effects of Korean Angelica versus Its Major Pyranocoumarins on Two Lineages of Transgenic Adenocarcinoma of Mouse Prostate Carcinogenesis

Abstract

We showed previously that daily gavage of Angelica gigas Nakai (AGN) root ethanolic extract starting 8 weeks of age inhibited growth of prostate epithelium and neuroendocrine carcinomas (NE-Ca) in the transgenic adenocarcinoma of mouse prostate (TRAMP) model. Since decursin (D) and its isomer decursinol angelate (DA) are major pyranocoumarins in AGN extract, we tested the hypothesis that D/DA represented active/prodrug compounds against TRAMP carcinogenesis. Three groups of male C57BL/6 TRAMP mice were gavage-treated daily with excipient vehicle, AGN (5 mg per mouse) or equimolar D/DA (3 mg per mouse) from 8 weeks to 16 or 28 weeks of age. Measurement of plasma and NE-Ca D, DA and their common metabolite decursinol indicated similar retention from AGN vs. D/DA dosing. The growth of TRAMP dorsolateral prostate (DLP) in AGN-and D/DA-treated mice was inhibited by 66% and 61% at 16 weeks and by 67% and 72% at 28 weeks, respectively. Survival of mice bearing NE-Ca to 28 weeks was improved by AGN, but not by D/DA. Nevertheless, AGN-and D/DA-treated mice had lower NE-Ca burden. Immunohistochemical and mRNA analyses of DLP showed AGN and D/DA exerted similar inhibition of TRAMP epithelial lesion progression and key cell cycle genes. Profiling of NE-Ca mRNA showed a greater scope of modulating angiogenesis, epithelial-mesenchymal-transition, invasion-metastasis and inflammation genes by AGN than D/DA. The data therefore support D/DA as probable active/prodrug compounds against TRAMP epithelial lesions, and they cooperate with non-pyranocoumarin compounds to fully express AGN efficacy against NE-Ca.

Flavokawain A induces deNEDDylation and Skp2 degradation leading to inhibition of tumorigenesis and cancer progression in the TRAMP transgenic mouse model

“…Three mice in control group exhibited neuroendocrine carcinoma, whereas one mouse in 0.6% FKA fed mice has neuroendocrine carcinoma. After excluding the mice with poorly differentiated neuroendocrine carcinomas from the analysis [ 27 ], the mean prostate weight for TRAMP mice in the control group is 0.80±0.16 gram versus 0.56±0.10 gram in 0.6% FKA treatment group ( p < 0.01, Fig. 5C panel b).…”

Pyranocoumarin Tissue Distribution, Plasma Metabolome and Prostate Transcriptome Impacts of Sub-Chronic Exposure to KoreanAngelicaSupplement in Mice

“…However, hot water was not efficient at extracting pyranocoumarins and other hydrophobic compounds from AGN. In fact, the D content in the AGN extract used in that study was 0.07% (Yun et al, 2015), more than 1000 times lower than that in the AGN ethanol extract with which our group used in PK and efficacy studies (Li et al, 2013b; Zhang et al, 2014; Tang et al, 2015). …”

“…Kim, Kyunghee University, Republic of Korea (Tang et al, 2015). The content of D/DA of AGN extract used in this study was ~50% per HPLC-UV analysis.…”

“…The anti-cancer, neuro-protective, pain killing and other biological activities of D and DA as well as AGN extract in cell culture and preclinical models have been documented in the past two decades and have been comprehensively reviewed (Zhang et al, 2012; Lu et al, 2015). We have recently shown chemopreventive activity of AGN extract against prostate carcinogenesis in a mouse model (Zhang et al, 2014) and that D and DA partially accounted for its efficacy (Tang et al, 2015). Although D and DA were identified by our group as novel and potent androgen receptor (AR) inhibitors in cell culture (Jiang et al, 2006; Guo et al, 2007), we and others have demonstrated that D and DA are rapidly converted to the much less potent AR inhibitor decursinol (DOH, metabolism summarized in Fig.…”

Decursin in Angelica gigas Nakai (AGN) Enhances Doxorubicin Chemosensitivity in NCI/ADR‐RES Ovarian Cancer Cells via Inhibition of P‐glycoprotein Expression

“…Angelica gigas Nakai (AGN, Korean Dang-gui) is used as a traditional Chinese medicine in Korea, China, and Japan (Tang et al, 2015). AGN is traditionally used for the treatment of cancer, inflammation, anemia, pain, infection, and articular rheumatism (Jiang et al, 2006;Kim et al, 2011;Park et al, 2012;Sarker and Nahar 2004;Shin et al, 2010;Zhang et al, 2012).…”